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Case Presentation: A 68-Year-Old Man With Multiple Myeloma

Natalie Callander, MD, presents a case of a 68-year-old man with multiple myeloma and reviews first-line treatment options.

EP: 1 . Case Presentation: A 68-Year-Old Man With Multiple Myeloma

Ep: 2 . second-line options after asct in mm, ep: 3 . considerations for third-line therapy in mm, ep: 4 . the evolving treatment landscape in mm, ep: 5 . clinical pearls for the management of mm.

Natalie S. Callander, MD: I’d like to start by presenting for you a case that is very emblematic of patients we see in all of our practices. This is a 68-year-old man who had a 5-month history of fatigue and hip pain. He didn’t have a whole lot of other comorbidities, just a little bit of hypertension, and when he comes in to see you, he is having some bone pain, particularly on the hips and the lower back. The pain is affecting his functioning, so his performance status is 1. On work-up, he’s found to be anemic with hemoglobin of 10.3 g/dL and a calcium of 11.4 mg/dL. His LDH [lactate dehydrogenase] is normal, and his creatinine is slightly elevated at 1.2 mg/dL. His albumin is normal, and his beta-2 macroglobulin is slightly elevated at 3.9 μg/mL. He has a monoclonal protein of 2.7 g/dL, which in this case is IgG [immunoglobulin G] lambda. His creatinine clearance, as you might guess, is a little bit reduced at 45 mL/min. He’s tested for hepatitis B and C and he’s negative, and he gets a skeletal survey showing lesions in the left hip. Cytogenetics and FISH [fluorescent in situ hybridization] studies show a deletion of 17p, and by Revised-ISS [Revised International Staging System] staging, because of his normal albumin his only slightly elevated beta-2 macroglobulin and a normal LDH, he is Revised-ISS stage 2.

There are a couple of things to note about this case. One thing is that most people in this day and age would probably do more than a skeletal survey if it’s available because advanced imaging can show you lesions that you don’t appreciate by just a straight-up skeletal survey. In addition, sometimes these patients…come up with extramedullary disease, so it’s important to get a good idea of how advanced a patient is at the time they present. This patient does look like they have high-risk cytogenetics. We’re learning more and more about 17p deletion, and in this case we’re just given information that there is a deletion present. We know that patients who have not just a deletion but perhaps a mutation in the remaining allele can have even worse prognosis. It’s something we’ll continue to note, but this would give the patient high-risk cytogenetics.

We started on what most people would consider a standard regimen of lenalidomide, bortezomib, and dexamethasone, for 8 cycles, and then receives an autologous stem cell transplant and is given lenalidomide maintenance. But he relapses quickly. This dimension of the case underscores a couple of things. In a patient with standard-risk myeloma, we typically expect, based on some previous studies such as the STaMINA trial and the IFM 2009 trial, to see a progression-free survival with a package of induction, transplant, and lenalidomide maintenance of around 3 to 4 years, based on those 2 large trials. This patient is obviously having far less, and that underscores that high-risk cytogenetic patients can have a worse outcome. There are even patients among them who look like they start off with easily treated myeloma, who then end up showing an early relapse, as this patient is.

This transcript was edited for clarity.

A 68-Year-Old Man with Multiple Myeloma

Initial Presentation

An active 68-year-old man presented with a 5-month history of fatigue and new onset hip pain
PMH: HTN, medically controlled
PE: tenderness appreciated on palpation at the hips and lower back

Clinical workup

Labs: Hb 10.3 g/dL, calcium 11.4 mg/dL, LDH 190 U/L, creatinine 1.2 mg/dL, albumin 3.9 g/dL, beta-2 microgloblulin 3.9 mcg/mL, M-protein 2.7 g/dL, lambda free light chains 4.1 mg/dL, CLCr 45mL/min
Hepatitis B and C negative
Skeletal survey showed lytic lesions in the left hip
Bone marrow shows 42% clonal plasma cells IgG k
FISH: del(17p)
Diagnosis: R-ISS stage II MM
Initiated lenalidomide + bortezomib + dexamethasone for 8 cycles
He underwent ASCT
He continued 15 months maintenance lenalidomide
Imaging at follow-up revealed progression of disease
Selinexor + bortezomib + dexamethasone was initiated

Teclistamab Shows Promise for People with Heavily Pretreated Multiple Myeloma

September 29, 2022 , by Elia Ben-Ari

Teclistamab forms a bridge between myeloma cells and T cells, enabling the T cell to recognize the cancer cell and trigger a series of events that leads to myeloma cell death.

UPDATE: On October 25, 2022, the Food and Drug Administration gave accelerated approval to teclistamab (Tecvayli) to treat some people with multiple myeloma. The approval, based on the results of the MajesTEC-1 trial, is for adults with multiple myeloma that has come back after at least four prior lines of treatment. Further details on the MajesTEC-1 trial are discussed in the story below.

People with advanced multiple myeloma , the second most common blood cancer, may soon have another treatment option, new clinical trial results suggest.

The trial tested an experimental immunotherapy drug teclistamab (Tecvayli) in people with multiple myeloma that did not respond to or came back after at least three different cancer treatments.

In the trial, nearly two-thirds of participants had at least a partial response to teclistamab , and almost 40% had a complete remission of their cancer. In addition, the study found, the median time that patients receiving teclistamab lived without their cancer getting worse was about 11 months. The responses lasted a median of 18 months.

These results make teclistamab “very exciting” compared with other commonly used options for patients who've already had a lot of different treatments, said Natalie Callander, M.D., a myeloma expert at the University of Wisconsin Carbone Cancer Center, who was not involved with the trial.

Such patients have few treatment options and usually only live for 8 or 9 months, said Saad Usmani, M.D., chief of the myeloma service at Memorial Sloan Kettering Cancer Center and one of the senior investigators on the trial.

The responses seen with teclistamab are “impressive, and compare favorably to the effects of CAR T-cell therapy ,” two of which have been approved for advanced multiple myeloma , said James Kochenderfer, M.D., a senior investigator in NCI’s Center for Cancer Research , who also was not involved with the trial.

In addition, several experts noted logistical challenges of using CAR T-cell therapy, including high cost, limited availability, and the time needed to manufacture the treatment.

Results of the trial, known as MajesTEC-1 , were published August 11 in the New England Journal of Medicine . The trial was funded by Janssen, the maker of teclistamab.

Based on these results, teclistamab was recently approved for use in the European Union to treat adults with multiple myeloma that did not respond to (was refractory) or came back (relapsed) after at least three other treatments for their disease.

The Food and Drug Administration (FDA) has not yet approved the drug for use in the United States, but experts believe it is just a matter of time. Janssen submitted an application to FDA last December to approve teclistamab for this same use in the United States.

If FDA approval comes through, Dr. Callander said, “having this drug available is going to be an important new addition for patients.”

New treatments target BCMA protein on myeloma cells

In multiple myeloma, abnormal plasma cells, a type of white blood cell, form tumors in the bones and other parts of the body. In almost all patients, the cancer eventually comes back, or relapses, after treatment. With each new treatment, the cancer becomes less likely to respond and the time before the disease comes back gets shorter.

Several newer treatments for multiple myeloma—including two recently approved CAR T-cell therapies ( one in 2021 and one in 2022 ), teclistamab, and more than half a dozen similar drugs still in development—target a protein called BCMA. This protein is commonly found on plasma cells but is often found at higher levels on multiple myeloma cells.

Teclistamab is known as a bispecific antibody , meaning it can bind to two different targets at the same time—in this case, BCMA and a protein called CD3, which is present on immune cells called T cells. By bringing myeloma cells and T cells together, the drug helps the T cell to recognize and destroy the tumor cell, Dr. Usmani explained.

Strong treatment responses, concerns about infection risk

The MajesTEC-1 trial enrolled 165 adults with relapsed or refractory multiple myeloma who had previously been treated with at least three types of drugs commonly used to treat multiple myeloma. Half of the study participants had received five previous lines of therapy, and 82% had a previous stem cell transplant .

Participants received teclistamab once a week as an injection under the skin and were followed for a median of 14.1 months. These treatments stopped the cancer from progressing for a median of 11.3 months, Dr. Usmani and his colleagues found. The team is continuing to follow patients to see how long they live while on teclistamab.

Because BCMA is found on normal plasma cells as well as on myeloma cells, treatments that target BCMA can also reduce the production of infection-fighting antibodies. Indeed, in the trial, the most common serious side effects were infections, along with low white and red blood cell counts. Almost all participants (95%) had at least one serious side effect.

Of note, 12 of the 165 participants in the trial, which began enrolling patients in March 2020, died of COVID-19. Doctors will need to be aware of the increased risk of infections in patients who are receiving teclistamab and take steps to reduce that risk when possible, Dr. Callander said.

The most common side effect seen with teclistamab was cytokine release syndrome , a potentially serious immune reaction that also occurs with CAR T-cell therapy. Although this reaction was mild or moderate in most of the 119 participants who experienced it, nearly all required supportive care to manage the symptoms.

In an attempt to reduce the risk of more severe reactions, participants were given two smaller “step-up” doses of teclistamab 2–4 days apart before starting on the full dose. Additionally, patients had to stay in the hospital when receiving the step-up doses and first full dose, because cytokine release syndrome typically occurs after the first two or three doses of a bispecific antibody drug.

Pros and cons of CAR T-cell therapy versus bispecific antibodies

In the clinical trials that led to FDA approval of two BCMA-targeted CAR T-cell therapies for advanced multiple myeloma, ide-cel (Abecma) and cilta-cel (Carvykti) , response rates were somewhat higher than those seen for teclistamab, ranging from 73% to 98%. The cancer did not progress for about 9 months or longer.

Although they have not been compared head-to-head, teclistamab and CAR T-cell therapy each have advantages and disadvantages, Dr. Usmani said.

Whereas CAR T-cell therapy, which uses a patient’s own T cells to treat their disease, takes at least 5 or 6 weeks to produce “even under the best of circumstances,” teclistamab can be started right away, he said.

In addition, he continued, “with bispecific antibodies you’ll be able to treat older patients who are not eligible for CAR T-cell therapies” based on current FDA criteria.

However, “teclistamab requires weekly infusions [to keep the cancer in check]. In contrast, CAR T cells only require a one-time treatment,” allowing patients to be off all drugs and free of side effects as long as the cancer remains at bay, Dr. Kochenderfer said.

High cost is also a concern with CAR T-cell therapy. And although the cost of teclistamab is not yet known, it is also expected to be high, Dr. Callander said. At least eight or nine other bispecific antibodies for treating multiple myeloma are in the pipeline, including several that also target BCMA, she said, but she does not expect that having more drugs will lead to lower costs.

CAR T-cell therapy requires that patients have access to specialized care centers. It remains to be seen, Dr. Callander said, whether giving teclistamab will require any specialized training or access to specialized facilities, which could limit access to the drug for people being treated in smaller community oncology practices.

Ongoing studies are investigating the use of teclistamab in combination with other drugs for people with multiple myeloma who haven’t already received multiple treatments, Dr. Usmani said. It will also be important to figure out how best (including in what order) to use teclistamab with other treatments that target BCMA, including CAR T-cell therapy, experts said.

Finally, Dr. Kochendorfer noted, “Neither CAR T cells nor teclistamab are likely to cure more than a very small percentage of [people with] multiple myeloma, so research on better treatments is needed.”

A multidisciplinary case report of multiple myeloma with renal and cardiac involvement: a look beyond amyloidosis

Samantha Innocenti 1 na1 ,
Beatrice Bacchi 2 na1 ,
Marco Allinovi ORCID: orcid.org/0000-0001-9949-3543 1 , 3 ,
Federico Perfetto 3 ,
Elisabetta Antonioli 4 ,
Niccolo’ Marchionni 5 , 6 ,
Carlo Di Mario 7 ,
Leonardo Caroti 1 ,
Francesco Cappelli 3 , 7 &
Pierluigi Stefàno 2 , 6

BMC Nephrology volume 23 , Article number: 370 ( 2022 ) Cite this article

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Multiple myeloma (MM) is a malignant neoplasm associated with kidney involvement in nearly half of the patients. Cast nephropathy, monoclonal immunoglobulin deposition disease (MIDD), and light chain (AL) amyloidosis are the most common monoclonal immunoglobulin-mediated causes of renal injury.

Cardiac involvement is also present in MM, characterized by restrictive cardiomyopathy generated by light chain deposit or amyloid. Thromboembolic complications such as deep vein thrombosis or pulmonary embolism are also described.

Case presentation

We present an unusual multidisciplinary case of a woman with a newly diagnosed MM associated with severe proteinuria and high natriuretic peptide. A renal and fat pad biopsy with Congo red staining were performed but amyloid deposition was not discovered. While immunofluorescence on fresh frozen unfixed tissue was not contributory, the immunofluorescence on fixed tissue and electron microscopy revealed the correct diagnosis.

During subsequent investigations, two intracardiac right-sided masses and massive pulmonary embolism were also detected.

Conclusions

This case highlights that multiple organ involvement in patients with MM may result from a combination of paraprotein-dependent and -independent factors. Moreover, renal diseases induced by monoclonal gammopathies are a group of complex and heterogeneous disorders. Their subtle presentation and their potential multiorgan involvement require the expertise of a multidisciplinary team able to provide the most appropriate diagnostic and therapeutic assessment.

Peer Review reports

Multiple myeloma (MM) is a malignant neoplasm associated with kidney involvement in nearly half of the patients [ 1 ]. Nephrotic-range proteinuria associated with monoclonal gammopathy can suggest different nephropathies [ 2 ]. Differential diagnosis can be extremely difficult due to multiple confounding factors: paraproteins 'masked' on immunofluorescence staining on fresh frozen tissue but positive on paraffin immunofluorescence, coexisting renal vein thrombosis, positive cardiac biomarkers highly suggestive of cardiac amyloidosis, and coexisting clinical aspects frequently associated with secondary focal segmental glomerulosclerosis.

Cardiac involvement is also present in MM, generally characterized by restrictive cardiomyopathy caused by light chain deposit or amyloid (Table 1 ).

Here, we describe a patient with a newly diagnosed MM associated with severe proteinuria, atypical cardiac involvement and thromboembolic complications.

A 52-year-old overweight white woman with hypertension and a 3-years history of chronic kidney disease stage II K-DOQI was referred to our Nephrology department for worsening renal function and resistant hypertension.

Laboratory analysis showed a mild asymptomatic anemia, serum creatinine 1.9 mg/dl, with non-selective nephrotic proteinuria, Bence-Jones proteinuria, and extremely elevated serum kappa free light chains (FLC). Total calcemia was persistently normal and no bone lesions or full-blown nephrotic syndrome were present. Although coagulation profile was persistently not evaluable, probably due to the interfering monoclonal protein, bleeding time was in the normal range (Table 2 ).

A bone marrow biopsy revealed a complete metaplasia of clonal plasma cells with > 90% of clonal plasma cells and cytogenetic analysis (FISH) confirmed the diagnosis of micromolecular kappa MM with high-risk chromosomal abnormalities, R-ISS 3. All clonal plasma cells carried translocation t(14;16) on IGH/MAF gene. Complete immunoparesis was also noticed, while CRAB criteria were not reported.

Patient showed increased NT-proBNP and high-sensitivity troponin (hs-cTnT) suggesting cardiac involvement. ECG showed tachycardia, first degree AV block and right axial deviation with right conduction delay. Unexpectedly, Congo-red stain on abdominal fat was negative for amyloid deposition. Transthoracic echocardiogram (TTE) revealed a 4.4 × 2.8 cm right atrial mass projecting through the tricuspid valve orifice, and a second 1.5 cm mass located at the right ventricle (RV) apex. Function and motility of both ventricles were preserved, and no sign of left ventricular (LV) hypertrophy was present (interventricular septum 10 mm, LV posterior wall 8 mm). No significant valvular regurgitations were identified.

A computed tomography (CT) pulmonary angiogram showed RV thrombi, a large thrombus involving the pulmonary trunk and its two main right and left branches, as well as the segmental basal branches of the left lung. A partial thrombosis was described in the inferior vena cava from its intrahepatic tract to the origin of the renal veins (extended for about 7,5 cm) (Fig. 1 ). Complete thrombosis of the left renal vein was also detected. Remarkably, the patient reported only mild asthenia, normal blood pressure, no dyspnea, and 99% oxygen saturation in room air. Since she was hemodynamically stable, unfractionated heparin was promptly started but, according to the thrombosis extension and the high risk of embolization, the patient was referred to cardiac surgery.

Pulmonary embolism and intracardiac masses. A , the thrombus involving the pulmonary trunk; B , “*” the right atrial mass projecting through the tricuspid valve orifice, and the mass “#” located at the right ventricle; C , D pulmonary branch’ and vena cava’ thrombus fragments, respectively

Through a midline-sternotomy approach, a bilateral pulmonary thrombus was removed en-bloc with attached casts of the lobar branches across an incision in the pulmonary artery.

Both masses from the right chambers were removed through the right atrium (Fig. 1 ), while the thrombus into the inferior vena cava was too firmly attached to the vessel wall to be extracted. Cardiopulmonary bypass was terminated without inotropic supports. After surgery, patient restarted anticoagulation therapy with unfractionated heparin, subsequently substituted by warfarin.

Meantime, a kidney biopsy was performed and light microscopy showed a moderately increased glomerular mesangial matrix without endo or extracapillary proliferation. No morphological lesions such as mesangial nodules or nodular glomerulosclerosis were recognized and none of the glomeruli were sclerotic. There was a grade 1 interstitial fibrosis (IF < 25%) with small areas of lymphocytic infiltrate. Also, rare inflammatory hyaline casts were found in the tubules in the absence of concurrent cast-nephropathy. Vascular compartment was practically normal according to patient’s age (Fig. 2 ). Congo red staining was once again negative. Immunofluorescence (IF) on fresh frozen unfixed tissue was not contributory, with only weak (± or 1 +) staining for C3 and kappa FLC (Fig. 3 C, D). Differently, IF on fixed tissue demonstrated an intense (3 +) linear staining for kappa FLC along the glomerular and tubular basement membranes, while IgG, lambda, and C3 staining were negative (Fig. 3 A, B). Electron microscopy showed segmentary “ground pepper-like” deposits in the subendothelial space and the glomerular basement membranes (GBM). Similar deposits were observed along the tubular basement membrane (TBM). Extensive podocyte foot process effacement was seen with no sub-epithelial or mesangial electron-dense deposits (Fig. 3 E). The final diagnosis was “kappa light chain deposition disease (LCDD)”.

Histopathological findings on light microscopy. A : moderately increased glomerular mesangial matrix with mild focal mesangial hypercellularity (white arrow), no significant arteriolar changes, absence of mesangial nodules or nodular glomerulosclerosis (Periodic acid Schiff stain, X400); B : small areas of interstitial fibrosis (IF < 25%) and lymphocytic infiltrate (white arrow), aspects of protein reabsorption in renal tubules (Periodic acid Schiff stain, X400)

Histopathological findings on immunofluorescence and electron microscopy. Immunofluorescence showed a positive linear tubular and glomerular basement membrane staining (3 +) for kappa ( A , 20x) and negative for lambda ( B , 20x) light chains on formalin-fixed paraffin-embedded tissue. Immunofluorescence staining on fresh frozen tissue was weakly positive (± or 1 +) for kappa ( C , 40x) and negative for lambda ( D , 40x) light chains. Electron microscopy ( E , 14000x) showed foot process effacement with cytoplasm vacuolization and ground-pepper-like subendothelial deposits (arrows)

The patient fully recovered from surgery. A new TTE showed preserved function of both ventricles (EF 58%, TAPSE 20 mm, RV-RA gradient 25 mmHg) or major valvular disease. No new intracardiac masses were detected (video, Additional file 1).

A 3-months follow-up CT showed the persistence of only a partially calcified thrombus in the right pulmonary artery’s distal branches, warfarin was continued.

After 4 cycles of VTD protocol (Bortezomib, Thalidomide, Dexamethasone), the patient presented a very-good partial hematologic remission. Afterwards, she received autologous hematopoietic stem cell transplantation, with a stable complete hematologic remission and a progressive improvement of proteinuria and renal function (Table 2 ).

Discussion and conclusions

This case proves that a step-by-step diagnostic flow chart and a multidisciplinary clinical evaluation are crucial to obtain the right diagnosis.

At the time of admission, the worsening of renal function with nephrotic-range proteinuria, elevated kappa FLC, increase NT-proBNP and hs-cTnT strongly suggested AL systemic amyloidosis with both renal and cardiac involvement. However, Congo red staining negativity of two biopsies, made a mandatory reassessment of differential diagnosis for cardiac and renal involvement.

Nephrotic range proteinuria without the full-blown nephrotic syndrome could suggest secondary/maladaptive focal segmental glomerulosclerosis, in particular when one or more risk factors are present, such as for obesity and reduced renal parenchymal mass [ 3 ], as observed in our patient. Moreover, the left renal vein thrombosis, observed on CT, could have explained at least in part the degree of proteinuria [ 4 ].

In the context of monoclonal gammopathies of renal significance, not all patients with high levels of paraprotein present with reduced renal function, although FLC levels > 800 mg/L are good predictors of severe renal failure [ 5 ]. However, despite the extremely high levels of kappa FLC, our patient showed only a mild-to-moderate worsening of kidney function and no histological signs of cast nephropathy. In fact, physicochemical properties of the secreted paraprotein may determine pathological features, for which a variety of Ig-dependent and -independent mechanisms have been described [ 6 ].

Among patients with monoclonal gammopathies, those presenting with heavy proteinuria and milder renal impairment are more likely to have AL amyloidosis, LCDD or HCDD [ 7 ]. Excluding the first, patients with LCDD usually present with proteinuria (nephrotic-range proteinuria is seen in about 50% of cases), microscopic hematuria, hypertension, and variable degrees of renal insufficiency. Clinical presentation depends on several histopathological aspects: the site of the FLC deposition in renal compartments, the extent of chronic lesions, the degree of foot process effacement, and overlap with myeloma cast nephropathy [ 2 ].

The IF is essential for the definitive diagnosis of LCDD. However, there are rare cases (as in our patient) in which the immune deposits and paraproteins are 'masked' on routine IF, resulting in false-negative staining on fresh frozen tissue, and paraffin immunofluorescence can be used to unmask FLC deposits [ 8 ]. LCDD diagnosis via kidney biopsy permitted to establish an early and correct chemotherapy regimen that led to a complete hematologic response, which is mandatory to improve renal and global outcomes.

In patients with clinical suspicion of AL amyloidosis or LCDD, increased NT-proBNP and hs-cTnT represent sensitive markers to identify cardiac involvement [ 9 ]. Surprisingly, echocardiography showed no signs of cardiac dysfunction [ 10 ], in particular no increased wall thickness, or diastolic dysfunction while, it demonstrated multiple right-sided cardiac masses. According to the patient’s history and masses aspects, only a few hypotheses were acceptable: heart thrombi [ 11 ], mobilized deep venous thrombi, and, less likely, primary or metastatic tumors [ 12 ].

In our case, since both right chambers were involved, a metastasis from a primary neoplasm (renal-cell carcinoma or hepatocellular carcinoma) extended through the inferior vena cava to the right side of the heart should be also considered. However, no evidence of renal or hepatic lesions was appreciated on an abdominal CT.

Of note, the right atrium is probably the predominant location of plasmacytoma involving the heart but it is a rare presentation of MM [ 13 ].

In our patient, histological examination of the intracardiac masses confirmed the thrombotic nature.

Among different complications of MM a high risk of venous thrombosis has been previously described. The thrombophilic state is multifactorial and often divided in three categories: (i) malignancy-related: is potentially characterized by the hyperviscosity syndrome due to increased paraprotein content, the release of inflammatory cytokines (as IL-6), and several changes in coagulation (as an increased von Willebrand factor or factor VIII) [ 14 ]; (ii) patient-related: such as the presence of central venous access devices, hypoalbuminemia, renal failure, immobilization and obesity [ 15 ], and (iii) therapy-related: as during treatment with immunomodulatory drugs (thalidomide lenalidomide and pomalidomide) which have a prothrombotic effect. Current literature lacks of data about a possible direct pathogenetic role of paraproteins in venous thrombosis [ 16 ]. In some case reports, the monoclonal light chain is identified as an interfering factor in functional assays and coagulation tests causing dysfibrinogenemia [ 17 ]. In our case, a lot of contributory factors are involved in the development of the prothrombotic state, such as obesity, very high levels of free light chains and hypoalbuminemia.

Considering the extension of the thrombosis and the plausible chronic state, anticoagulant therapy alone was considered insufficient.

In case of acute pulmonary embolism with hemodynamic instability, thrombolysis is recommended while surgical embolectomy is considered as an alternative in patients not responsive to thrombolytic therapy or with acute hemodynamic deterioration. Surgical thrombosis removal, instead, is the treatment of choice in chronic thrombosis of the pulmonary tree [ 18 ]. In our report, the operability of the patient was approved by a multidisciplinary team after evaluation of several parameters: NYHA class, the risk of rapid hemodynamic deterioration, and the patient’s quoad vitam prognosis. Therefore, surgical thrombectomy was considered the best option. Moreover, the heart surgical intervention was crucial in order to prevent acute RV dysfunction, recurrent pulmonary embolism and thus cardiogenic shock.

The natural history and prognosis of MIDD depend on the severity of renal failure at diagnosis, the presence of an underlying MM, and the delay in the hematologic response to chemotherapy. Additionally, LCDD patients with cardiac involvement have poorer survival and a significantly higher risk of treatment-related mortality after ASCT [ 19 ]. Moreover, our patient showed several parameters associated with unfavorable MM outcome. Some negative prognostic factors are widely accepted, such as high-risk chromosomal abnormalities, high serum β2-microglobulin (≥ 5.5 mg/L), and low serum albumin [ 20 ]. Other prognostic factors are not widely validated, such as immunoparesis, which have a negative impact on the progression-free survival [ 21 ], high serum IL-6 levels [ 22 ], or extremely high levels of FLC [ 23 ], which have been shown to play a prominent role in the development of kidney damage.

Overall, both early diagnosis and prompt treatment with bortezomib and ASCT-based combinations can improve the prognosis of LCDD, by reducing circulating immunoglobulins, preserving renal function, and improving overall survival, even in patients with a severe disease at onset.

In conclusion, in patients with MM, multiple organ involvement may result from a combination of paraprotein-dependent and -independent factors, and the therapeutic success requires the early recognition of all the pathogenetic elements involved. This case reminds that sometimes, to reach the right diagnosis, looking beyond the surface is mandatory. Moreover, in patients with not acute massive pulmonary embolism and intracardiac right masses, surgical pulmonary embolectomy should be promptly performed to preserve RV function and prevent pulmonary hypertension development. This case also demonstrated that both early diagnosis and prompt treatment with bortezomib and ASCT-based combinations can improve the prognosis of LCDD, even in patients with a severe disease at onset.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Multiple myeloma

Free light chains

Transthoracic echocardiogram

Right ventricle

Left ventricle

Computed tomography

Immunofluorescence

Light chain deposition disease

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Acknowledgements

Special thanks to Fabio Pagni and Vincenzo L'Imperio from the Pathology Unit at University of Milano-Bicocca (Monza, Italy), and to Marco Delsante from the Nephrology Unit at Azienda-Ospedaliero Universitaria di Parma (Parma, Italy) for their help and support.

This research received no external funding.

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Samantha Innocenti and Beatrice Bacchi contributed equally to this work.

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Nephrology, Dialysis and Transplantation Unit, Careggi University Hospital, Largo Brambilla 3, 50134, Florence, Italy

Samantha Innocenti, Marco Allinovi & Leonardo Caroti

Department of Cardiac Surgery, Careggi University Hospital, Florence, Italy

Beatrice Bacchi & Pierluigi Stefàno

Tuscan Regional Amyloid Center, Careggi University Hospital, Florence, Italy

Marco Allinovi, Federico Perfetto & Francesco Cappelli

Haematology Unit, Careggi University Hospital, Florence, Italy

Elisabetta Antonioli

Department of Cardiothoracovascular Medicine, Careggi University Hospital, University of Florence, Florence, Italy

Niccolo’ Marchionni

Department of Experimental & Clinical Medicine, University of Florence, Florence, Italy

Niccolo’ Marchionni & Pierluigi Stefàno

Division of Interventional Structural Cardiology, Cardiothoracovascular Department, Careggi University Hospital, Florence, Italy

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The authors listed below have made substantial contributions to the intellectual content of the paper in the various sections described below. Conceptualization, M.A., S.I., B.B., F.P., F.C.; methodology, M.A., F.P., E.A., N.M., C.D.M., L.C., F.C., P.S.; writing—original draft preparation, M.A., S.I., B.B., F.C.; writing—review and editing, M.A., E.A., N.M., C.D.M., L.C., F.C., P.S.; supervision, M.A., F.P., C.D.M., P.S. All authors have read and agreed to the published version of the manuscript.

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Additional file 1. Intracardiac thrombi. The video shows echocardiography performed before and after surgery.

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Innocenti, S., Bacchi, B., Allinovi, M. et al. A multidisciplinary case report of multiple myeloma with renal and cardiac involvement: a look beyond amyloidosis. BMC Nephrol 23 , 370 (2022). https://doi.org/10.1186/s12882-022-02984-4

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Patient Case Studies and Panel Discussion: Plasma Cell Neoplasms

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Managing patients with plasma cell neoplasms, diseases in which abnormal plasma cells or myeloma cells form tumors in the bones or soft tissues of the body, poses numerous challenges for clinicians. At the NCCN 2019 Annual Congress: Hematologic Malignancies, a panel of experts discussed evidenced-based approaches for the treatment of patients with these diseases. Moderated by Dr. Andrew D. Zelenetz, the session focused on patients with transplant-ineligible newly diagnosed multiple myeloma, active multiple myeloma, and light chain amyloidosis.

Plasma cell neoplasms are diseases in which abnormal plasma cells or myeloma cells form tumors in the bones or soft tissues of the body. At the NCCN 2019 Annual Congress: Hematologic Malignancies, a panel of experts identified clinical challenges in managing patients with plasma cell neoplasms. Moderated by Dr. Andrew D. Zelenetz, the session focused on 3 case studies, which were used to develop an evidence-based approach for the treatment of these patients.

Patient Case Study 1: Transplant-Ineligible, Newly Diagnosed Multiple Myeloma

In the first case study, a 75-year-old man presented with new back pain and fatigue. The patient was able to perform all activities of daily living and resided approximately 70 miles away from the treatment center. Figure 1 shows results from imaging, laboratory tests, and bone marrow biopsy.

Results from laboratory, imaging, and biopsy studies for the patient in case study 1.

Abbreviations: FISH, fluorescence in situ hybridization; IFE, immunofixation electrophoresis; KLC, kappa light chain; LDH, lactate dehydrogenase; SPEP, serum protein electrophoresis; SUV, standard uptake value; ULN, upper limit of normal.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 11.5; 10.6004/jnccn.2019.5034

Although the patient did not harbor high-risk fluorescence in situ hybridization (FISH) changes, his lactate dehydrogenase (LDH) level was elevated at diagnosis. Elevated LDH as a risk factor has been associated with inferior outcomes, 1 , 2 and is also factored into risk stratification by the Revised International Staging System (R-ISS) as the only nongenetic parameter, 3 said Muhamed Baljevic, MD, University of Nebraska Medical Center.

Yvonne A. Efebera, MD, MPH, The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, noted that although this patient is transplant-ineligible, a 3-drug regimen is preferred over 2-drug options.

“This has been shown several times in newly diagnosed patients,” said Dr. Efebera. “In the SWOG SO777 study, bortezomib with lenalidomide and dexamethasone showed better progression-free survival [PFS] and overall survival versus lenalidomide and dexamethasone alone. 4 Furthermore, in the MAIA trial, the addition of daratumumab to lenalidomide and dexamethasone improved PFS versus lenalidomide and dexamethasone alone. 5 However, because we don’t have overall survival data from the MAIA trial, the triplet of bortezomib/lenalidomide/dexamethasone is the only one to show survival benefit,” she said.

Dr. Baljevic noted that bortezomib/lenalidomide/dexamethasone is a category 1 NCCN recommendation for both transplant-eligible and transplant-ineligible patients based on the SWOG SO777 data. Although recent data from the ALYCONE trial suggest that quadruplet regimens may surpass triplet regimens, 6 this particular induction combination may be more relevant to European practice patterns. The combination of daratumumab + bortezomib/melphalan/prednisone led to increased overall response rates and PFS. 6 For transplant-eligible patients, transplant is still preferred to induce the deepest remission possible, Dr. Zelenetz noted, “but we’re not seeing overall survival differences like we used to in the long-term.”

This patient received bortezomib, lenalidomide, and dexamethasone and experienced a very good partial response after 6 cycles. The patient then switched to maintenance lenalidomide, 10 mg daily. Complete responses encompass very deep remissions and clearly detectable disease, said Dr. Zelenetz, who noted that data have shown that undetectable minimal residual disease status is associated with better outcomes. 7 Nevertheless, panelists agreed that minimal residual disease testing to guide therapy for this patient would not have be useful in clinical practice.

“This is a very expensive test, and to make it worthwhile, you want to be able do something with the information obtained,” said Michael M. Green, MD, Kaiser Permanente. “For this patient in particular, I don't think there was much utility.”

Early-Relapse Disease: No Clear Choice for Treatment

The patient received continuous maintenance therapy with lenalidomide. After 2 years of maintenance, he experienced toxicity from lenalidomide (diarrhea and fatigue) and took a treatment holiday. The first relapse occurred at a PFS time of approximately 39 months. Laboratory results showed a hemoglobin level of 10.2 g/dL and a PET scan showed several new lytic bone lesions. Bone marrow biopsy showed 60% kappa plus plasma cells and FISH identified t(14;16), del(17p), and gain(1q) (4 copies).

Although many new agents are available for relapsed/refractory multiple myeloma, panelists agree that triplet regimens remain the standard, with daratumumab combinations appearing quite effective. The sequencing of agents is still undefined, however. Several novel agents are in development, with early data on venetoclax and B-cell maturation antigen–targeted therapies showing promise.

“There are lots of positive trials and lots of options in this setting, but there is no clear, unequivocal correct answer, which is an important point,” said Dr. Zelenetz.

“Oftentimes, when we’re making a decision about what the next line of treatment will be at first relapse, we're really thinking about what the third-line option will be down the road,” Dr. Green added. “Whatever decision we make up front is going to impact the kinds of options available later on.”

Patient Case Study 2: Active Multiple Myeloma

In the second case study, a 53-year-old man presented with persistent swelling and pain around the left shoulder for several months. A small mass was detected on his left clavicle on physical examination. Medical history showed hypertension, schizoaffective disorder, and chronic hepatitis B, and a diagnosis of active multiple myeloma was the panelists’ consensus. Figure 2 shows test results for this patient. The patient was treated with lenalidomide, bortezomib, and dexamethasone (continued for 15 months). Approximately 1 month after starting treatment, he received radiotherapy to his left clavicle for 2 weeks.

Results from laboratory, imaging, and biopsy studies for the patient in case study 2.

Abbreviations: FISH, fluorescence in situ hybridization; SUV, standard uptake value.

Nina Shah, MD, UCSF Hellen Diller Family Comprehensive Cancer Center, noted that a carfilzomib + lenalidomide and dexamethasone (KRD) combination may have been the better option because of the patient’s 17p deletion and high-risk disease.

“Data from the University of Chicago seem to show that when you gave patients at high risk more-aggressive induction of KRD followed by transplant and KRD consolidation and lenalidomide maintenance, their outcomes are similar to those with standard risk,” said Dr. Shah. “That’s a very small trial subset and there are a lot of caveats, but we have to do something different for patients at high risk than we're doing for those at standard risk.”

Dr. Efebera added that for patients at high risk, 2-drug maintenance may yield better outcomes than single-agent maintenance. “We don’t have any prospective studies, and only 15% of patients are high-risk, but retrospective analysis at Emory has shown that 2-drug maintenance is feasible and possibly better. The jury is still out,” she said.

Dr. Baljevic noted that the field is moving toward 4-drug combinations for both standard- and high-risk disease, which raises legitimate questions regarding financial toxicity. “The possibility of moving toward pentads (5-drug combinations) with molecularly adapted regimens has even been discussed,” he said. “Provided safety profiles would not be prohibitory, the idea would be to treat patients for a shorter period of time upfront, and see if less therapy in the long term is possible.”

Although autologous stem cell transplantation (ASCT) was discussed, this patient elected not to move forward with it due to social concerns. Approximately 1 month after stopping treatment, he experienced disease recurrence characterized by progressive disease in the sternum and rib.

“Patients may be initially resistant to transplant for a number of reasons, but after the disease comes back early, they may be more amenable,” said Dr. Efebera, who noted that insurance companies are more frequently paying for collection of stem cells and storage.

This patient was started on daratumumab, pomalidomide, and dexamethasone, which he continued for 10 months before experiencing cytopenias with daratumumab and pomalidomide. Approximately 1 week after starting therapy, he received radiotherapy to the sternum (for 2 weeks).

“Radiotherapy should be used for symptomatic lesions and should not delay systemic therapy,” said Dr. Zelenetz. He noted that 3 weeks after the patient started therapy, bone marrow biopsy showed <5% atypical plasma cells. However, major complications and adverse events occurred during treatment, leading to drug disruptions and treatment delays. The patient’s disease recurred 10 months after starting therapy. He was admitted for altered mental status, hypercalcemia, back pain, and was treated with carfilzomib, cyclophosphamide, and dexamethasone.

“There are other treatment options for extramedullary disease, but there really is no right answer,” said Dr. Shah. “This patient should go to a clinical trial for CAR-T cell therapy or should undergo a transplant.”

“For high-risk disease and for people who are young, undergoing transplant upfront is strongly recommended,” added Dr. Green. “It could save the patient from getting into these situations.”

Patient Case Study 3: Light Chain Amyloidosis

For the final case study, a 63-year-old man presented with easy bruising, foamy urine, and red tongue, with no prior medical history. Figure 3 shows his test results.

Results from laboratory and imaging studies for the patient in case study 3.

Based on the diagnosis of light chain amyloidosis, panelists agreed that urine immunofixation should be performed for optimal diagnostic sensitivity. As Dr. Zelenetz reported, one study found that not performing urine immunofixation led to missing 6% of amyloidogenic clones. 8

“For patients with light chain amyloidosis, I really want to stress the importance of mass spectroscopy in terms of identifying the clone and the type of amyloid,” Dr. Efebera added. “It’s been shown that 13% of patients with TTR [transthyretin] familial amyloidosis are treated as having light chain amyloidosis due to having monoclonal gammopathy of undetermined significance [MGUS] unrelated to their amyloidosis 9 ; 3% of the general population aged ≥50 years have MGUS. It’s very important that mass spectroscopy is incorporated into your tissue biopsy.”

“Fat pad biopsies are easy and cheap,” said Dr. Zelenetz. “If you’re not sure, it’s worth it to do a biopsy.”

Following work-up, the Mayo Clinic Staging System for light chain amyloidosis was used. For those inexperienced with this system, Michaela Liedtke, MD, Stanford Cancer Institute, reassured the audience that this system is relatively straightforward and is routinely used in practice. “You basically plug in the numbers for the N -terminal pro–B-type natriuretic peptide and troponin, and the differential of the free light chains,” she said. “The ratio is not as important as the difference between the involved light chain that produces the amyloid deposits and the uninvolved light chain.”

“Although this is a prognostic tool, it also provides a lot of information about whether somebody is a transplant candidate or not,” Dr. Baljevic explained. “After induction therapy and tumor reduction, recent data show that it’s actually possible to make someone who was not initially a transplant candidate into a candidate.” 10

“Patients with amyloid differ significantly from patients with myeloma,” Dr. Baljevic continued. “With light chain amyloidosis, it’s even more important to try to get patients to transplant. It’s one of the most important measures in terms of long-term outcomes that we can offer them.” 11

This patient was treated with 4 cycles of cyclophosphamide, bortezomib, and dexamethasone and experienced a hematologic very good partial response. “Depth of response is important in myeloma, but even more important in amyloidosis because you want to reduce the light-chain burden as much as possible,” said Dr. Liedtke.

According to Dr. Zelenetz, the key to making the diagnosis of light chain amyloidosis is suspecting the diagnosis in the first place. “This is the heart and soul of what we do as physicians,” he concluded. “When you approach the patient, you have to have the right differential diagnosis. You’ve got to suspect, because you can’t make the right diagnosis you’re not thinking about.”

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Disclosures: Dr. Zelenetz has disclosed that he received consulting fees from AbbVie, Inc., Amgen Inc., AstraZeneca Pharmaceuticals LP, Celgene Corporation, Gilead Sciences, Inc., Janssen Pharmaceutica Products, LP, Novartis Pharmaceuticals Corporation, Adaptive Biotechnologies Corporation, Genentech, Inc./Roche Laboratories, Inc., and Pharmacyclics; is a scientific advisor for AbbVie, Inc., AstraZeneca Pharmaceuticals LP, and MorphoSys AG; and receives grant/research support from BeiGene, Gilead Sciences, Inc., MEI Pharma Inc., and Roche Laboratories, Inc. Dr. Baljevic has disclosed that he received consulting fees from Cardinal Health and Takeda Pharmaceuticals North America, Inc., and served as an internal review committee member for Karyopharm Therapeutics and a scientific advisor for Takeda Pharmaceuticals North America, Inc. Dr. Efebera has disclosed that she has received honoraria from Janssen Pharmaceutica Products, LP, and Takeda Pharmaceuticals North America, Inc, and is a scientific advisor for Akcea Therapeutics. Dr. Green has disclosed that he has no financial interests, arrangement, affiliations, or commercial interests with any manufacturers of any products discussed in this article or their competitors. Dr. Liedtke has disclosed that she receives grant/research support from Agios, Inc., Amgen Inc., Celator Pharmaceuticals, Celgene Corporation, Genentech, Inc., Gilead Sciences, Inc., Janssen Pharmaceutica Products, LP, bluebird bio, Inc., Prothena, Pfizer Inc., and Takeda Pharmaceuticals North America, Inc; received consulting fees from Amgen Inc.; and is a scientific advisor for Celgene Corporation, Janssen Pharmaceutica Products, LP, and Jazz Pharmaceuticals Inc. Dr. Shah has disclosed that she receives grant/research support from Celgene Corporation, Janssen Pharmaceutica Products, LP, bluebird bio, Inc., Sutro Biopharma; is a scientific advisor for Genentech, Inc., Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision Biosciences, Glaxo Smith Kline, Nektar, Amgen, Indapta Therapeutics, and Sanofi; and owns stock in Indapta Therapeutics.

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Case Study: Supportive Care in Multiple Myeloma

A 62-year-old man with recently diagnosed multiple myeloma (MM) presented to clinic for follow-up. One month prior, he presented with fatigue and was found to have anemia and renal dysfunction.

His lab results showed a hemoglobin of 9.1 g/dL and hematocrit of 28 percent, serum creatinine of 2.8 mg/dL, albumin 3.5 g/dL, and a β-2 microglobulin of 4.5 mg/dL. Serum protein electrophoresis with immunofixation revealed a monoclonal IgG κ of 2.8 g/dL and serum-free κ light chain of 78 mg/L (κ/λ ratio of 52). Bone marrow demonstrated 15 percent plasma cells as well as normal cytogenetics and fluorescence in situ hybridization studies. Skeletal survey demonstrated no evidence of lytic lesions, and positron emission tomography revealed no evidence of bone involvement.

The patient was started on cyclophosphamide, bortezomib, and dexamethasone two weeks prior. He is then started on prophylactic antimicrobial therapy. Routine lab results revealed stable hemoglobin of 9.1 g/dL and serum creatinine at 2.8 mg/dL, with an estimated creatinine clearance of 34 mL/min.

In addition to his current therapy, which of the following therapies is most appropriate to add for this patient?

Denosumab 120 mg subcutaneously every four weeks
Zolendronic acid 4 mg intravenously every four weeks
Enoxaparin 1 mg/kg subcutaneously twice daily
Aspirin 325 mg orally daily
Rivaroxaban 10 mg orally daily

Patients with MM are at risk for significant disease- and therapy-related complications. These include infections, thrombosis, and skeletal-related events (SREs). 1

Thromboprophylaxis remains controversial in MM. 1,2 Patients on immunomodulatory agents such as lenalidomide and thalidomide are at higher risk of thrombosis. Guidelines suggest that these patients should be on full-dose aspirin or therapeutic anticoagulation depending on other risk factors. In this case, the patient is being treated with bortezomib, a proteasome inhibitor, and has no other clear risk factors requiring treatment with aspirin (choice D), therapeutic enoxaparin (choice C), or prophylactic dose rivaroxaban (choice E).

SREs are a major cause of morbidity and mortality in patients with MM. 3 Patients at high risk for SREs are those with osteoporosis and/or lytic lesions. However, all patients starting antimyeloma therapy should be started on prophylaxis for SREs.

Bisphosphonates, zoledronic acid, and pamidronate have been the mainstay of therapy to prevent SREs for several years. In the Myeloma IX Trial 4 , zolendronic acid versus oral clodronic acid improved progression-free survival (PFS) by a median of two months and overall survival (OS) by a median of 5.5 months. Therefore, zolendronic acid has been the preferred agent of most clinicians. It is renally metabolized, and adverse events include osteonecrosis of the jaw and renal toxicity. In patients with pre-existing renal issues with creatinine clearance between 30 to 39 mL/min, zolendronic acid must be dose reduced to a maximum of 3 mg intravenously every four weeks. In the above case, zolendronic acid should be dose reduced (choice B). Dose-reduced pamidronate can be used in patients with renal dysfunction.

Denosumab is a fully human monoclonal antibody that binds and inhibits RANK ligand. RANK ligand is hypersecreted by myeloma cells and is a mediator of osteoclast formation and activation. Unlike bisphosphonates, denosumab is not cleared renally. In a phase III trial 3 , denosumab 120 mg subcutaneously every four weeks was compared to zolendronic acid 4 mg intravenously every four weeks. The study met its primary endpoint, which was noninferiority of denosumab versus zoledronic acid for time to first SRE. This subsequently led to its approval for use in MM. Additionally, PFS improved by 10.7 months in the denosumab arm compared to zolendronic acid (p=0.036) without a statistically significant difference in OS. Denosumab was associated with lower renal toxicity, with rates of creatinine greater than 2 mg/dL of 4 percent versus 7 percent. There was no difference in rates of osteonecrosis of jaw (4% vs. 3%), and denosumab was associated with higher rates of hypocalcemia (17% vs. 12%).

In patients with MM, denosumab is noninferior to zoledronic acid in preventing SREs. It is not metabolized by the kidney and is associated with lower renal toxicity; however, similar rates of osteonecrosis of the jaw and higher rates of hypocalcemia were observed. Of note, denosumab is also significantly more expensive with a severalfold difference in price.

Case study submitted by Arun Singavi, MD, of Medical College of Wisconsin, Milwaukee, Wisconsin.

Resources

Snowden JA, Ahmedzai SH, Ashcroft J, et al. Guidelines for supportive care in multiple myeloma 2011 . Br J Haematol. 2011;154:76-103.
NCCN Guidelines. Multiple Myeloma (version 4.2018) . NCCN. Last accessed July 23, 2018.
Raje N, Terpos E, Willenbacher W, et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study . Lancet. 2010;376:1989-1999.
Morgan GJ, Davies FE, Gregory WM, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial . Lancet. 2010;376:1989-1999.

American Society of Hematology. (1). Case Study: Supportive Care in Multiple Myeloma. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/supportive-care-in-multiple-myeloma .

American Society of Hematology. "Case Study: Supportive Care in Multiple Myeloma." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/supportive-care-in-multiple-myeloma (label-accessed May 20, 2024).

"American Society of Hematology." Case Study: Supportive Care in Multiple Myeloma, 20 May. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/supportive-care-in-multiple-myeloma .

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In recent years, the field of cancer treatment has witnessed remarkable breakthroughs that have revolutionized the landscape of care for cancer patients. While traditional pillars such as surgery, chemotherapy, and radiation therapy have long been available, a cutting-edge therapeutic approach called CAR T-cell therapy has emerged as a game-changer in treating multiple myeloma (MM). This novel treatment method complements options like autologous stem cell transplants and immunomodulatory medications, such as proteasome inhibitors, by utilizing protein complexes or anti-CD38 antibodies with potent complement-dependent cytotoxic effects. Despite the challenges and obstacles associated with these treatments, the recent approval of the second FDA multiple myeloma CAR T-cell therapy has sparked immense promise in the field. Thus far, the results indicate its potential as a highly effective therapeutic solution. Moreover, ongoing preclinical and clinical trials are exploring the capabilities of CAR T-cells in targeting specific antigens on myeloma cells, offering hope for patients with relapsed/refractory MM (RRMM). These advancements have shown the potential for CAR T cell-based medicines or combination therapies to elicit greater treatment responses and minimize side effects. In this context, it is crucial to delve into the history and functions of CAR T-cells while acknowledging their limitations. We can strategize and develop innovative approaches to overcome these barriers by understanding their challenges. This article aims to provide insights into the application of CAR T-cells in treating MM, shedding light on their potential, limitations, and strategies employed to enhance their efficacy.

Anti-BCMA CAR T-cell therapy in multiple myeloma: can we do better?

CAR T cell therapies for patients with multiple myeloma

CAR T-cell therapy in multiple myeloma: more room for improvement

Introduction.

Multiple myeloma (MM) is the second most common hematological cancer, characterized by the abnormal proliferation of plasma cells and contributes to 2% of cancer-related deaths in the United States [ 1 ]. Initially addressed with melphalan, advances in disease understanding have transformed the therapeutic landscape. The introduction of immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), histone deacetylase inhibitors, and FDA-approved monoclonal antibodies (daratumumab and elotuzumab), has broadened treatment options for MM patients [ 2 , 3 , 4 ]. Despite these advancements, multiple myeloma remains predominantly incurable, especially for high-risk patients who do not benefit from the current treatment options [ 4 ]. In this context, immunotherapy-based medications present promising advancements in the treatment of multiple myeloma, encompassing checkpoint inhibitors, antibody-drug conjugates, bispecific T cell engagers (BiTEs), and adoptive T cell therapy (ACT) [ 5 , 6 , 7 , 8 , 9 ]. A particularly promising immunotherapeutic avenue is Chimeric Antigen Receptor (CAR) T-cell therapy, which has shown remarkable results in B-cell malignancies [ 10 , 11 ] FDA-approved CAR T-cell therapies, such as tisagenelcleucel/Kymriah (Novartis) and Brexucabtagene Autoleucel/Tecartus (Kite Pharma) for acute lymphoblastic leukemia (ALL), axicabtagene ciloleucel/Yescarta (Gilead/Kite) and lisocabtagene maraleucel/Breyanzi (Bristol Myers Squibb), and Idecabtagene Vicleucel/Abecma (Bristol Myers Squibb and bluebird bio) for MM, underscore the efficacy of CAR T-cell therapy in cancer treatment [ 12 , 13 ]. A notable milestone was achieved in February 2022 with FDA approval granted to ciltacabtagene autoleucel/Carvykti (Janssen Biotech) for MM treatment [ 13 ]. Immunotherapy, particularly CAR T-cell therapy, emerges as a promising frontier in the ongoing pursuit of effective multiple myeloma treatment.

CAR T-cell therapy

Chimeric Antigen Receptors (CARs) are fusion proteins designed to target specific antigens expressed on cell surfaces. The first chimeric receptor was developed by Eshhar’s group at the Weizmann Institute of Science in 1989 [ 14 ]. Since their initial development, CAR T-cells have rapidly evolved through various generations. CARs consist of three essential domains: extracellular, transmembrane, and intracellular domains [ 15 ]. The intracellular domain plays a crucial role in signaling T lymphocytes, enabling the killing of malignant cells independent of the human leukocyte antigen (HLA) [ 16 ]. CAR T therapy has revolutionized cancer treatment by offering personalized treatment based on the specific type of cancer and the patient’s requirements. This approach involves genetically modifying the patient’s own T cells, which are then able to recognize and bind to tumor antigens. After the modified T cells undergo proliferation, they are infused back into the patient’s body to target and eliminate cancer cells (Fig. 1 ) [ 17 ]. The extracellular domain, transmembrane domain, and intracellular domain are the three major components of a CAR [ 18 ]. The extracellular domain consists of a single-chain variable fragment (scFv), which is a fusion protein of the antibody’s light and heavy chains’ variable regions. This domain is connected to the transmembrane domain via a spacer and further linked to the intracellular signaling domain, leading to cancer cell cytolysis [ 16 ]. The extracellular scFv facilitates the attachment of CAR T-cells to specific cells, while the intracellular domain aids in T cell activation [ 19 ]. Within the intracellular signaling domain, there are primary stimulatory and secondary costimulatory domains (Fig. 2 ).

The production of autologous CAR T cells begins with a patient’s leukapheresis, followed by T cell enrichment and activation. To promote the introduction and perhaps permanent integration of the CAR transgene, activated T cells are transduced (e.g., with a lentiviral vector). T cells that have been genetically engineered are then grown in either static or dynamic culture, cryopreserved, and reintroduced into the patient.

A The structure of CAR T-cells. B The first-generation CAR signaling domain has solely a CD3-derived signaling domain. A co-stimulatory domain is also present in second-generation CARs. CARs of the third generation have two co-stimulatory domains. Fourth-generation CAR T cells express chemokines such as IL-12 when activated. Fifth-generation CARs have a unique co-stimulatory domain that activates specific signaling pathways, such as JAK/STAT3.

CARs targeting MM antigens often utilize the CD3zeta intracellular stimulatory domain, which contains immunoreceptor tyrosine activation motifs (ITAMs) that generate “signal 1”. CAR T-cells are categorized into various subgroups based on the presence of costimulatory domains (Fig. 2B ) [ 20 ]. First-generation CARs, lacking costimulatory domains, were not efficient enough for clinical use. However, NKG2D CARs are an exception due to their natural ligands, possessing an endogenous costimulatory domain that functions independently [ 21 ]. Second-generation CARs, incorporating either CD28 or 4-1BB (CD137) costimulatory domains, are the most commonly employed in multiple myeloma. While 4-1BB CARs exhibit a memory stem cell-like phenotype and longer persistence, CD28-based cells are more potent with greater growth capacity [ 22 ], suggesting a predominance of 4-1BB in CAR designs. Other costimulatory domains, such as OX40 (CD134), CD27, inducible T cell costimulatory (ICOS), CD40, and MYD88, have been developed, but they have only been investigated at the preclinical level [ 20 ]. Third-generation CARs with two or more costimulatory domains show increased effectiveness and persistence. However, designing and developing such CARs is more complex, and they are still in the early stages of development, making them less effective than single-antigen targeting. Moreover, if tumor cells lose one of the antigens, the costimulatory CAR is not triggered [ 12 , 20 ]. In addition, fourth- and fifth-generation MM antigen-targeted CARs have been developed, capable of producing immunomodulatory molecules (IL-7, CCL19) in response to antigen stimulation [ 23 ]. These CARs interact with tumor cells, forming an immune synapse that leads to target cell killing through various pathways, including the release of cytotoxic molecules (perforins, granzymes), induction of apoptosis via the Fas-Fas ligand molecular pathway, and cytokine production. These pathways also stimulate lymphocyte proliferation and activate other immune cells [ 24 ].

CAR T-cell therapy in MM

Surprisingly, CAR T-cell therapy has emerged as a widely utilized treatment for various hematological cancers, including acute and chronic leukemia, lymphoma, and multiple myeloma [ 25 , 26 ]. Despite initial concerns regarding its efficacy and safety, CAR T-cell therapy has proven to be one of the most promising and potent treatment options available. One prevalent form of CAR T-cells targets CD19 and has been extensively developed for the treatment of leukemias and lymphomas [ 22 ]. In addition, CAR T-cells targeting CD22 and CD20 have shown promise in treating ALL [ 27 ] and relapsed/refractory NHL, respectively [ 28 ]. CAR T-cells can also target other antigens in various cancers, such as CS-1, CD30, CD38, and CD138Prior studies have successfully identified a range of target antigens present on cancer cells. These antigens are pivotal for the development of specialized CAR T-cells. In the context of Multiple Myeloma, notable antigens such as CD19, CD38, CD138, BCMA (B-cell Maturation Antigen), Kappa (κ) light chain, SLAMF7, NKG2D, and GPRC5D have been identified as effective targets for CAR T-cell therapy (Fig. 3 ). BCMA, a protein present in high concentrations on a small subset of healthy blood cells and multiple myeloma cells, is the most extensively studied CAR target for myeloma. BCMA, a tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is preferentially expressed on plasma cells but not on CD34+ hematopoietic stem cells, making it a promising antigenic target [ 29 ]. The binding and activation of ligands such as B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) to BCMA enhance plasma cell development and proliferation in the bone marrow [ 30 ]. Although BCMA expression is heterogeneous [ 31 ], it is found in all multiple myeloma cells, and its overexpression has significant prognostic implications [ 32 ]. The first BCMA-directed CAR was developed a decade ago and demonstrated effective targetability in preclinical studies [ 29 ]. Subsequently, the first-in-human Phase I clinical trial to evaluate the efficacy of BCMA-targeted CAR T-cells in relapsed/refractory multiple myeloma (RRMM) was conducted (NCT02215967) [ 33 , 34 ]. The trial reported an overall response rate (ORR) of 81%, with 63% achieving very good partial (VGPR) or complete response (CR) [ 33 , 34 ]. Consequently, there has been a widespread effort to develop new anti-BCMA CARs and optimize existing ones. This article explores the development of CAR T-cells against these antigens and discusses the efficacy of CAR T-cell therapy in multiple myeloma.

Antigens associated with multiple myeloma, including CD19, CD38, CD138, BCMA (B-cell maturation antigen), Kappa (κ) light chain, SLAM7, NKG2D, and GPRC5D, can be exploited to create particular CAR-T cells efficiently.

bb2121 anti-BCMA CAR T cell

Following the promising results of preliminary studies, a Phase I clinical trial was conducted, involving 33 patients with Relapsed and Refractory Multiple Myeloma (RRMM) who were administered anti-BCMA CAR T-cells (known as bb2121) featuring anti-BCMA ScFv, CD3, and 4-1BB domains (NCT02658929) [ 35 ]. This trial comprised two distinct phases. In the initial dose-escalation phase, patients received bb2121 (manufactured by Celgene) at varying doses: 50 × 10 6 , 150 × 10 6 , 450 × 10 6 , or 800 × 10 6 CAR + T cells. Subsequently, in the dose expansion phase, patients received a total of 150 × 10 6 to 450 × 10 6 CAR + T cells [ 35 ]. Encouragingly, the median duration without disease progression was 11.8 months, with a 95% confidence interval ranging from 6.2 to 17.8 months. Out of the 16 patients who attained a partial response or superior outcome, all underwent rigorous assessment for minimal residual disease (MRD), and none displayed any evidence of MRD presence, with sensitivity down to 104 nucleated cells. Remarkably, among the patients assessed, an impressive overall response rate (ORR) of 85% was documented. However, it is crucial to note that this therapeutic approach was not without its challenges. Notably, a substantial proportion of patients, specifically 76%, experienced cytokine release syndrome (CRS), a severe systemic inflammatory response frequently observed in CAR T-cell therapies. Symptoms of CRS varied in intensity and included fever, fatigue, nausea, muscle aches, difficulty breathing, low blood pressure, and in severe cases, organ dysfunction. In addition, 42% of patients encountered neurotoxicity as an adverse event [ 35 ].

In the Phase 1 CRB-401 trial (NCT02658929), an updated analysis of ide-cel’s application in Relapsed and Refractory Multiple Myeloma (RRMM) revealed a median progression-free survival (PFS) of 8.8 months, alongside an overall survival (OS) of 34.2 months. Notably, a discernible dose-dependent effect was observed, with more favorable responses and survival outcomes seen when administering ≥150 × 10 6 CAR + T cells [ 36 ].

A pivotal phase II single-arm KarMMa clinical trial (NCT03361748) was conducted to confirm the efficacy and safety of idecabtagene vicleucel versus conventional care (CC). Patients with RRMM who were resistant after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled [ 37 , 38 ]. The median progression-free survival (PFS) was reported as 8.6 months, while the overall survival (OS) was 24.8 months [ 39 , 40 ].

Another update on the use of ide-cel in RRMM indicated that patients with triple-class exposed (TCE) RRMM who received a single infusion of ide-cel experienced significant improvements across various health-related quality of life ((HRQoL) categories during a 24-month follow-up [ 41 ]. The phase II KarMMa trial, which utilized ide-cel, demonstrated efficacy in high-risk, heavily pretreated RRMM patients. The trial showed an ORR of 73%, CR rate of 33%, and time to first response of one month. In 79% of individuals with CR, minimal residual disease negativity was achieved, with a median overall survival (OS) of 24 months and a median progression-free survival (PFS) of 8.6 months. The probability of progression-free survival increased with greater response depth and was dose-dependent. The most common adverse effects included grade 3 cytopenias, any-grade CRS occurring in 84% of cases with a time to onset of 1 day, and any-grade neurotoxicity in 18% of cases with a time to onset of 2 days, which is consistent with expectations for CAR T-cell therapy [ 41 ].

The Food and Drug Administration (FDA) approved idecabtagene vicleucel (Abecma), ide-cel, in March 2021.The approval was based on a single-arm study involving 100 adult patients with RRMM who were treated with ide-cel. The study evaluated patients’ overall response rate (ORR), complete response rate (CRR), and response durability (DOR) following treatment with ide-cel after lymphodepleting treatment with cyclophosphamide and fludarabine [ 42 ].

Among the 100 patients in the efficacy evaluable sample, the ORR was 72% (95% confidence interval [CI]: 62–81), with a strict CR rate of 28% (95% CI: 19–38). After a median follow-up of 10.7 months, the median DOR in responders (partial response or better) was 11 months (95% CI: 10.3–11.4), and in patients who achieved strict CR, it was 19 months (95% CI: 11.4 months, not estimable [NE]). Safety evaluation of 127 patients revealed that serious adverse events occurred in 67% of cases. Neurologic toxicities and grade 3 or higher cytokine release syndrome occurred in 9% and 4% of cases, respectively, leading to the implementation of a Risk Assessment and Mitigation Plan. Macrophage activation syndrome/hemophagocytic lymphohistiocytosis occurred in 4% of cases, resulting in two deaths. Long-term cytopenia requiring hematopoietic rescue was observed in 2% of patients (3/127), including two deaths [ 42 ].

The long-term results from the CRB-401 study, last updated in August 2023 by Lin et al., continue to demonstrate the safety and tolerability of ide-cel in treating heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). Ide-cel, at target dose levels of ≥150 × 10 6 CAR + T cells, showed deep and durable responses, presenting a favorable clinical benefit-risk profile. The study also identified translational correlates for durable response to ide-cel, potentially advancing autologous CAR T cell therapy by helping select patients likely to have the most durable responses. Furthermore, the efficacy of ide-cel is being explored in several ongoing trials for earlier stages of myeloma treatment (KarMMa-2, KarMMa-3, KarMMa-4, and KarMMa-7) [ 43 , 44 , 45 ].

bb21217 anti-BCMA CAR T cell

One notable advancement in CAR T-cell therapy for the treatment of MM is the development of bb21217, an anti-BCMA CAR T-cell therapy (NCT03274219), building on the investigational therapy bb2121 [ 45 , 46 , 47 ]. The treatment incorporates the same single-chain variable fragment (scFv), 4-1BB costimulatory motif, and CD3-zeta T cell activation domain found in bb2121. However, it also includes the phosphoinositide 3 kinase inhibitor bb007 during its ex vivo culture process. This addition is specifically aimed at enhancing the composition of the drug product, particularly enriching it with T cells that exhibit a memory-like phenotype, reducing the number of highly differentiated or senescent T cells. CRB-402 (NCT03274219) is a phase 1 clinical trial evaluating bb21217 in patients with relapsed or refractory multiple myeloma (RRMM) [ 47 , 48 ]. The trial involves patients who have undergone at least three prior treatments and tests the safety, pharmacokinetics, efficacy, and duration of bb21217’s effects. This next-generation CAR T-cell therapy has shown promise in early clinical trials. The main objective of the trial was to evaluate adverse events and dose-limiting toxicities. Other objectives included evaluating the quality and duration of the clinical response, monitoring minimal residual disease, and measuring progression-free and overall survival. The trial also aimed to quantify the CAR+ cells in the blood post-treatment [ 47 , 48 ]. As of February 16, 2021, in the multicenter phase I study (NCT03274219) [ 45 ], 72 patients with RRMM were enrolled and treated in doses ranging from 150 to 450 × 10 6 CAR + T cells. The median follow-up period was 9 months. These patients had undergone an average of 6 prior treatments, 68% being triple refractory. A common side effect observed was cytokine release syndrome (CRS), affecting 75% of patients, mostly of mild to moderate severity, with one severe case and two deaths. CRS typically began 2 days after treatment, managed with tocilizumab and corticosteroids. Neurotoxicity was noted in 15% of patients, occurring around 7 days post-treatment. In terms of efficacy, CAR + T cells remained detectable in 81% of patients at 6 months and 60% at 12 months post-infusion. Among patients achieving complete response, 93% were minimal residual disease (MRD) negative. The analysis also found that patients with higher levels of CD8 + CAR + T cells displaying less differentiated, more proliferative characteristics had significantly longer response durations [ 49 ].

The results of the study revealed encouraging outcomes, particularly in terms of CAR T-cell expansion within the patients. Notably, significant growth of CAR T-cells was observed, indicating successful engraftment and proliferation of the modified cells in the treated individuals. This is an important milestone as robust expansion of CAR T-cells is crucial for the therapy to target and eliminate cancerous cells effectively. The study concludes that while adverse events align with typical CAR T cell therapy toxicities, the efficacy results, including a median duration of response of 17 months, are promising. The findings support the hypothesis that the memory-like T cell phenotype associated with bb21217 leads to prolonged response durations, and highlight the encouraging therapeutic potential of bb21217 in treating of RRMM [ 49 ].

LCAR-B38M anti-BCMA CAR T cell

A chimeric antigen receptor T cell product known as LCAR-B38M has been developed to target two distinct B cell maturation antigen epitopes, incorporating [two VHH binding domains [ 50 ]. The LCAR-B38M lentiviral construct utilizes a tandem heavy chain-based CAR llama-derived to enhance avidity [ 50 ]. In addition, it contains a 4-1BB/CD3 intracellular signaling domain and two single-domain antibodies that specifically target BCMA [ 50 ].

In a multicenter study (NCT03090659) [ 50 ], the efficacy of a bispecific CAR T-cell therapy (LCAR-B38M) was evaluated in advanced RRMM patients, targeting the VHH1 and VHH2 epitopes of BCMA. The preliminary results of the first 57 patients treated with LCAR-B38M anti-BCMA CAR T-cells at The Second Affiliated Hospital of Xi’an Jiaotong University showed an overall response rate (ORR) of 88 percent and a CR rate of 68 percent [ 50 ]. In addition, 63% of these patients achieved negative minimal residual disease (MRD) status. However, side effects, including CRS, leukopenia, thrombocytopenia, and pyrexia, were documented [ 50 ].

In 2022 the authors reported long-term safety and efficacy data from a median follow-up of 4 years. A phase 1, single-arm, open-label study named LEGEND-2 was conducted at four authorized locations in China [ 51 ]. Over a four-year period, LCAR-B38M showcased significant effectiveness, achieving an overall response rate (ORR) of 87.8%, a minimal residual disease (MRD) negativity rate of 67.6%, and a median progression-free survival (PFS) of 18 months in relapsed/refractory multiple myeloma (RRMM). Interestingly, despite a declining trend in PFS, the overall survival (OS) curve showed signs of stabilizing, indicating effective response to later treatments in progressing patients. Furthermore, this treatment demonstrated a manageable safety profile, balancing efficacy with tolerability [ 51 ].

P-BCMA-101 anti-BCMA CAR T cell

P-BCMA-101 represents an exciting breakthrough in the field of CAR T-cell therapy. This innovative treatment utilizes a novel design that incorporates fully-humanized anti-BCMA ScFv extracellular domains, CD3 signaling domains, and 4-1BB signaling domains. By utilizing these components, P-BCMA-101 CAR T-cells exhibit a more potent structure, enabling enhanced targeting and destruction of cancer cells expressing BCMA (B-cell maturation antigen) [ 52 ].

One of the key advantages of P-BCMA-101 is its use of a transposon system instead of viral vectors. This approach not only enhances the expression levels of CAR T-cells but also minimizes the risk of immunogenicity, thus improving the overall safety profile of the therapy. By bypassing the use of viral vectors, P-BCMA-101 CAR T-cells can be generated with high efficiency, providing a reliable and scalable manufacturing process [ 52 ].

To evaluate the efficacy and safety of P-BCMA-101 CAR T-cells, a phase I clinical trial (NCT03288493) [ 52 ] was conducted in patients with RRMM. In this trial, a total of twelve patients were enrolled, and their responses were closely monitored. Encouragingly, approximately one out of twelve patients achieved a CR, indicating a significant reduction or even eradication of cancer cells [ 52 , 53 ]. It is worth noting that during the trial, one patient experienced grade 2 CRS. The incidence of CRS in this trial was relatively low, suggesting that P-BCMA-101 CAR T-cells demonstrate a favorable safety profile [ 52 , 53 ].

These findings from the phase I clinical trial provide promising preliminary evidence of the potential effectiveness and safety of P-BCMA-101 CAR T-cell therapy in patients with RRMM.

As of June 30, 2021, 90 patients were treated with P-BCMA-101 at various dose levels, both as a single agent and in combination with Rituximab (Rit) or Lenalidomide (Len) [ 54 ]. The patients, mostly in their early sixties, had extensively received prior treatments, including proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). The therapy showed a favorable safety profile with no significant toxicities. Mild to moderate cytokine release syndrome (CRS) was noted in 25% of patients and neurological side effects in 7%. The most common side effects included low blood counts, infections, and general symptoms. The response rate to the therapy was high (73% with Rit and 71% with Len). Due to its safety, 25% of the treatments were administered on an outpatient basis. The development of P-BCMA-101 CAR T-cells brings hope for improving the treatment outcomes and quality of life for patients with multiple myeloma, paving the way for a new era of personalized and targeted cancer therapies [ 54 ].

MCARH171 anti-BCMA CAR T cell

In a phase I dose-escalation trial (NCT03070327) [ 55 ], the effectiveness of MCARH171, a next-generation anti-BCMA CAR T cell, was investigated in patients with RRMM. This CAR T-cell incorporated a humanized anti-BCMA ScFv, CD3, 4-1BB, and a truncated epidermal growth factor receptor. This huEGFRt is functionally inert, meaning it lacks the N-terminal ligand-binding domains and receptor tyrosine kinase activity typical of the full-length EGFR. Despite these omissions, huEGFRt retains its native amino acid sequence, type I transmembrane localization, and a binding epitope that remains intact and recognizable by the anti-EGFR monoclonal antibody cetuximab (Erbitux). The utility of truncated protein is highlighted in several ways, as selection marker ex vivo and in vivo tracking. In addition, huEGFRt also serves as a target for cetuximab-mediated antibody-dependent cellular cytotoxicity. This allows for the potential elimination of the modified T cells in vivo, which can be an important safety feature in therapeutic applications [ 56 ].

Patients were administered four doses of CAR T-cells (72 × 10 6 , 137 × 10 6 , 475 × 10 6 , and 818 × 10 6 ), resulting in a 64% overall response rate (ORR). However, a significant concern arose from the negative impact observed, as up to 40% of patients experienced grades 1–3 CRS [ 55 ]. Overall, the findings from this phase I trial provide promising insights into the potential of MCARH171 CAR T-cell therapy as a targeted approach for RRMM. Further investigations are warranted to refine the dosing regimen and develop strategies to mitigate CRS and other treatment-related toxicities, thereby enhancing the therapeutic efficacy and improving the long-term outcomes for patients with relapsed/refractory multiple myeloma [ 55 , 57 ].

BRD015 anti-BCMA CAR T cell

The effectiveness of BRD015, an anti-BCMA CAR T-cell therapy, was investigated in a phase I clinical trial (ChiCTR-OPC-16009113) involving 28 patients with RRMM [ 58 , 59 ] BRD015 is composed of anti-BCMA ScFv, CD3ζ, and CD28 domains derived from mice. The therapy was administered at a dose ranging from 5.4 to 25.0 million CAR T-cells per kilogram. Among the patients who had high levels of BCMA expression on their multiple myeloma cells, an impressive overall response rate (ORR) of 87% was achieved [ 59 ]. This means that a vast majority of these patients experienced a significant reduction in tumor burden or even complete elimination of detectable cancer cells. In addition, a remarkable CR rate of 73% was observed in this subgroup, indicating a substantial and durable treatment response. Even more encouraging were the outcomes observed in patients with lower levels of BCMA expression on their tumor cells. This subgroup displayed an astounding 100% ORR, suggesting that BRD015’s anti-tumor activity extends beyond high BCMA expression levels. Although the complete response rate in this subgroup was slightly lower at 33%, the fact that all patients achieved a response is highly encouraging and highlights the potential broad applicability of BRD015 across a range of BCMA expression levels [ 59 ].

These findings from the phase I trial shed light on the promising therapeutic potential of BRD015 in RRMM [ 59 ]. The high response rates observed, both in patients with high and low BCMA expression, demonstrate the effectiveness of this novel CAR T-cell therapy in targeting multiple myeloma cells. Further studies and clinical trials are warranted to explore the long-term durability, safety profile, and potential combination therapies involving BRD015, with the aim of optimizing its efficacy and providing an innovative treatment option for patients with relapsed/refractory multiple myeloma.

Descartes-08 anti-BCMA CAR T cell

Descartes-08 is an innovative CD8 + CAR T-cell product that has undergone genetic modification to express anti-BCMA CAR for a specific duration through mRNA transfection [ 60 ]. This controlled expression of anti-BCMA CAR for one week reduces the risk of uncontrolled proliferation.

One of the remarkable features of Descartes-08 is its high cytolytic activity against myeloma cells, irrespective of the presence of myeloma-protecting bone marrow stromal cells, exogenous proliferation-inducing ligands, or drug resistance, including resistance to IMiDs. In fact, in an aggressive disseminated human myeloma mouse model, Descartes-08 significantly suppresses myeloma growth that is specific to the BCMA CAR (p 0.0001) and greatly improves the survival of the host [ 60 ].

These promising preclinical results, combined with the ongoing clinical trial of Descartes-08 in relapsed/refractory myeloma patients (NCT03448978) [ 60 ], demonstrating preliminary durable responses and a favorable therapeutic index, have provided the foundation for the design of a recently initiated trial involving an optimized and humanized version of Descartes-08 known as Descartes-11. This trial aims to evaluate Descartes-11 in newly diagnosed myeloma patients with residual disease following induction therapy.

Furthermore, Escartes-08 exhibits notable efficacy against primary myeloma cells and MM cell lines, including those resistant to immunomodulatory drugs like lenalidomide and pomalidomide [ 60 ]. Encouraging results from a Phase I/II clinical trial in patients with relapsed/refractory multiple myeloma (NCT03448978) suggest the potential to achieve deep and long-lasting responses, such as stringent complete remission (sCR), without significant CAR T-cell-related toxicities like CRS or neurotoxicity. These findings support the recent completion of a Phase II study on Descartes-11, a humanized anti-BCMA mRNA CAR T-cell therapy, for frontline treatment of myeloma.

CT103A anti-BCMA CAR T cell

CT103A BCMA-targeted CAR T cell, another next-generation CAR T cell, was tested in 18 patients with RRMM, including four who had previously been treated with a murine (mouse-origin) BCMA CAR therapy. (ChiCTR1800018137) [ 61 , 62 ]. During the trial, patients received varying doses of CT103A CAR T-cells (1, 3, and 6 × 10 6 CAR-positive T cells/kg) during the dose-escalation phase, and at 1 × 10 6 CAR-positive T cells/kg in the expansion phase. The results obtained from this trial were exceptionally encouraging, as they demonstrated a remarkable overall response rate (ORR) of 100%. In addition, an impressive 72.2% of patients achieved a CR, indicating a substantial reduction or elimination of MM cells Among the four patients previously treated with murine BCMA CAR therapy, three achieved stringent complete response, and one achieved a very good partial response. The progression-free survival rate at one year was 58.3% for all cohorts, and 79.1% for patients without extramedullary myeloma. The most common adverse events were hematologic toxicities. About 70.6% of patients experienced grade 1 or 2 cytokine release syndromes. CAR transgenes were detectable in 77.8% of patients up to the cutoff date of the study, with a median persistence of 307.5 days. Only one patient developed antibodies against the therapy [ 61 , 62 ].

CD19-CAR T cell

CD19, a member of the immunoglobulin superfamily, plays a vital role as a multimolecular complex signaling component on mature B cells. In addition, it serves as a common target antigen expressed on various B cell hematological malignancies, including acute and chronic leukemias, as well as lymphomas [ 63 ]. The presence of CD19 on these malignancies makes it an attractive candidate for targeted therapy also in the treatment of MM though certain limitations are to be considered.

Multiple Myeloma is notably heterogeneous, characterized by significant variability in the cancer cells’ properties, such as antigen expression. While CD19 is typically absent in the majority of MM cells, it may be found in minor cell subsets with unique capabilities for propagating the disease. Addressing this, Garfall and colleagues embarked on a pioneering clinical trial (NCT02135406) to evaluate the efficacy of autologous T cells, engineered to express a chimeric antigen receptor (CAR) targeting CD19, referred to as CTL019 [ 64 ].

This innovative clinical trial was designed to synergize with standard MM therapy, integrating the use of CTL019 with autologous stem cell transplantation (ASCT) and high-dose melphalan. The objective was to explore the combined effect of these treatments in producing a significant clinical response in MM patients [ 64 ].

The study enrolled 12 patients with advanced-stage MM and aimed to evaluate the impact of this combination treatment approach on progression-free survival (PFS) rates. The results of the study were highly promising. The combination of ASCT, high-dose melphalan, and CTL019 therapy led to a significant increase in PFS rates for MM patients with advanced-stage disease [ 64 ]. This suggests that targeting CD19 with CTL019 in conjunction with the standard treatment regimen can potentially improve outcomes and extend survival in this patient population. The findings of this study highlight the potential of CD19 as a valuable therapeutic target to improve duration of response in the standard management of MM.

CD19/BCMA CAR T cell

Fu et al. conducted a noteworthy clinical trial (NCT03196414) to explore the potential of third-generation CAR T-cell therapy in the treatment of RRMM. Their study aimed to evaluate the efficacy and safety of CAR T-cells engineered with an extracellular component comprising anti-BCMA and anti-CD19 single-chain variable fragments (ScFv). The CAR T-cells were further enhanced with a CD3 signaling domain and supplemented with CD28 and OX40 costimulatory molecules [ 65 ].

In this trial, a cohort of eight RRMM patients was enrolled, reflecting the pressing need for novel treatment options in this challenging disease setting. The patients received infusions of the genetically modified CAR T-cells, and the study team closely monitored their response to the therapy. By harnessing the specificity of anti-BCMA and anti-CD19 ScFv, along with the robust activation provided by the CD3 signaling domain and the additional costimulatory support from CD28 and OX40, the CAR T-cells aimed to effectively target and eliminate malignant plasma cells in the patients’ bodies. Moreover, another phase II clinical trial (ChiCTR-OIC-17011272) was carried out, where a group of twenty RRMM patients was treated with a combination therapy approach. This regimen involved the administration of both humanized anti-CD CAR T-cells (at a dosage of 1 × 10 6 cells/kg) and murine anti-BCMA CAR T-cells (also at a dosage of 1 × 10 6 cells/kg). By combining the two CAR T-cell therapies, the researchers sought to maximize the therapeutic response and potentially overcome any limitations associated with targeting a single antigen [ 66 ].

The results of this combined treatment approach were highly promising, as the study reported an impressive overall response rate (ORR) of 95%. This finding indicates that a significant majority of the RRMM patients experienced a positive response to the dual CAR T-cell therapy, underscoring the potential of such combination strategies in enhancing treatment outcomes.

Kappa (κ) light chain-CAR T cell

Immunotherapy-based techniques have emerged as promising strategies for targeting specific subsets of light chains expressed on mature B cells. By leveraging the unique characteristics of light chains, these techniques enable the selective targeting of MM tumor cells in MM patients, while sparing healthy B cells. This targeted approach holds great potential for improving the efficacy and safety of MM treatments. In the context of immunoglobulins, it is worth noting that they are not typically expressed on the surface of plasma cells. However, evidence suggests that immunoglobulins may be expressed on MM stem cells, which are thought to play a crucial role in disease progression and relapse [ 67 ]. This finding opens up new possibilities for developing immunotherapeutic approaches that specifically target these elusive MM stem cells, potentially leading to more effective and durable responses. In their phase 1 clinical trial (NCT00881920), Ramos and colleagues treated 16 patients with relapsed or refractory κ+ non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) [ 68 ]. Among the seven MM patients, four responded to the treatment. Notably, Patients 4 and 7 achieved stable disease (SD) for 17 and 24 months, respectively. Patient 4 reached minimal residual disease (MRD) post high-dose melphalan and autologous stem cell transplantation (ASCT), maintaining it for 17 months after κ.CART infusion. Patient 7 experienced reduced paraprotein levels and improved anemia for two years.

Patients 8 and 14 showed transient SD with significant paraprotein level changes. Patient 8, re-treated with κ.CART after 1.5 years and additional conventional therapy, achieved transient SD once more. However, the remaining three patients, including two who received chemotherapy just before κ.CART infusion, did not respond to the therapy. Overall, the study observed moderate anti-myeloma effects, such as decreased paraprotein levels, reduced free κ light chains, and improved anemia, lasting up to 24 months. The authors suggested that the modest responses in MM patients might be linked to low light chain expression on malignant plasma cells, and recommended further investigation into the distribution and persistence of κ.CARTs in the bone marrow of MM patients [ 68 ].

NY-ESO-1-CAR T cell

In a preclinical investigation, engineered NY-ESO-1-CAR-T (or New York Esophageal Squamous Cell Carcinoma 1) cells were administered to a mouse model with NYESO-1/HLA-A2 MM, leading to notable tumor cell inhibition. This promising finding suggests the potential efficacy of NY-ESO-1-CAR-T cells in targeting NYESO-1-positive malignancies. Interestingly, the researchers also explored the combination of NYESO1-expressing synthetic T cells with membrane-bound IL-15, which demonstrated a synergistic effect. This combination not only enhanced anti-tumor cytotoxicity but also improved the persistence of memory CAR T-cells, providing a foundation for developing more effective immunotherapeutic strategies [ 69 ].

While the therapeutic potential of CAR T-cell therapies is immense, they can be accompanied by side effects. Reversible monocytopenia has been identified as a major concern associated with CD44v6-CAR T-cells. However, it is worth noting that this side effect may serve a beneficial purpose by preventing CRS By carefully balancing the modulation of immune response, it may be possible to leverage reversible monocytopenia to mitigate CRS while still maintaining the therapeutic benefits of CAR T-cells.

In addition to managing side effects, researchers have explored the integration of safety switches to enhance the safety profile of CAR T-cell therapies. Suicide genes, such as the thymidine kinase gene and the inducible caspase 9 gene, can act as safety switches to enable control over CAR T-cell activity. These genes can be engineered into CAR T-cells, allowing their activation or elimination when necessary. By incorporating such safety switches, the risk of adverse events and potential toxicity associated with CAR T-cell therapies can be reduced, offering an additional layer of safety and control [ 70 ].

These advancements in preclinical investigations not only shed light on the potential of NY-ESO-1-CART cells and combination therapies but also highlight the importance of addressing safety concerns in CAR T-cell therapies. With further research and development, these findings have the potential to pave the way for more effective and safer immunotherapeutic approaches in the treatment of cancer. While NY-ESO-1 has emerged as a promising target antigen in CAR-T therapy for Multiple Myeloma (MM), several critical limitations must be acknowledged. A key challenge is that NY-ESO-1 is not uniformly expressed across all MM cells. Its expression levels can significantly differ from one patient to another and may even vary among the cells within the same patient. Since NY-ESO-1 is only expressed in a subset of multiple myeloma cases, therapies targeting this antigen are not applicable to all patients with this disease. This limits the overall utility of NY-ESO-1-targeted therapies in the broader context of multiple myeloma treatment. A study evaluating LAGE-1 and NY-ESO-1 expression in MM patients found that NY-ESO-1 mRNA was expressed in only 26% of the MM samples analyzed by RT-PCR. In addition, both LAGE-1 and NY-ESO-1 protein expression were detected in just two cases by immunohistochemistry (IHC) [ 71 ].

It’s important to note that research is ongoing, and efforts are being made to address these limitations. This includes developing strategies to enhance CAR-T cell persistence, reduce side effects, and expand the range of targetable antigens in multiple myeloma.

CD56-CAR T cell

Clinical trials, such as NCT03473496 and NCT03271632, have investigated the efficacy of CAR T-cell treatment targeting CD56, along with additional antigens expressed on MM cells. This approach aims to enhance the specificity and effectiveness of CAR T-cell therapy by targeting multiple antigens simultaneously. However, it is essential to consider the potential neurologic toxicity associated with CD56-CAR T-cells. Since CD56 is expressed not only on MM cells but also in both the central and peripheral nervous systems, there is a risk of adverse effects on the nervous system during CD56-CAR T-cell therapy [ 72 ].

CD70-CAR T cell

CD70 (also known as CD27L) is a member of the tumor necrosis factor family and plays a crucial role in plasma cell development. While it is modestly expressed in healthy cells, CD70 has been found to be overexpressed in both solid tumors and hematological malignancies [ 73 ]. In the context of MM cases, various monoclonal antibodies (mAbs) such as BMS-936561 and SGN-75 have been developed to target myeloma cells. Notably, a preclinical study demonstrated that anti-CD70 CAR T-cells effectively and safely targeted CD70 + MM cells [ 74 ]. However, the use of anti-CD70 CAR T-cells in MM patients is currently limited due to the lower and variable expression of CD70 on MM cells [ 75 ].

CD138-CAR T cell

CD138, also known as syndecan 1, is an adhesion molecule belonging to the syndecan family of heparan sulfate proteoglycans. It plays a crucial role in cell proliferation and the adhesion process by binding to collagen and fibronectin, which are extracellular matrix (ECM) molecules [ 76 ]. In MM, CD138 is often overexpressed, especially in relapsed or progressive cases, contributing to cancer progression [ 77 ]. Consequently, targeting CD138 holds promise as a potential therapeutic strategy for MM patients. One approach in treating MM patients involves the use of the anti-CD138 antibody-drug combination BT062 (indatuximab) as a treatment therapy. However, targeting CD138 with immune cells poses challenges due to CD138 shedding from MM cells, allowing them to evade the immune system. To address this issue, CD138-CAR T-cells could be utilized in conjunction with CAR T-cells targeting other antigens present on the surface of MM cells [ 78 ]. This combined approach could enhance the effectiveness of the treatment by targeting multiple antigens simultaneously.

Overall, CD138 presents an attractive target for therapy in MM, and further exploration of CD138-CAR T-cells and combination treatments holds promise in improving outcomes for MM patients.

SLAMF7-CAR T cell

SLAMF7, also known as CD319 or CS1, is a transmembrane receptor belonging to the lymphocyte signaling activation molecule family [ 79 ]. It plays a crucial role in the phagocytosis of various hematological malignant cells by macrophages [ 75 ]. SLAMF7 is commonly found on immune cells such as CD4 and CD8 T cells, NK cells, activated B cells, plasma cells, dendritic cells, and monocytes [ 80 ]. Initially discovered as a receptor on NK cells [ 80 ], therapeutic antibodies targeting SLAMF7 have been developed, including the FDA-approved humanized monoclonal antibody, Elotuzumab (mAb). Elotuzumab, in combination with lenalidomide and dexamethasone, is used for the treatment of multiple myeloma patients [ 81 ]. In ongoing clinical trial research (NCT03710421), SLAMF7-CAR T-cells have been engineered by incorporating an anti-SLAMF7 single-chain variable fragment (ScFv), memory-enriched T cells, and a truncated EGFR (EGFRt) molecule to target multiple myeloma cells [ 82 ].

To address safety concerns associated with CAR T-cell therapy, a novel approach involving the use of cetuximab (an EGFR monoclonal antibody) has been explored. By employing cetuximab as an antibody-based safety switch, CAR T-cell suicide can be induced, thereby reducing the occurrence of severe immune-mediated adverse events following CAR T-cell administration, as previously mentioned [ 83 ].

Since SLAMF7 is not exclusively expressed on myeloma cells, therapies targeting this antigen may also affect other cells expressing SLAMF7. This can lead to unintended consequences or side effects, as healthy cells might be inadvertently targeted and damaged. The non-specificity of the antigen may result in a less effective treatment against myeloma cells. If the antigen is also present on normal cells, the therapy might not be as aggressive against cancer cells as it would be with a more specific target. There is a potential for the development of resistance. Cancer cells could adapt or mutate in a way that diminishes the efficacy of the treatment, especially if the therapy does not robustly discriminate between cancerous and non-cancerous cells. while targeting a non-specific antigen like SLAMF7 in myeloma has its limitations, such as the risk of off-target effects and potential resistance, it also offers opportunities for broader application and can be a valuable part of combination therapies. The impact of such approaches extends beyond immediate treatment efficacy, contributing to the ongoing evolution of cancer treatment paradigms [ 83 ].

Anti-TACI CAR T cell

The transmembrane activator and CAML interactor (TACI), also known as TNFRSF13B, is a member of the tumor necrosis factor receptor (TNFR) superfamily [ 84 ]. It shares the activating ligands APRIL and BAFF with BCMA, promoting MM development and survival by binding to their respective receptors [ 84 ]. This led to the development of ligand-based CAR T-cells targeting APRIL, which simultaneously affect the TACI and BCMA signaling pathways [ 80 , 81 ]. In an in vivo model, APRIL-directed CAR T-cells successfully eliminated BCMA + TACI and BCMATACI tumors, while monospecific anti-BCMA CAR T-cells were ineffective against BCMA cells, suggesting the potential use of APRIL-directed CAR T-cells in cases of BCMA loss [ 85 , 86 ]. Trimeric APRIL-based CAR T-cells exhibited improved binding to BCMA and TACI receptors and demonstrated enhanced cytolytic activity compared to their monomeric counterparts.

In a recent study by Wong et al., non-viral gene delivery was employed to create BAFF CAR T-cells and a chimeric antigen receptor (CAR) based on BAFF ligands [ 87 ]. Through in vitro and in vivo experiments using various xenograft models, BAFF CAR T-cells specifically targeted the three BAFF receptors (BAFF-R, BCMA, and TACI) and effectively eliminated several B cell malignancies, including MM [ 87 ]. This ligand-based BAFF CAR T approach reduces the risk of antigen escape in the treatment of B cell malignancies by targeting three distinct receptors, including TACI [ 87 ].

Larson and colleagues developed a novel antibody against TACI that specifically recognizes TACI+ cells, excluding non-B cell peripheral blood mononuclear cells [ 88 ]. Using the antibody’s single chain variable fragment (scFv), they created second-generation CAR T-cells against TACI. In vitro, anti-BCMA CAR and anti-TACI CAR demonstrated comparable cytotoxicity against MM1S and RPMI-8226 multiple myeloma cell lines. Anti-TACI CARs also expanded in the peripheral blood of xenografted multiple myeloma animals and exhibited in vivo functionality [ 88 ]. The study indicated that the proximity of the anti-TACI scFv to the CD3 signaling domain influenced its effect on CAR functionality, with greater impact when closer to the domain [ 88 ].

TACI is present not only on myeloma cells but also on immunosuppressive regulatory T cells (Tregs) [ 89 , 90 ]. Targeting TACI offers a two-pronged strategy, as it has the potential to indirectly manipulate the adverse milieu provided by Tregs and directly induce cytotoxicity through cytolysis [ 89 ].

CAR T-cell therapy has significantly improved the outlook for patients with recurrent/resistant hematologic malignancies, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and MM [ 12 ]. Table 1 provides a list of clinical trials evaluating CAR T-cell treatment for MM patients conducted at various centers.

CAR T-cell FDA-approved

Currently, six CAR T-cell treatments have been authorized by the FDA: Tisagenlecleucel (Kymriah), Axicabtagene Ciloleucel (Yescarta), Brexucabtagene Autoleucel (Tecartus), Lisocabtagene Maraleucel (Breyanzi), Idecabtagene Vicleucel (Abecma), and iltacabtagene autoleucel (Carvykti) [ 91 ].

The FDA recently approved ciltacabtagene autoleucel (Carvykti), also known as cilta-cel, for adults who have either treatment-resistant or relapsed multiple myeloma. This groundbreaking approval was granted on February 28, 2022 [ 92 , 93 , 94 , 95 ]. Ciltacabtagene autoleucel incorporates two single-domain antibodies that specifically target B-cell maturation antigen. It is indicated for patients who have undergone four or more lines of therapy, including treatment with three major types of multiple myeloma medications: an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulating agent. This approval provides new hope for patients who have exhausted these treatment options. Various clinical trials utilizing ciltacabtagene autoleucel are currently underway to investigate its efficacy in treating patients with relapsed or refractory multiple myeloma (NCT03548207, NCT04133636, NCT04181827, NCT04923893, NCT03548207) [ 96 ].

The ongoing clinical trial CARTITUDE-1 (NCT03548207) investigates the use of cilta-cel in patients with multiple myeloma who have received multiple prior therapies. This study served as the basis for FDA clearance [ 93 , 97 , 98 ]. In the trial, each of the 97 participants received a single infusion of cilta-cel. Nearly all of them (98 percent) responded to the treatment, indicating a partial reduction in cancer burden. Impressively, 78 percent of individuals showed no evidence of cancer in their bone marrow or blood, demonstrating a complete response. In patients with RRMM who have undergone extensive prior treatments, a single infusion of cilta-cel resulted in deeper and durable responses with a manageable safety profile at a median follow-up of 2 years (MFU). The two CAR T-cell products licensed by the FDA (ide-cel and cilta-cel) target the BCMA protein on the surface of myeloma cells and have shown efficacy in treating multiple myeloma. Furthermore, several meta-analyses conducted by Costa et al. using available indirect treatment comparison (ITC) data demonstrated that cilta-cel provides a significant advantage over physician’s choice of treatment (PCT) for patients with triple-class exposed RRMM [ 99 ]. These findings highlight the efficacy of cilta-cel as a therapeutic option for patients with triple-class exposed RRMM [ 99 ]. In general, the long-term outcomes of patients with triple-refractory multiple myeloma treated with BCMA CAR T-cell therapies ide-cel and cilta-cel in the KarMMa and CARTITUDE-1 trials have demonstrated improved outcomes for patients with poor prognoses [ 100 ].

CAR T-cell therapy limitations for MM

Despite achieving high response rates in several BCMA-targeted CAR T-cell therapies, the durability of responses remains a therapeutic challenge in the treatment of MM. A significant proportion of patients experience relapse [ 89 ], indicating the complex nature of CAR T-cell therapy failure in MM. This failure can be attributed to a combination of patient-specific factors, characteristics of the malignancy itself, and immune-related variables, which are analogous to those observed in CD19 + B lymphoid malignancies.

One of the key underlying mechanisms of relapse after cellular immunotherapy is the emergence of tumors with low or negative antigen expression, thereby evading CAR T-cell elimination. This phenomenon, known as antigen escape, has been observed in patients who relapse following CAR T-cell treatment. Notably, the expression of B-cell maturation antigen (BCMA), the target antigen for CAR T-cell therapy in MM, has been found to be downregulated or lost in these relapsed patients [ 101 , 102 , 103 ]. Unlike CD19+ lymphoid malignancies, no DNA alterations have been reported as contributing factors in MM relapses, suggesting alternative mechanisms at play.

Another potential mechanism that could result in lower target antigen density is CAR T-cell-mediated trogocytosis. This process involves the removal of malignancy-associated surface proteins from tumor cells through direct contact with lymphocytes. It has been suggested that CAR T-cells can strip off BCMA or other targeted antigens from the surface of malignant plasma cells via trogocytosis [ 104 ]. This phenomenon may contribute to the reduced levels of target antigen available for CAR T-cell recognition and subsequent elimination.

In addition to antigen-related factors, the lack of CAR T-cell persistence has been identified as another aspect contributing to recurrence in MM patients. The transient presence of CAR T-cells in the body limits their ability to provide sustained therapeutic effects. Efforts are being made to enhance the persistence of CAR T-cells through various strategies, including genetic modifications and the use of co-stimulatory molecules, in order to improve treatment outcomes [ 105 ].

Furthermore, the immunosuppressive effects of the tumor microenvironment (TME) and malignant plasma cells within MM patients may play a significant role in their resistance to immune-based therapy. The TME, characterized by its unique composition and interactions, can create a hostile environment that hampers the effectiveness of CAR T-cells. Factors such as the presence of inhibitory immune checkpoints, immunosuppressive cytokines, and regulatory immune cells can impede CAR T-cell function and limit their ability to eliminate malignant plasma cells effectively [ 88 , 106 ].

Understanding and addressing these multifaceted mechanisms of CAR T-cell therapy failure in MM is crucial for improving treatment outcomes and achieving long-term remissions. Ongoing research efforts are focused on developing strategies to enhance target antigen expression, improve CAR T-cell persistence, and overcome immunosuppressive barriers within the tumor microenvironment. These advancements hold promise for the future of CAR T-cell therapy in the management of multiple myeloma.

Clinical CAR T-cell manufacturing in MM

The remarkable success observed in early-phase clinical studies with CD19-targeted CAR T-cells for treating hematologic malignancies has generated significant interest in CAR T cell-based therapies [ 22 ]. Currently, there is a growing focus on targeting different types of tumors by incorporating additional tumor-associated antigens such as PSMA, mesothelin, GD2, HER2, and epidermal growth factor receptors. This area of research is highly active and numerous clinical trials are underway [ 107 ].

While the designs and tumor-specific single-chain variable fragments (scFvs) may vary, the manufacturing technique for CAR T-cells remains consistent. The process involves collecting and processing T-cell sources, followed by CAR T-cell preparation which includes T-cell selection and/or activation, genetic modification using a CAR cDNA, large-scale expansion, and end-of-process formulation. To ensure the quality of the final product, in-process and quality control release testing is closely integrated into the production process. In clinical trials, CAR T-cells derived from the CD3+ population are commonly used [ 107 ]. However, recent studies from various laboratories have demonstrated that specific subsets of T cells, such as naive, central memory, and memory stem cells, may possess functional advantages. Consequently, techniques for the clinical-scale selection, transduction, and expansion of these T-cell subsets have also been developed [ 107 ]. Although it is tempting to initiate CAR T-cell manufacturing with specific T-cell populations, there is still a need to establish which T-cell subsets offer the best therapeutic efficacy, least toxicity, and are compatible with a robust and reproducible manufacturing process [ 107 ].

Challenges of CAR T-cell therapy for MM

Tumor antigen heterogeneity.

Multiple Myeloma (MM) presents a significant challenge in oncology due to its complex tumor antigen heterogeneity, a critical aspect of the disease’s pathology. This malignancy is primarily characterized by monoclonal plasma cell proliferation, stemming from cells with identical variable-diversity-joining (VDJ) recombination at immunoglobulin loci [ 108 ]. Such malignancy demonstrates notable variability, both genomically and transcriptomically, varying significantly across patients. This heterogeneity, influenced by diverse clonal evolution patterns and a complex tumor microenvironment, creates substantial challenges in understanding and addressing the impact of polyclonality on tumor progression and patient outcomes [ 108 ].

Further complicating MM’s pathology is its extensive inter-patient genomic heterogeneity, resulting from various initiating events [ 109 ]. Insights from multi-region sequencing studies highlight spatial differences within MM, with progression events such as TP53 mutations often confined to specific focal lesions. This degree of heterogeneity is a significant factor in clinical outcomes, influencing everything from prognostic categorization to therapeutic approach and response assessment [ 109 ].

Intratumor Heterogeneity (ITH) in MM also plays a crucial role in these clinical outcomes [ 108 ]. High ITH is associated with tumor immune escape and resistance to treatment. While the connection between neoantigens and ITH is recognized, the specific details and functional implications of this relationship require further elucidation [ 110 ].

MM is further characterized by both inter- and intratumoral heterogeneity [ 111 ]. It undergoes a clonal evolutionary process influenced by clonal competition, the tumor microenvironment, host immunity, and therapy. Cytogenetically, MM is divided into two primary groups: one with recurrent translocations at the immunoglobulin heavy chain locus, and the other characterized by hyperdiploidy involving odd-numbered chromosomes. The disease typically initiates with a preneoplastic phase, known as monoclonal gammopathy of undetermined significance, and can progress to symptomatic MM over variable periods [ 111 ].

This tumor heterogeneity, evolving over time and space, has significant implications for clinical management, including challenges in disease classification, risk stratification, and during maintenance therapy, where clonal evolution can complicate monitoring and contribute to drug resistance. The identification and understanding of dominant neoplastic clones are essential for personalized therapy, especially in cases of disease progression or transformation.

These insights into MM’s tumor antigen heterogeneity highlight the necessity for a comprehensive research and treatment approach. This approach should integrate genetic, molecular, and clinical data to better understand and tackle the complexities of this multifaceted disease.

Immunosuppressive tumor microenvironment

The presence of a tumor microenvironment characterized by an abundance of cells and inhibitory chemicals can significantly impede the effectiveness of CAR T-cell therapy. To overcome this challenge, extensive research efforts have been dedicated to enhancing the performance of CAR T-cells under adverse conditions by modifying their metabolic profiles [ 112 ].

In malignancies, high levels of adenosine and reactive oxygen species (ROS) often impact T cell responses. Cancer-associated fibroblasts (CAFs), which are prominent components of the tumor microenvironment, express a significant amount of fibroblast activation protein (FAP) and play a critical role in establishing an immunosuppressive milieu. They also release extracellular matrix (ECM) proteins that hinder T cell infiltration in solid tumors [ 113 ].

While the mechanism through which anti-CTLA-4 antibodies enhance endogenous T cell responses to cancer is still uncertain, their potential to augment CAR T-cell responses is an intriguing area of exploration. In addition, by reducing CTLA-4+ Treg cells, anti-CTLA-4 antibodies may trigger an immune response in a cell-extrinsic manner, thereby potentially aiding CAR T-cells in their function [ 114 ].

Circumventing the immunosuppressive microenvironment in cancer therapy, Alabanza et al. in 2022, put forth the innovative concept of ‘armored CAR T cells.’ This design involves engineering CAR T cells to combat TGF-β-induced suppression, a common hurdle in effective cancer treatment. By integrating a BCMA-targeting CAR with a specialized DN-TGF-βIIR ‘armor,’ these armored CAR T cells gain an enhanced ability to withstand TGF-β‘s suppressive effects, even under prolonged exposure. This breakthrough in CAR T cell design is particularly significant for improving treatment efficacy and durability in multiple myeloma (MM) patients [ 115 ].

Clinical challenge of CAR T-cell therapy for MM

Car t-cell treatment toxicity profiles.

Cytokines and other immunological proteins released from the infused cells and/or host cells, such as macrophages, contribute to the toxicities associated with CAR T-cell therapy [ 116 ] The elevation of inflammatory mediators in the bloodstream, including IL-6, TNF, and IFN, among others, leads to acute onset CRS [ 116 ]. While fever is the most common symptom of CRS, it can also manifest as tachycardia, hypotension, hypoxia, and other symptoms [ 116 ]. Neurological toxicities are another significant side effect of CAR T-cells, which can present as headache, aphasia, delirium, and, less frequently, seizures and obtundation due to cerebral edema [ 116 ]. Hematologic toxicity following CAR T-cell infusion is complex and multifactorial, involving lymphodepleting chemotherapy, inflammation, HLH, infections, disease recurrence, and subsequent neoplasms, including myelodysplastic syndrome [ 116 ].

Neurotoxicity events, such as immunological effector cell-associated neurotoxicity syndrome (ICANS), can occur following CAR T-cell infusion. These events can vary in nature and manifest with a wide range of clinical presentations [ 116 , 117 , 118 ]. Signs of ICANS may include aphasia, altered consciousness, cognitive impairment, motor weakness, seizures, and cerebral edema. It is believed that ide-cel and cilta-cel, which carry 4-1BB domains, pose a reduced risk and severity of ICANS compared to CD28-carrying CAR T-cell products. The slower T-cell expansion caused by these domains is thought to mitigate the severity of ICANS [ 116 , 117 , 118 ]. One of the an important, albeit rare, fatal case has been reported in the study by Van Oekelen et al. on a case involving a patient with multiple myeloma (MM) who was treated with BCMA-targeting CAR-T cell therapy as part of the CARTITUDE-1 trial [ 119 ]. Approximately three months after receiving ciltacabtagene autoleucel, a BCMA-targeted CAR-T cell infusion, the patient developed a progressive movement disorder with parkinsonism features. This condition was associated with the persistence of CAR-T cells in the blood and cerebrospinal fluid and lymphocytic infiltration in the basal ganglia. The study also found BCMA expression on neurons and astrocytes in the patient’s basal ganglia. This observation, along with public transcriptomic datasets showing BCMA RNA expression in the caudate of normal human brains, suggests that the neurological symptoms might be an on-target effect of anti-BCMA therapy. The paper highlights the importance of close neurological monitoring for patients undergoing BCMA-targeted T cell therapies, especially considering reports of similar parkinsonism symptoms in other patients treated with this therapy [ 119 ].

Dual CAR-T cells to improve MM specific

Dual-targeting with different CAR T-cells offers the advantage of individually controlling CAR expression in each CAR T-cell product (Fig. 4 ). Moreover, this technique enables sequential delivery of CAR T-cells, which may reduce the risk of severe CRS [ 120 ]. In recent clinical trials involving newly diagnosed and relapsed refractory patients, BCMA/CD19 dual CAR T-cell targeting was achieved by using two pools of single CAR Transduced T-cells (NCT03706547, NCT03767725). To minimize the potential for exacerbated cytokine release syndrome, patients received CAR T-cells in a sequential manner. Both groups of patients experienced tolerable CRS without any neurological damage. Evaluation of clinical responses demonstrated that sequential combination of BCMA and CD19 CAR T-cells could enhance therapeutic outcomes [ 120 , 121 , 122 ]. However, since these studies lacked a control group (i.e., a single-arm design), it is crucial to examine the results of a recently launched study (NCT03549442) that investigates the comparative success and safety of dual-targeting BCMA/CD19 as opposed to BCMA targeting alone. Clinical trials are currently underway to explore dual CAR T-cell targeting with combinations of BCMA/CD19 and BCMA/SLAMF7, utilizing bicistronic vectors (NCT04156269, NCT04162353) [ 120 ]. Several other clinical trials employing non-specific dual targeting techniques are investigating BCMA/CD38, BCMA/NY-ESO1, and CD38/CD19 combinations (NCT03125577, NCT03767751, NCT03473496, NCT03271632, and NCT03638206). In the clinic, BCMA/GPRC5D dual CAR T-cells are being tested through co-infusion, co-transduction, or creation using a bicistronic vector [ 122 ]. In addition, inhibitory CARs (iCARs) are used in another type of dual CAR design to enhance specificity. The iCAR method, first described by Fedorov et al. in 2013, involves combining a CAR T-cell with a standard second-generation CAR, which has a scFv binding domain coupled with an inhibitory cytoplasmic domain such as CTLA-4 and PD-1 [ 123 ] (Fig. 4B ).

Challenges of CAR-T cell therapy for MM include: Tumor antigen heterogeneity, Immunosuppressive tumor microenvironment, and Trafficking and infiltration into tumor tissue.

Split-dual CAR T-cells to improve MM-specificity

Split-dual CAR technology utilizes two separately expressed CARs targeting carefully selected antigens, which individually may not be tumor-specific but demonstrate tumor-specific expression when combined (Fig. 5 ). The primary activation and co-stimulation signals for T-cells are divided between these two CARs. This ensures that dual CAR Transduced T-cells are fully activated only when both CARs engage their targets on tumor cells simultaneously, while avoiding recognition of a single antigen on normal tissues. By splitting the initial and co-stimulatory T-cell activation signals, split-dual CARs enhance tumor specificity (Fig. 5 ) [ 124 ].

Dual CAR T-cell targeting is one of the essential strategies for targeting MM using CAR T-cell, which includes improvement in efficacy and specificity. (1) Efficacy improvement. A Dual CAR: depicts a myeloma cell expressing two antigens (Antigen 1 and Antigen 2); two separate CAR T cells, infused together or sequentially, each with a distinct CAR (CAR 1 and CAR 2), target each antigen; the co-stimulatory domain and CD3ζ domain in both CARs lead to complete activation of the T cells upon binding to their respective antigens, destroying the cancer cell. B Bicistronic CAR (1/2 construct): a single T cell with a bicistronic CAR construct can express two different CARs; full T cell activation occurs upon dual binding, suggesting improved efficacy through bispecific targeting. C Tandem CAR (scFv1/2 construct): a single T cell with a tandem CAR construct containing two binding sites (scFv1 and scFv2) for the two antigens; binding of both sites results in full T cell activation, suggesting another approach for enhancing efficacy through tandem CAR design. D ligand-based CAR construct: a T cell with a ligand-based CAR construct is shown to recognize and bind to the ligand; upon binding, full activation of the T cell occurs, indicating that ligand-based targeting can also improve the efficacy of CAR T-cell therapy. (2) Specificity improvement. A Bicistronic CAR/CCR construct: a T cell with a bicistronic CAR construct that includes a CAR and a co-stimulatory receptor (CCR) is shown; the T cell requires binding to both antigens for full activation, suggesting that dual antigen recognition can improve specificity and reduce off-target effects. B Inhibitory CAR (iCAR): shows a healthy cell with a TAA (tumour-associated antigen) and a self-antigen not present in the tumour cells; a T cell with a dual construct: a CAR for the TAA and an inhibitory CAR (iCAR) for the self-antigen; if the T cell encounters a healthy cell that expresses the self-antigen, the iCAR sends an inhibitory signal to prevent T cell activation, enhancing the specificity of the therapy by avoiding damage to healthy cells.

While the main objective of split-dual CAR T-cells is to improve specificity, they can also enhance the affinity of CAR T-cells for the tumor target. BCMA, for instance, exhibits limited expression in healthy cells except for plasma cells, making split signaling less necessary to enhance BCMA CAR T-cell specificity. However, incorporating MM antigens that are not exclusive to plasma cells and myeloma cells, particularly those strongly expressed on MM cells but with lower expression on healthy cells (e.g., CD138, CD38, and SLAMF7), can offer advantages and open new possibilities [ 125 ]. Combining a non-specific MM target with an iCAR targeting a self-antigen could enhance the specificity and safety of MM CAR therapy. Split-signaling CAR T-cells and dual CAR/iCAR T-cells can be generated through the co-transduction of two independent vectors or the use of a bicistronic vector, each with its own advantages and disadvantages [ 126 ].

To enhance the antimyeloma efficacy of CAR T-cell therapy and prevent myeloma cells from evading treatment through antigen loss and downregulation, dual-antigen targeting of BCMA and other myeloma antigens such as SLAMF7, CD19, and GPRC5D has been proposed [ 127 , 128 ]. A novel approach to dual-antigen targeting involves not only targeting the tumor cells but also eradicating the cancer-associated fibroblasts (CAFs) that create the myeloma niche in the bone marrow, as demonstrated by Sakemura et al. [ 129 ]. In preclinical models, both in vitro and in vivo, T-cells directed against BCMA combined with either SLAMF7 or fibroblast-associated protein (FAP) exhibited significantly improved antimyeloma efficacy. These enhanced CAR T-cells displayed greater cytolytic activity, cytokine production, and proliferation against multiple myeloma cells in the presence of CAFs, surpassing the performance of standard CAR T-cells targeting BCMA as a single antigen [ 130 ].

Strategies to overcome clinical challenges to MM

Anti-IL-6 receptor antibodies, such as Tocilizumab, along with corticosteroids, have been widely utilized in the treatment of CRS. However, when it comes to managing neurological toxicities, corticosteroids are commonly favored over anti-IL-6 receptor antibodies [ 131 ]. In an effort to minimize potential side effects associated with this type of therapy, CAR T-cell products are now being developed with genes that incorporate a biological suicide switch. This innovative feature allows for the activation of the suicide switch and subsequent induction of CAR T-cell apoptosis following the administration of a specific medication infusion.

The incorporation of a biological suicide switch in CAR T-cell therapy holds promise for addressing safety concerns. By providing a controlled means of eliminating CAR T-cells when necessary, this technology offers an additional layer of safety and control. The suicide switch can be triggered in response to specific circumstances, such as the occurrence of severe adverse events or the completion of the desired therapeutic effect. This ensures that CAR T-cells can be selectively removed from the patient’s system, reducing the risk of potential long-term complications or adverse reactions.

The activation of the suicide switch prompts a programmed cell death mechanism, leading to the apoptosis of CAR T-cells. This process involves the activation of genes encoding proteins that induce cell death pathways, such as apoptosis-inducing receptors or pro-apoptotic enzymes. Once activated, these proteins initiate a cascade of events that ultimately result in the targeted elimination of CAR T-cells. By employing this precise mechanism, the biological suicide switch offers a reliable and controllable way to modulate the activity of CAR T-cells and mitigate potential toxicities associated with their prolonged presence.

The introduction of a suicide switch in CAR T-cell therapy not only enhances safety but also provides reassurance to patients and healthcare providers. The ability to deactivate CAR T-cells if necessary alleviates concerns about uncontrolled cellular proliferation, immune overactivation, or potential long-term effects. It empowers clinicians to intervene promptly and manage adverse events effectively, fostering a more personalized and tailored approach to CAR T-cell therapy.

In conclusion, the integration of a biological suicide switch into CAR T-cell products represents an exciting advancement in the field of immunotherapy. This innovation holds promise for improving the safety profile of CAR T-cell therapies, particularly by reducing the potential side effects associated with prolonged CAR T-cell activity. By enabling the selective elimination of CAR T-cells when needed, the suicide switch technology provides an additional layer of control and enhances the overall effectiveness and safety of CAR T-cell therapy.

Conclusion and future perspectives

Despite recent breakthroughs, the treatment options for patients with multiple myeloma remain limited and ineffective. One promising approach is the use of CAR T-cells, which are engineered T cells equipped with lymphocyte-like signaling molecules. These cells have shown potential in targeting specific genes that are preferentially expressed in malignant cells, making them a potential therapeutic avenue for boosting the immune system’s response against cancerous cells.

If we can fully understand the potency of CAR T-cell therapy in controlling multiple myeloma over the long term, it could have a disruptive effect in the field of cancer treatment. Clinical trials involving CAR T-cells in hematological malignancies are already underway, exploring thousands of combinations of therapies in this area. However, one challenge lies in finding more effective targets for CAR T-cell therapy and identifying suitable combination therapies.

To decrease the risk of relapse in multiple myeloma after CAR T-cell therapy, researchers are focusing on novel antigens that can be targeted either alone or in combination with B-cell maturation antigen (BCMA). In addition, pharmacological drugs can be used to enhance the density of target antigens on multiple myeloma cells, potentially improving clinical outcomes. Modifying the design of CAR T-cells by altering the antigen-binding, co-stimulatory, hinge, and transmembrane domains can also enhance their effectiveness. Furthermore, incorporating a suicide switch system into CAR T-cell therapy can enhance overall safety.

Another approach to improving the effectiveness of CAR T-cell therapy is the addition of maintenance therapy following CAR T-cell infusion or replacing standard lymphodepleting chemotherapy regimens with more potent drugs against multiple myeloma. By combining these strategies, researchers hope to achieve more durable and profound responses in patients.

In order to advance the field of CAR T-cell therapy, it is crucial to conduct basic mechanistic research, alongside bioengineering and various clinical trials. Such research provides insights into the fundamental biology of T cells and helps in the development of “fitter” CAR T-cells that exhibit increased proliferation and durability. The emergence of CRISPR-Cas9 technology has opened up new possibilities, allowing for genome-wide screening to identify novel genes that, when modified, can enhance the resilience and capabilities of CAR T-cells (Fig. 6 ).

A cancer patient’s blood was used to isolate T cells. The CRISPR-Cas9 strategy was used for gene editing in normal T cells. After injecting the patient with the gene-edited T cells again, patients were observed to determine the efficacy and safety of the treatment.

Furthermore, understanding the heterogeneity of multiple myeloma and the distinct genomes and transcriptomics of cancer cells could provide valuable information on how different surface targets can be utilized for immune targeting. Single-cell analysis of plasma cell leukemia patients has already revealed the presence of multiple subsets of CAR T-cells with varying expression, proliferation, and cytotoxicity characteristics, indicating stage-specific changes in their development. Exploring the influence of specific genomic and transcriptomic features, such as T-cell classes and RNA editing signatures, on the expression of surface targets could shed light on new avenues for immune targeting in multiple myeloma.

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Acknowledgements

We are grateful to all those who have contributed to this paper.

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These authors contributed equally: Rosario Vicidomini, Naresh Poondla.

Authors and Affiliations

Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran

Mohsen Sheykhhasan & Amirhossein Ahmadieh-Yazdi

Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi, University of Medical Sciences, Yazd, Iran

Amirhossein Ahmadieh-Yazdi

Section on Cellular Communication, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA

Rosario Vicidomini

Icahn School of Medicine at Mount Sinai, New York, USA

Naresh Poondla

Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Hamid Tanzadehpanah

Department of Microbiology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran

Ashkan Dirbaziyan

Vascular & Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Hanie Mahaki

The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran

Hamed Manoochehri

Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom, Iran

Naser Kalhor

School of Life Sciences, University of Sussex, Brighton, BN1 9QG, UK

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MS and PD designed the concept. MS, AAY, AD, NP, RV, HT, HM, HM, NK, and PD searched the literature. MS, AD, NP, RV, HT, HM, HM, and NK wrote the manuscript. AAY created the figures. PD revised the manuscript. The authors read and approved the final manuscript.

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Sheykhhasan, M., Ahmadieh-Yazdi, A., Vicidomini, R. et al. CAR T therapies in multiple myeloma: unleashing the future. Cancer Gene Ther 31 , 667–686 (2024). https://doi.org/10.1038/s41417-024-00750-2

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Case Presentation: A 74-Year-Old Woman with Relapsed/Refractory Multiple Myeloma

Jonathan L. Kaufman, MD
Ajay K. Nooka, MD

Experts discuss the case of a woman with relapsed/refractory multiple myeloma and the available treatment options, including novel BCMA-targeted agents.

EP: 1 . Emory Experts Discuss Multi-Agent Induction Regimens for Transplant-Eligible Newly Diagnosed Myeloma

EP: 2 . Newly Diagnosed Multiple Myeloma: The MASTER and GMMG-HD7 Trials

EP: 3 . Treatment Approaches for Patients with Newly Diagnosed Multiple Myeloma

EP: 4 . Maintenance Therapy Strategies for Transplant Eligible Multiple Myeloma

Ep: 5 . case presentation: an 82-year-old woman with transplant-ineligible multiple myeloma, ep: 6 . transplant-ineligible multiple myeloma: the maia trial, ep: 7 . defining high-risk multiple myeloma, ep: 8 . transplant-ineligible multiple myeloma: the swog0777 study, ep: 9 . blood-based mrd testing and transplant-ineligible multiple myeloma, ep: 10 . case presentation: a 74-year-old woman with relapsed/refractory multiple myeloma, ep: 11 . novel therapies in multiple myeloma, ep: 12 . unmet needs and the future of multiple myeloma.

EP: 13 . Recap: Emory Experts Review Treatment Strategies for Transplant-Ineligible Multiple Myeloma

Sagar Lonial, MD: Let’s start this next discussion with another case. Dr Joseph?

Nisha Joseph, MD: This is a 74-year-old woman who initially presented with anemia and hypercalcemia after presenting to a primary care physician with acute onset severe rib pain after sneezing. She was subsequently diagnosed with IgG kappa myeloma. Her marrow showed 30% to 40% clonal plasma cells, FISH [fluorescence in situ hybridization] with multiple trisomies, as well as loss of 1p and gain of 11q. PET [positron emission tomography]–CT confirmed lytic disease throughout the spine with multiple ribs involved and nondisplaced rib fractures bilaterally. The patient was started on lenalidomide, bortezomib, and dexamethasone. She completed 5 cycles with a VGPR [very good partial response] followed by autologous stem cell transplant, and then she started on lenalidomide maintenance.

At 6-year restaging, she was found to have progressive disease. At that time, she was started on salvage therapy with daratumumab, pomalidomide, and dexamethasone in April 2020. Initially, pomalidomide was started at 4 mg on days 1 through 21, and dexamethasone and daratumumab were dosed standardly. The patient unfortunately developed persistent neutropenia, attributable to the pomalidomide. She was started on growth factor twice weekly, with subsequent improvement in her ANC [absolute neutrophil count], and she was continued on pomalidomide dosed at 4 mg. At last follow-up, the patient continues in VGPR and is tolerating therapy well without issue.

Sagar Lonial, MD: This sets up a lot of exciting stuff in myeloma. We know that drugs for the treatment of patients with relapsed/refractory disease always seem to migrate earlier in the treatment paradigm. We’ve seen that in the discussions we’ve had about quadruplets vs triplets, where daratumumab, approved in 2015 or 2016 for refractory myeloma, has moved all the way up front in just under 6 years.

When we think about early relapse in a patient who isn’t daratumumab resistant—they can’t have been daratumumab exposed but aren’t daratumumab resistant—that’s the backbone. Am I going to partner it with an IMiD [immunomodulatory drug] or a PI [proteasome inhibitor]? There are lots of data looking at carfilzomib, bortezomib, and pomalidomide in combination with CD38 antibodies to treat patients with early relapse.

When you get to the later relapse, where we’ve exhausted the efficacy of the Big 6 or the Big 5, depending how you do the math, then we get into a little more limited spray of areas, and you guys are going to talk about that. We’ve got agents like selinexor, with or without other combinations. We’ve got data on belamaf [belantamab mafodotin], which we’ll hear a little about. Then we’ve got 2 approved CAR [chimeric antigen receptor] T cells in that space as well. We have options, and there’s a lot more coming that we’re going to try to cover in the next few moments.

Before we get to that, Dr Kaufman, let me ask you about this concept that we often hear and that’s a holdover from old school medical oncology, which is don’t use your best drugs early, save them for later. Our good friend Dr Rafael Fonseca had an abstract about this, particularly in the older, frailer patient population. Do you want to talk about those data and how to make it useful for clinical practice?

Jonathan Kaufman, MD: He had an interesting analysis where he took both clinical trial and real-world data and ran simulations on expected survival. One key thing he identified and that we likely underestimate in practice is the attrition rate between lines of therapy. The attrition rate in lines of therapy is much higher in the older- or frail-patient population, and ultimately he argues that we need to put our best foot forward up front.

In his simulation, the best foot forward up front in the older non–transplant-eligible population was the combination of daratumumab, lenalidomide, and dexamethasone. With that regimen, as noted before, with the impressive 5-year progression-free survival, which translated to an improvement in overall survival, these patients were able to get the best therapy up front. Even if there was attrition after that, their first remission was the longest remission, as Dr Nooka says all the time. It’s something we repeat over and over, that the first remission is the longest remission. Not only do we have clinical trial data, but this analysis of the clinical trial and real-world data showed that while we don’t have a head-to-head comparison of daratumumab-lenalidomide-dexamethasone vs RVd [lenalidomide, bortezomib, dexamethasone] modified, RVd lite, it looks like daratumumab-lenalidomide-dexamethasone is going to be superior from an overall survival standpoint.

Sagar Lonial, MD: It’s an important and interesting analysis. It clearly has its anchor in the older-, frailer-patient population. But even as we begin to talk about quadruplets in induction therapy, there’s some sense that this is important there as well, where we’ve all clearly talked about the benefit of early anti-CD38 antibodies to try to improve depth of response early on that can then be consolidated and built on in the maintenance setting. Dr Joseph, let me ask you to talk a little about novel BCMA-targeted agents that have been approved in refractory myeloma as well.

Nisha Joseph, MD: Sure. It’s almost been 2 years that we’ve had the approval of the belantamab mafodotin, which is an anti-BCMA antibody-drug conjugate approved based on results from the DREAMM-2 study. That study looked at a highly pretreated population with belantamab dosed at 2.5 mg/kg given every 3 weeks and found an overall response rate of around 30%. Importantly, in subset analysis, when you look at patients who received over 7 lines of therapy compared with those who received fewer lines of therapy, you’re still seeing that response maintained, which is important because that’s where there’s an unmet need and where we’re often using this drug in folks who aren’t clinical trial eligible.

There are ongoing clinical trials looking at belantamab in combination and in different settings in myeloma, in the maintenance phase and earlier. The ALGONQUIN study looked at belantamab with pomalidomide and dexamethasone, which is an approach we’re sometimes utilizing. There are ongoing DREAMM studies looking at different combinations, including pembrolizumab and the DREAMM 5 basket study looking at the belantamab with other small molecule inhibitors.

In addition to belantamab, we also have 2 recent approvals, as you referenced. An anti-BCMA CAR T, cilta-cel [ciltacabtagene autoleucel], was just approved, and ide-cel [idecabtagene vicleucel] was approved in March 2021. Of course we have ongoing development of multiple anti-BCMA therapies, including bispecific T-cell engagers targeting BCMA and CD3, many of which we have at Emory [University] that we’re using in our relapsed/refractory patients.

Sagar Lonial, MD: The list of new agents and targets has more than you can fit on a single slide and still read at a given point.

Transcript edited for clarity.

A panel of 4 experts on multiple myeloma

Cilta-cel Yields Sustained Responses in R/R Multiple Myeloma

Findings from the CARTITUDE-2 trial support the use of cilta-cel in patients with multiple myeloma, says Tina Glow, AAS, RN, BSN.

Administering CAR T-Cell Therapy and Bispecific Agents in Nursing Practice

Registered nurses discuss research related to agents like ciltacabtagene autoleucel presented at the 2024 Oncology Nursing Society Congress.

Cranial Nerve Palsy Present Across CARTITUDE Trials in Multiple Myeloma

Patients enrolled across the CARTITUDE trials who experienced cranial nerve palsy after treatment with cilta-cel were generally male.

Frontline Forum: Real-World Practice in Newly Diagnosed Multiple Myeloma

Experts discuss key data updates in real-world newly diagnosed multiple myeloma practices, and how these findings may change the treatment paradigm.

ODAC Approves MRD End Point in Multiple Myeloma Trials

Minimal residual disease can now be considered an end point in trials leading to accelerated approvals by the FDA for multiple myeloma.

$Investigators also look to assess linvoseltamab in relapsed/refractory multiple myeloma as part of the phase 3 LINKER-MM3 trial.$

Linvoseltamab Shows Responses, Safety in Relapsed/Refractory Myeloma

Investigators also look to assess linvoseltamab in relapsed/refractory multiple myeloma as part of the phase 3 LINKER-MM3 trial.

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Lung Involvement in Multiple Myeloma - Case Study

Mimi niŢu.

1 University of Medicine and Pharmacy, Craiova, Pneumology Department

EMILIA CRIȘAN

Cristina cĂlĂraŞu.

2 "Victor Babeş" Hospital of Infectious Diseases and Pneumology, Craiova

MĂDĂLINA OLTEANU

M.r. popescu.

Introduction: Mutiple mieloma (MM) cells are rarely found in extramedullary sites. The sites of extramedullary dissemination reported in the literature are spleen, liver, lymph nodes, kidneys, thyroid gland, adrenal gland, ovary, tests, lung, pleura, pericardium, intestinal tract and skin. We report a case in which the myeloma was diagnosed after we discovered the presence of monoclonal plasma cells in the bronchoalveolar lavage fluid (BAL). Matherial and method: a case in which diagnosis was established from bronchoalveolar lavage (BAL) fluid demonstrating the presence of monoclonal plasma cells in Craiova Pneumology Departament. Results: Analysis of BAL fluid for the presence of plasma cells and for cytoplasmic immunoglobulin DNA provides a noninvasive means of establishing the diagnosis. Conclusions: Pulmonary parenchyma is an uncommon site of extramedullary involvement in multiple myeloma. Interstitial lung disease as pulmonary manifestation of multiple myeloma is even rarer; only isolated cases with histological proofs have been reported in the literature.

Introduction

Multiple myeloma is a malignant monoclonal gammopathy characterized by proliferation of myeloma cell clones responsible for their osteolytic lesion appearance (favoring pathological fractures and nerve compression), bone marrow infiltration (with the advent of bone marrow failure), abnormal protein production – M component (responsible for damage kidneys, the hyperviscosity syndrome and secondary amyloidosis), installing of immune deficiency (favoring infections).

Infections are the most common complications in multiple myeloma, followed by bleeding complications, neurological, renal, hypercalcemia related complications and amyloidosis.

The mechanism of developing these infectious complications is mixed and involves several pathophysiological links like:

- Proliferation of myeloma cells in the bone marrow resulting in decreased normal hematopoiesis with bone marrow failure and peripherals cytopenias including leukopenia and granulocytopenia;

- Monoclonal immunoglobulins secreted by malignant clone can adhere to leukocytes causing their functional capacity decrease (phagocytosis, bactericidal activity) or to some fractions of complement, inducing abnormal opsonized capacity;

- Humoral immune deficiency - increased monoclonal component myeloma - is accompanied by a decrease in other normal immunoglobulin with polyclonal hypogammaglobulinemia installation. The decrease in number and functional capacity of polyclonal B lymphocytes affects the ability of B lymphocytes to respond to specific antigens and inhibition of antibody formation in the primary and secondary immune response and thus decrease the body's defense capacity.

- Cellular immunity dependent on T lymphocytes is less affected - expressed in vitro by the decrease of reactivity of T cell lymphocytes to mitogens. Abnormal T lymphocytes, NK cells and monocytes increase humoral immune deficiency - immunosuppression due to corticosteroid and cytostatic treatment increases the risk of infections. [ 1 ]

Myeloma cells may be extramedullary located due to extramedullary plasmacytoma or extramedullary dissemination of MM.

Extramedullary plasmacytoma involves submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without affecting the red bone marrow. It's an excellent prognosis MM type that responds well to local irradiation.

Case Report

A 60 years old man, smoker, with no history of respiratory hospitalization and relative good past health was admitted in our hospital with fever, chronic cough, significant weight loss and progressive dyspnea in the previous two months. His symptoms were not influenced by previous antibiotic treatment.

Physical examination then showed pale skin, fine crepitation over bilateral lung bases, pain in some small joints, blood pressure was normal but he had sinus tachycardia (132’/min), SaO2=90%.

Chest X-ray evidenced diffuse, bilateral lower-zone reticulo-nodular shadowing. Repeated exams of sputum smear were negative for Mycobacterium tuberculosis (both microscopy and culture).

His hemoglobin was half of the normal value but renal function and calcium level were within normal limits.

Chest computed tomography revealed scattered ground glass opacities in both lungs that were suggestive of interstitial lung disease and no suspect thoracic lymph nodes.

So the next step was bronchoscopy and bronchoalveolar lavage (BAL) fluid was examined and it revealed the presence of monoclonal plasmatic cells in BAL.

We transferred the patient to Hematology where he was further investigated and treated for his severe anemia.

He was diagnosed with Multiple myeloma IgG type stage III subclass A. After this the pacient had a rapid decrease of cardiac and respiratory function and the chest x-ray after 4 months showed the extension of the interstitial infiltrates in lower fields of both lungs. Because of his cardiac condition (ischemic heart disease, cardiomyopathy and sinus tachycardia) he couldn’t start specific chemotherapy for MM so his prognosis is severe.

Extramedullary dissemination involves the spleen, liver, lymph nodes, thyroid, adrenal, ovary, testis, lung, pleura, pericardium, gastrointestinal tract and skin.

Antemortem diagnosis of extramedullary dissemination in the lungs can be determined by bronchoalveolar lavage (monclonale plasma cells are found) or lung biopsy (interstitial infiltrate of plasma cells).[ 2 ]

Pulmonary parenchyma is an uncommon site of extramedullary involvement in multiple myeloma; only isolated cases with histological proofs have been reported in the literature.

One study described 13 cases with lung involvement of multiple myeloma, of which six had pneumonia, two had mass lesions, two had multiple nodular lesions, and three had interstitial infiltrates.[ 3 ]

Approximately 10% of patients with multiple myeloma demonstrate pulmonary findings during the course of their disease. The findings most commonly described include bacterial and fungal infections, pleural-based plasmacytoma, pleural effusions, and well-circumscribed pulmonary plasmacytoma. [ 4 , 5 , 6 ]

Identifying malignant plasma cells in BAL fluid from multiple myeloma patients may be difficult, especially when the plasma cells are mature in appearance or low in number.

Diffuse pulmonary myelomatous involvement therefore may be more frequent than has previously been reported.

A high index of suspicion is required because infection, hemorrhage, idiopathic pneumonia, edema of the lung, and plasma cell infiltration may have identical radiologic manifestations.

Citologic examination of the sputum and BAL fluid and an analysis of cytoplasmic immunoglobulin DNA provide a simpler means of confirming diagnosis and may obviate the more invasive needle biopsy or open lung biopsy.

Conclusions

We present one such case in which diagnosis was established from bronchoalveolar lavage (BAL) fluid demonstrating the presence of monoclonal plasma cells.

Diffuse parenchymal infiltrates in the lung due to MM are rare but should be considered when finding pulmonary infiltrates.

Analysis of BAL fluid for plasma cells is a noninvasive method to establish a diagnosis. Associated comorbidities increase the risk for severe infectious complications.

Pulmonary MM is associated with rapid progression of the disease unlike primary pulmonary plasmacytomas that has good prognosis.

Acknowledgments

All authors contributed equally to the article.

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http://orcid.org/0000-0003-2997-5867 Anouchka Seesaghur 1 ,
Natalia Petruski-Ivleva 2 ,
Victoria Louise Banks 1 ,
Jocelyn Ruoyi Wang 2 ,
Ali Abbasi 1 ,
David Neasham 1 ,
Karthik Ramasamy 3
1 Center for Observational Research (CfOR) , Amgen Ltd , Uxbridge , UK
2 Science , Aetion, Inc , Boston , Massachusetts , USA
3 Department of Haematology , Oxford University Hospitals NHS Foundation Trust , Oxford , UK
Correspondence to Dr Karthik Ramasamy; karthik.ramasamy{at}ndcls.ox.ac.uk

Objectives Patients with multiple myeloma (MM) experience significant delays in diagnosis due to non-specific symptomatology. The aim of this study was to characterise the frequency and timing of clinical features in the primary care setting prior to MM diagnosis.

Design Population-based cohort study.

Setting Electronic health records data of approximately 17 million patients (2006–2016) within the UK Clinical Practice Research Datalink.

Participants Patients aged ≥18 years with newly diagnosed MM (NDMM), no history of solid tumours and ≥2 years registration in a primary care practice prior to MM diagnosis.

Main outcome measures Clinical features and symptoms including bone pain, skeletal-related events (SREs), investigation and confirmation of MM diagnostic CRAB criteria (hyperCalcaemia, Renal impairment, Anaemia, Bone lesions) during the 2 years prior to MM diagnosis; time between symptom manifestation and/or relevant investigation and diagnosis of MM.

Results Among 2646 patients with NDMM, 47.5% had a bone pain record during the 2-year period prior to MM diagnosis, mainly affecting the back. Regardless of baseline bone pain, investigations for serum calcium level were used in 36.4% of patients prior to MM diagnosis, followed by haemoglobin (65.6%) or renal function (74.1%). Median (Q1, Q3) time from first-recorded bone pain to MM diagnosis was 220 (80, 476) days. Median (Q1, Q3) time from first-recorded hypercalcaemia, renal impairment or anaemia to MM diagnosis was 23 (12, 46), 58 (17, 254) and 73 days (28, 232), respectively. An imaging investigation or referral for imaging was recorded for 60.0% of patients with bone pain/SRE and 32% without.

Conclusions Nearly half of patients diagnosed with NDMM presented with bone pain approximately 7 months prior to MM diagnosis. Investigations to evaluate all CRAB criteria, including targeted imaging, were underused. Early recognition of myeloma clinical features and optimised use of investigations in primary care may potentially expedite MM diagnosis.

primary care
epidemiology

Data availability statement

Data may be obtained from a third party and are not publicly available. Data sharing agreements under licence from CPRD prohibit the patient-level data to be publicly available. No additional data available.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2021-052759

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Strengths and limitations of this study

Our study provides more clarity to the occurrence and timing of key myeloma clinical features and use of diagnostic investigations prior to the diagnosis of multiple myeloma (MM).

Our study is the first attempt to provide key diagnostic information such as patient symptoms and laboratory testing on a large representative sample of patients who are newly diagnosed with MM in primary care over a 10-year period.

Demographic characteristics, comorbidities, symptoms, clinical events, drug exposures and laboratory investigation definitions have been validated during a reproducibility study and published separately.

This study relies on the quality and completeness of data collected in the Clinical Practice Research Datalink database.

In this study, medications, investigations or events occurring typically within the hospital settings may be under-reported.

Introduction

Multiple myeloma (MM) is the second most common haematological malignancy in Europe, with an estimated age-standardised incidence of 9.6 per 100 000 people in the UK for the year 2017, projected to increase to 12 per 100 000 people by 2035. 1 2 The UK-based Haematological Malignancy Research Network (HMRN) raised awareness on potential diagnostic delays in primary care, recognising non-specific symptomatology as a main barrier to MM diagnosis. 3 4 Patients with myeloma have one of the longest time-to-diagnosis intervals among cancers, with an average time between symptom onset and MM diagnosis of 99 days. 5 6 Compared with patients with other cancers, they also have the most repeated consultations occurring in primary care before referral to a specialist, with 50% experiencing three or more repeat consultations. 7 While 57% of patients are ultimately diagnosed through general practitioner (GP) referral, timely recognition and diagnosis of MM are challenging; 8 patients typically present to their GPs or family physicians with a myriad of non-specific symptoms such as bone pain or aches occurring at multiple sites, and fatigue. 9 Because the average age of MM presentation is 70 years, 10 these clinical signs may be overlooked as gradual ageing. Furthermore, the average primary care physician in an individual clinical practice may see fewer than ten patients with MM throughout their career given the rare cancer status of MM.

Despite the presentation of non-specific symptoms, MM causes disabling complications including skeletal-related conditions (destructive lytic lesions, osteoporosis and hypercalcaemia, skeletal-related events (SREs)), renal impairment, infection, neurological complications and anaemia. 9 11 12 The 1-year survival of patients diagnosed through GP referral or emergency presentation after MM diagnosis was 70% and 42%, respectively. 13 Early detection is a high priority for patients and improves survival; 84% of patients with myeloma survive for >5 years if diagnosed at the earliest stage, compared with only 26% if diagnosed at advanced stage. 14 Early diagnosis and subsequent management of myeloma improve patients’ quality of life and reduce symptom burden and serious complications of the disease. 15 The International Myeloma Working Group (IMWG) recommends a series of laboratory and imaging investigations to evaluate patients with a suspected diagnosis of MM, namely diagnostic imaging and blood tests to assess the CRAB (hyperCalcaemia, Renal impairment, Anaemia, Bone lesions) diagnostic criteria for MM. 8 In the primary care setting, access to laboratory testing (eg, haemoglobin, calcium levels, kidney function, paraprotein and light chains) is readily available and diagnostic testing can identify underlying cause of clinical features following evidence gained through the physical examination (signs and symptoms). The presence of bone pain in combination with laboratory abnormalities, such as anaemia, hypercalcaemia or unexplained renal impairment, have a high diagnostic certainty for MM. 16

The extent to which these common clinical features have been used to diagnose MM in the primary care setting has not been widely investigated. Most existing studies on MM have represented a population with more advanced disease in clinical secondary care settings. 9 As the first point of contact for patients, primary care practices provide an opportunity to investigate patients presenting with clinical features underlying MM and direct the diagnostic pathway for patients with suspected MM. In our study, we used primary care electronic medical records (EMRs) to characterise early clinical features of patients newly diagnosed with MM in the UK and describe investigations for the diagnostic CRAB criteria undergone by patients prior to MM diagnosis.

Study design and data source

This study was a population-based cohort study of newly diagnosed MM (NDMM) patients using the UK Clinical Practice Research Datalink (CPRD) GOLD database. The CPRD is based on standardised EMR systems in UK primary care. 17 The database contains routinely collected GP data from patients registered in over 600 primary care practices. The geographical distribution of GP practices has been shown to be representative of the UK and the patients are broadly representative of the UK general population in terms of age and sex distributions as reported by the national population census. 18

Study population

The study population included NDMM patients over the age of 18 at diagnosis who were registered with GP practices across the UK and contributed to the CPRD database. Patients who were continuously registered with GP practices during a minimum 2-year baseline period prior to (and not including) the MM diagnosis date (index date) were included in the cohort on their first record of MM diagnosis between 1 January 2006 and 31 December 2016. Patients were eligible for inclusion if their record was labelled as acceptable by CPRD quality control. Patients were excluded if they had one or more record of a solid tumour (including skin cancer) diagnosis during any time prior to (and including) the index date to avoid the inclusion of patients experiencing bone pain due to metastases of their tumour to the bone. Figure 1 presents the study design diagram. 19

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Study design. The study design diagram visually displays study design implementation. The vertical line represents the cohort entry date (index date), which is the first-order temporal anchor. The boxes represent second-order temporal anchors (time windows). The brackets in the boxes show time intervals anchored on day 0. Dx, diagnosis; EXCL, exclusion; MM, multiple myeloma.

Defining MM and clinical features

Primary care Read codes were used to identify MM diagnosis, comorbidities, bone pain and SREs from clinical and referral records. 20 Product codes were used to identify prescribed medications. Laboratory investigations and confirmation of the CRAB criteria, including serum calcium, haemoglobin and creatine level, were identified using Read codes from clinical and referral records and Entity type from Test records. Investigation and confirmation of bone lesions was identified through Read codes from clinical and referral records, Entity type and Medcodes from Test records ( figure 2 ). Testing of interest included haemoglobin level, blood calcium level, serum creatinine level and diagnostic imaging (bone scan, CT scan, MRI scan, positron emission tomography scan and any X-ray). Reasons for imaging procedures were not available and patients may have received those for reasons not related to the CRAB criteria work-up. Details and lists of Read code have been previously described. 21

CRAB criteria for multiple myeloma investigation and confirmation. *Plain radiographs coded as a record of X-ray; other imaging studies coded as a record of bone scan or CT scan or MRI or positron emission tomography scan; diagnostic imaging investigations.

Symptoms of MM, including bone pain and SREs prior to diagnosis, and clinical features of the CRAB criteria during the baseline period were retrieved.

Statistical analysis

Patients were described in terms of demographic characteristics at baseline, prevalent comorbidities, clinical features and symptoms. Prescribed medications related to bone health and pain management including bisphosphonates, considered standard of care for bone disease, were also described. 22 Summary statistics included frequencies (%) for categorical variables and mean (SD) and median (Q1, Q3) for continuous variables such as time of the diagnostic interval from first recorded bone pain, SRE and CRAB investigations. Time of symptom presentation or relevant diagnostic CRAB criteria to the diagnosis of MM were also evaluated. Results were stratified by the presence of a record for bone pain and/or SRE at baseline (symptomatic) or absence of bone pain and/or SRE at baseline (asymptomatic).

All analyses were conducted using the Aetion Evidence Platform (V.3.12), a rapid-cycle analytic tool which has been validated in a range of studies and therapeutic areas including oncology. 23

Patient and public involvement

Although, there has been no specific patient or public involvement (contact) in this retrospective database study, CPRD works diligently and independently with contributing practices to ensure patients are aware of how their anonymised data are used and of their right to opt out of their data being shared for research ( https://www.cprd.com/public ).

At the time of analysis, the CPRD database contained 17 756 119 patients. Among 4823 patients with NDMM, 2177 patients were excluded for not meeting the eligibility criteria, leading to a total of 2646 NDMM patients between 2006 and 2016 included in our analysis ( online supplemental figure S1 ). Among all patients with NDMM, the median (Q1, Q3) age was 71 (63, 79) years and 54.7% were men. On average, patients were observable in the CPRD database for 11.5 years prior to their initial MM diagnosis and for 2.7 years post MM diagnosis. Overall, 43.8% of patients with NDMM had at least one musculoskeletal comorbid condition (29.2% with osteoarthritis and 10.8% with osteoporosis); 45.0% of all patients had hypertension, 21.2% chronic kidney disease, 20.2% cardiovascular disease.

Supplemental material

Figure 3 shows the baseline demographic and clinical characteristics of the NDMM patients by the presence (symptomatic) or absence (asymptomatic) of bone pain/SREs at baseline. Musculoskeletal comorbidities were observed among symptomatic patients and asymptomatic patients, including osteopenia (6.2% and 4.7%), osteoporosis (14.8% and 7.0%) and osteoarthritis (32.8% and 25.7%), respectively. Both symptomatic and asymptomatic patients frequently received analgesics during baseline, including non-opioid analgesics (88.1% and 62.4%, respectively), weak opioid (73.4% and 40.9%) and strong opioid use (41.8% and 14.6%). A prescription for bisphosphonates was observed for 17.3% of symptomatic patients during baseline ( online supplemental table S1 ). Among a subgroup of 361 patients with NDMM and a prescription of oral bisphosphonates in the 2 years prior to MM diagnosis, 62.3% (n=225) had a record of bone pain or SRE and 37.7% (n=136) did not.

Baseline clinical characteristics and CRAB-related presentation prior to multiple myeloma (MM) diagnosis among patients with symptomatic and asymptomatic MM. Percentage of patients for each characteristic is shown among symptomatic patients with bone pain and/or SRE (red bars) and asymptomatic patients without bone pain and/or SRE (orange bars). For CRAB diagnostic investigations, the percentages of patients tested for hypercalcaemia, renal impairment, anaemia and bone lesions are shown for symptomatic patients (red bars) and asymptomatic patients (orange bars). Percentages of patients with confirmation are shown for symptomatic (pink bars) and asymptomatic patients (light orange bars). CRAB criteria investigations and confirmations prior to MM diagnosis between 2006 and 2016. A maximum of 2 years minus 90 days before (and not including) the MM index date was used. Patients were required to be continuously enrolled throughout each time window to be included into these subgroups. CRAB, hyperCalcaemia, Renal impairment, Anaemia, Bone lesions; NDMM, newly diagnosed MM; SRE, skeletal-related event.

Combination of CRAB investigations for hypercalcaemia, renal impairment, anaemia and diagnostic imaging for bone lesion. The frequency of CRAB criteria testing was assessed in the 12 months prior to and not including the cohort entry date. The testing includes laboratory tests only; total tests measure the number of patients who had the specific test or combination of tests, alone or with additional tests. CRAB investigation categories are not mutually exclusive. Patients included in each category were required to have, at minimum, the tests indicated by the black circles; they may or may not have had the tests indicated by the white circles. CRAB, hyperCalcaemia, Renal impairment, Anaemia, Bone lesions.

Clinical features and CRAB investigation

Overall, 49.1% of the patients with NDMM were symptomatic with either bone pain and/or SRE during baseline. Among patients with NDMM, 47.5% of patients had a baseline bone pain record, mainly affecting the back (33.7%) or other joints (17.3%). Only 4.8% of patients with NDMM had a record of an SRE, mostly captured as pathological fracture (3.7%). Records of spinal cord compression and surgery to bone were rare (<1%) ( online supplemental table S2 ). An imaging investigation or referral for an imaging investigation was recorded for 60.0% of symptomatic bone pain/SRE and 31.7% of asymptomatic patients. Among NDMM patients who had an imaging investigation, 19.0% had an MRI and 22.1% had a CT scan ( online supplemental table S3 ). Confirmed bone lesions were recorded in 8.1% of symptomatic patients and 2.2% of asymptomatic patients ( online supplemental table S4 ).

During the baseline period, most patients with NDMM received a laboratory investigation for renal impairment (approximately 74%) or anaemia (approximately 65%), regardless of being symptomatic or asymptomatic ( figure 3 , online supplemental table S4 ). Confirmation of hypercalcaemia was infrequently observed prior to MM diagnosis regardless of the presence or absence of bone pain/SRE ( figure 3 , online supplemental table S4 ). The proportion of patients who met any one of the CRAB criteria was 0.8% and 0.7% for hypercalcaemia, 3.4% and 7.3% for renal impairment, 11.9% and 15.6% for anaemia among symptomatic and asymptomatic patients, respectively ( online supplemental table S4 ).

During the 12 months prior to MM diagnosis, the proportion of CRAB-related diagnostic test combinations received by patients were 75.7% for renal impairment and anaemia, 50.4% for hypercalcaemia and renal impairment, 50.2% for hypercalcaemia and anaemia, and 48.9% for hypercalcaemia, renal impairment and anaemia. Only 18.9% of all patients with NDMM underwent investigations for all four CRAB criteria ( figure 4 , online supplemental table S5 ). We observed complete CRAB criteria testing with all four components in 26.7% of symptomatic patients and 11.5% of asymptomatic patients ( online supplemental table S5 ).

Timing of clinical features and CRAB investigation

Among all patients with NDMM, the median time (Q1, Q3) between MM diagnosis and the initial laboratory diagnostic workup to ascertain renal impairment or anaemia were 488 (203, 626) and 380 (95, 594) days, respectively. We observed a 6-month interval between MM diagnosis and the initial investigation for hypercalcaemia (median (Q1, Q3) of 176 (44, 507) days) ( online supplemental table S6 ). The median time (Q1, Q3) between date of ascertainment of renal impairment or anaemia (via the first record of a confirmed abnormal test result) and date of MM diagnosis were 58 (17, 254) and 73 (28, 232) days, respectively. The median (Q1, Q3) diagnostic interval between a confirmed hypercalcaemia and the MM diagnosis was only 23 (12, 46) days ( figure 5 , online supplemental table S7 ).

Timing of clinical CRAB (hyperCalcaemia, Renal impairment, Anaemia, Bone lesions) criteria between confirmation to diagnosis of MM. The timing and event occurrence were measured during baseline period, 730 days to 1 day prior to the MM diagnosis date; the time periods were counted starting from the first ever laboratory investigation or diagnosis during the 730 days prior to and including the cohort entry date. MM, multiple myeloma.

Overall, we observed a 6-month interval between the initial investigation for bone lesion (median (Q1, Q3) of 195 (59, 452) days) and MM diagnosis ( online supplemental table S6 ), and a median (Q1, Q3) diagnostic interval of 105 (30, 346) days between confirmed imaging results for bone lesions and the MM diagnosis. Among symptomatic patients, the median (Q1, Q3) time from the initial bone pain record to MM diagnosis was 220 (80, 476) days. The median (Q1, Q3) time from bone pain to investigations with bone X-ray, MRI scan, bone scans or CT scan was 34 (8, 175) days, 93 (38, 256) days, 112 (44, 259) and 181 (58, 406) days, respectively ( online supplemental table S8 ).

This population-based cohort study using real-world data revealed that nearly half of 2646 patients with NDMM had a record of symptomatic bone pain, approximately 7 months prior to MM diagnosis in primary care. Approximately 71% of symptomatic patients presented with back pain. Diagnostic intervals (ie, the time from investigation to MM diagnosis) ranged from 6 months to over 12 months among both symptomatic and asymptomatic patients. Abnormal laboratory results for the CRAB criteria were observed closer to MM diagnosis time, with a median time of 1–2 months. Investigations for hypercalcaemia were uncommon in patients presenting with bone pain, and diagnostic tests to identify CRAB criteria were underused. Among symptomatic patients (with bone pain/SRE), advanced bone imaging investigation recommended by IMWG and National Institute for Health and Care Excellence (NICE) 24 with MRI or CT scan was limited; 20% of symptomatic patients had a record of MRI or CT imaging.

Strengths and limitations

The main strength of our study is that it fills the knowledge gap about key clinical features and diagnostic timing leading up to the diagnosis of myeloma in a primary care setting by providing a comprehensive picture for both symptomatic and asymptomatic patients. Our study is based on electronic health records data from a large representative sample of the UK population registered with GPs in the primary care setting with a wide geographic coverage. 16 Over a 10-year study period, our study captured a large number of newly diagnosed patients with MM. Additionally, to minimise misclassification, a group of clinical experts and epidemiologists developed algorithms to identify conditions of interest. We also investigated the frequency of bone pain recording on an annual basis over the study period and found consistency in recording of the symptom across the different years.

The study also has some limitations. First, since our study relies on recorded diagnoses in electronic health records, conditions or comorbidities not reported to the GPs might not be captured. Similarly, CPRD data are collected at the time of GP clinical care and not for research purposes; therefore, the completeness of medical information from specialists and inpatient care, is not known. Our study only focused on the CRAB diagnostic criteria and did not investigate other relevant tests such as protein electrophoresis, Bence-Jones protein urine test, serum free light chain test or erythrocyte sedimentation rate, which may also be conducted to assess myeloma. In addition, plain radiographs and other imaging studies were part of the CRAB criteria for bone lesions; however, patients may have received a chest X-ray for other reasons not related to the CRAB criteria work-up. Reasons for imaging procedures were not available and patients may have received those for reasons not related to the CRAB criteria work-up. Finally, the study only looked at bone pain in the 2 years prior to diagnosis and patients may have had bone pain prior to the start of the baseline assessment period.

Comparison with existing literature

Previous studies have reported that most patients with MM complained about their bone pain at presentation. In a comprehensive review of the literature, Nador et al showed that 59% of patients with MM presented with bone pain. 11 Goldschmidt et al conducted an analysis using EMRs and Israeli Health Maintenance Organization data and reported that back pain was the most common complaint during the 2 years before MM diagnosis. 25 In our study, the frequency of bone pain recorded in primary care was consistent with these studies despite differences in geographic region and data source. As previous studies highlighted, findings about diagnostic delays in MM can vary from one study to another due to differences in data sources, data collection methods, study design and study periods. For example, Howell et al , used data from the UK-based HMRN, and estimated that the total interval between time to help-seeking (self-reported symptoms) was 163 days. 4 In a systematic review and meta-analysis of seven studies, Koshiaris et al reported that the median diagnostic interval between first presentation to primary care and MM diagnosis was approximately 109 days. 26 Our observational findings support substantial delays between recorded symptoms and MM diagnosis in a primary care setting. However, there is considerable heterogeneity in symptoms (patient-reported vs predefined symptoms) and time periods reported in previous studies, 26 which makes comparing findings across studies difficult. 4

Clinical and policy implications

The current pathway to diagnosing myeloma is recognised as being complex, with multiple GP appointments and significant delay before diagnosis. There is limited evidence regarding the clinical scenarios in which MM should be suspected. 13 16 Our study provides more clarity on the occurrence and timing of key clinical features and diagnostic investigations leading to the diagnosis of MM.

Our findings suggest that GPs could have significant input in improving the time to diagnosis of MM. The first National Audit of Cancer Diagnosis in Primary Care collected data on primary care referrals submitted voluntarily by GPs on their patients diagnosed with cancer in England. This audit showed avoidable delays in 27% of patients with MM receiving their diagnosis in primary care in England. 5 During the COVID-19 pandemic, there have been additional delays in myeloma diagnosis due to markedly reduced CT and MRI imaging, longer waiting times for investigations, and a fall in urgent cancer referrals. 27 28 At the end of September 2020, there were a total of 215 463 patients waiting for a diagnostic MRI, and the number of patients waiting 6 weeks or more for an MRI increased by 20% compared with September 2019. 29 30 Further research is warranted to quantify the impact of delays in MM diagnosis and treatment on patient quality of life and outcomes.

To reduce delays in diagnosing of MM in the primary care, there is a need for improved diagnostic safety netting, that is, the process of managing diagnostic uncertainty during the GP consultation and communicating to patients when and how to follow-up on potential symptoms. 31 Various stages of the pathway to MM diagnosis would benefit from tailored safety nets to manage diagnosis uncertainty and timely evaluation. Reflecting on insights from our study and other published studies, we propose a plethora of actions in different settings to be undertaken by both the patient and the GPs, using the action, actor, context, target, time framework ( figure 6 ). 32

Proposed action, actor, context, target, time specification to improve diagnosis of multiple myeloma (MM) (adapted from Presseau et al ). 32 CRAB, hyperCalcaemia, Renal impairment, Anaemia, Bone lesions; GP, general practitioner.

One aspect of safety netting is to provide advice on potential red-flag symptoms and on accessing further medical care. Targeted awareness campaigns co-produced with patients and the public on the clinical features and symptom profiles of MM may help reduce delays in MM diagnosis in primary care. Tailored GP education programmes on MM diagnosis through their regular channels would be an enabler for early diagnosis. Back pain combined with other symptoms such as fatigue and weight loss, or back pain combined with abnormal blood tests warrant definitive investigation for MM. 33 34 Such focused approach may be more impactful to address the delays in seeking help, representation and diagnosis. Such delays, with myeloma patients taking half a month to 7 months from initial symptom/health change to first seeking help, were recently reported. 35

In the case of patients without bone pain and/or SRE (asymptomatic), further research is required ( figure 6 ) 36 to identify biomarkers/precursors of MM, and to help identify those who may benefit from early screening haematological investigations. For example, Koshiaris et al used CPRD data to develop a prediction tool based on patient characteristics, symptoms and blood tests to identify patients at risk of MM in primary care. 37 Patients with monoclonal gammopathy of unknown significance (MGUS), however, were excluded from the analysis. Since premalignant plasma cell disorders such as MGUS often precedes MM, research is currently underway to monitor MGUS in community or secondary care, identify biomarkers and better predict patients who progress from MGUS to myeloma.

Another aspect of safety netting includes the follow-up and management of investigations. Improved access to diagnostic facilities may enable GPs to request timely laboratory and advanced imaging investigations, thereby accelerating the time to MM diagnosis. There is already a call for one stop shop diagnostic services directly within the community, closer to patients’ homes. 38 39 This cross-collaboration aligns with efforts across the UK, as outlined in the National Health Service Long Term Plan, to focus on a radical overhaul of services for the diagnosis of suspected cancer, including the introduction of Rapid Diagnostic Centres, and the organisation of imaging networks with better access to MRI and CT scanners. 40 41

Early recognition of red-flag symptoms and self or GP referral to these diagnostic services with rapid turnaround time for results will result in early diagnosis and prompt treatment. Further research, in close partnership with the patient, their support networks and the public, is required on the development, implementation and effectiveness of these potential safety netting. 42

Nearly half of patients with NDMM presented with a bone pain symptom in primary care, approximately 7 months prior to MM diagnosis. Diagnostic tests to explore evidence of the CRAB criteria were underused. Investigations for hypercalcaemia and advanced imaging were not frequent in patients presenting with bone pain. Increased awareness of clinical features of MM, including its early presentation as bone pain, may lead to early recognition and testing of MM in primary care, thereby potentially accelerating disease diagnosis and timely medical care.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

The research protocol was reviewed and approved by the Independent Scientific Advisory Committee (reference ISAC, protocol No 18_292). In this study, all data were completely anonymised and no participant’s consent was required.

Acknowledgments

We wish the acknowledge Edwin Hoeben, George Kafatos, Joe Maskell, Shannon Reynolds and Andrew Weckstein for their contribution to the research project and Pattra Mattox, CMPP, Aetion, for her editorial assistance to the manuscript. We also acknowledge Dr William Murk, J L Novosad and Aditya Rajan for their contribution to the data visualisations. The authors thank the peer-reviewers for their helpful comments on an earlier version of the manuscript.

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Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Data supplement 1

Contributors AS, NP-I, VLB, DN made substantial contributions to the design of the work. NP-I, VLB and JRW contributed to the analysis of the data. AS, NP-I, JRW, AA and KR contributed to the interpretation of data. AS, NP-I, AA drafted the work; AS, NP-I, VLB, JRW, AA, DN and KR made substantial contributions to substantively revise the manuscript. All authors provided final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. AS is the guarantor and accepts full responsibility for the work and/or the conduct of the study, had access to the data and controlled the decision to publish.

Funding This work was supported by Amgen. Award/Grant number is not applicable.

Competing interests AS and DN are employees of and hold stock options in Amgen. AA is a contract worker at Amgen. During the study conduct and reporting, VLB was a contract worker for Amgen. NP-I and JRW were employees of Aetion at the time the study was conduct and reporting and hold equity in Aetion. KR reports honoraria, research grant and advisory board from Janssen, Celgene, Takeda and Amgen.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Patient Presentation

Differential diagnosis, examination.

Investigations

Final Outcome

Evaluation - Questions & answers

A 59 year old male presents to the medical out patient department with a one month history of progressively increasing fatigue and backache.

Acknowledgement

This case study was kindly provided by Dr Monica Mercer, MBChB from Immunopaedia

For the last month the patient has been feeling exhausted for no apparent reason and due to this extreme tiredness, is finding it difficult to work and look after himself. He comes home in the late afternoon often too tired to eat and goes straight to bed; a change from his former energetic lifestyle.

He has also been complaining of some backache which he treats with over the counter analgesics and he has been suffering from more colds and flu then usual over the last year.

He has also found that for the last 6 months there has been a decline in his ability to speak clearly. His tongue has enlarged and become firm which makes moving it for speech formation and eating solid foods difficult and at times painful.

He has had an unintentional weight loss of ± 15kg in the last 6 months.

Past medical history

Previously well, no chronic disease, no previous admissions.

Past surgical history

No history of any surgical procedures.

Family History

Father died of a myocardial infarction at age 63 yrs with hypercholesterolaemia.
Mother has hypertension on treatment and reports good control.
No positive family history for any other chronic diseases including diabetes and cancer.

Social history

Lives alone in a town house.
Employed as an accountant.
30 year history of smoking.
Significant alcohol history for 12 years, now in recovery for the last 5 years.
Vitamin B12/folate deficiency
Heart failure

Multiple myeloma

Monoclonal gammopathy of undetermined significance (MGUS)
Waldenstrom’s macroglobulinaemia
Ill looking, pale and underweight middle-aged gentleman
Awake and alert, able to give an accurate history
Significant dysarthria for the last 3 months, making him difficult to understand.
Blood pressure 100/68
Heart rate 84
Respiratory rate 18
Mild pallor
No lymphadenopathy
No signs of dehydration
No jaundice
No stigmata of HIV
Tongue red and enlarged with deep imprints from the teeth on both sides of the tongue. Very reduced mobility; unable to protrude or lift up and very limited sideways movement.

Respiratory

Trachea centrally located.
Chest clear on auscultation.

Cardiovascular

No raised JVP
Normally placed apex beat
S1 and S2 heart sounds present, no murmurs.
No abnormalities detected
Not distended
Soft and non tender
Bowel sounds present

Neurological

Higher function intact, although difficult to understand
Gait normal
Power 5/5 globally
Tone normal globally
Reflexes 2/4 for both upper and lower limbs

Dermatological/Haematlogical

Some small bruises on arms and legs of various ages
No petaechial bleeds

This case study looks at a disease caused by the accumulation of neoplastic plasma B cells in bone marrow, which produce a monoclonal immunoglobulin protein found in the serum or urine. In serum, this is called an M protein or paraprotein. In urine, Bence-Jones proteins can be found which are specifically immunoglobulin light chains. We will examine the immunological basis of multiple myeloma, which is marked by upregulation of osteoclast activity due to overexpression of cytokines, causing lytic bone lesions. Multiple myeloma occurs in both men and women, but more common in men and manifests from age 40 with a peak at 60 years.

In this discussion we will look at the destructive disease process which symbolises multiple myeloma with the aid of our full colour graphics.

Collectively, the genetic aberrations commonly found include:

Translocation of immunoglobulin heavy chain coding regions onto other chromosomes located near proto-oncogenes (c-myc, n-myc and MAF) or cell- proliferation proteins (cyclin D, FGFR3 , MMSET).
Duplication of chromosomes (3, 5, 7, 9 11 and 21) or loss of chromosomes (13).
Mutations in oncoproteins ( N-ras and K-ras ) or in tumour suppressor genes (p53).

Myeloma plasma B cells constitutively produce monoclonal immunoglobulins resulting in a gammopathy, which can cause amyloidosis due to deposition of excess insoluble proteins. Common sites for this include the tongue, kidneys and heart, as in this presenting case.

Adhesion of myeloma plasma B cells to bone marrow stromal cells

Myeloma plasma B cells migrate to the bone marrow. This homing is regulated by the chemokine stromal cell derived factor-alpha (SDF-1α) binding to the CXCR4 receptor, expressed on the myeloma plasma B cell . The myeloma plasma B cells also express cellular adhesion molecules, which interact with bone marrow stromal cell ligand . This interaction maintains myeloma B cells in an anti-apoptotic state and unresponsive to chemotherapeutic drugs.

The accompanying bone disease is characterised by the presence of lytic bone lesions that result from an imbalance of bone formation , mediated by osteoblasts, and bone resorption, mediated by osteoclasts, which together remodel the bone microenvironment.

Clinical markers of multiple myeloma

The process of bone resorption creates lytic bone lesions, which liberates calcium phosphates from the mineral bone matrix. This is measurable as hypercalcaemia and hyperphosphataemia in the peripheral blood, as observed in our patient. Lytic bone lesions are visible on X-rays and most often seen on chest X-rays when examining the ribs as well as the skull (where the lesions are seen as a pepper pot skull). The increased number of plasma B cells in bone marrow can be identified from a bone marrow biopsy and are usually present at greater than 10% of the total cells: indicating a neoplastic condition. To confirm the diagnosis, multiple myeloma plasma B cells can be phenotypically characterized as CD38 , CD138 and CD56 positive and negative for CD19 , CD20 and CD21 expression. Genetic analysis to identify abnormal translocations, loss or duplication of chromosomes or mutations can also be used to confirm the diagnosis.

Since this is a disease of post-germinal centre B cells which implies that the B cells have isotype-switched, the gammopathy usually involves IgG (most common), IgA and IgE monoclonal antibodies and rarely IgD and IgM. In this case study, a rare IgM gammopathy indicates the absence of a class switch following post-germinal activation. We can speculate that the formation of a myeloma plasma B cell phenotype was associated with incomplete heavy chain class switching or may have resulted from aberrant light chain recombination and/or affinity maturation.

Download images for this case

Multiple myeloma.

On admission patient was transfused with three units of packed red cells to correct the anaemia.
Zoledronic acid (Zometa) was given to control the hypercalcaemia and protect the patient from other skeletal events such as spinal cord compression and pathologic fractures.
Patient was treated with Decadron 20 mg IV daily ( dexamethasone )
Patient was rehydrated and treated with IV fluids in an attempt to improve her renal function before administration of chemotherapy.
Plan was to give patient chemotherapy- VAD ( vincristine , doxorubicin [Adriamycin], and dexamethasone) to decrease the tumor burden in multiple myeloma. This is typically used in preparation for autologous stem cell transplantation. VAD is administered as a 4-day continuous intravenous infusion of vincristine and doxorubicin, with 4 daily oral doses of dexamethasone. Patients require a central venous catheter for delivery of the infusion. In selected patients, this therapy can be performed in an outpatient setting.
Although not administered in this patient Thalidomide is a treatment of choice for multiple myeloma patients.

The patient developed renal failure, which remained refractory to treatment. He also developed a cardiac myopathy due to cardiac amyloidosis and died two days later from cardiac failure.

Vallet S et al. (2010). “Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease.” Proceedings of National Academy of Science USA, 1 March

Link to Abstract Edwards CM et al. (2008). “The pathogenesis of the bone disease of multiple myeloma.” Bone Jun:42(6):1007-13

Link to Abstract Roodman GD. (2009). “Pathogenesis of myeloma bone disease.” Leukemia Mar:23(3):435-411

Link to Abstract

Hideshima T et al. (2007). “Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets.” Nat Rev Cancer 7(8):585-98

Evaluation – Questions & answers

What is the diagnosis?

What is the cause of macroglossia in this patient?

What else is linked to the above condition?

Which cell-type becomes neoplastic and is implicated in multiple myeloma?

What types of genetic aberrations occur in multiple myeloma?

translocation of immunoglobulin heavy chain coding regions onto other chromosomes located near oncogenes or cell-proliferation proteins
duplication or loss of chromosomes
mutations in oncogenes or in tumour-suppressor genes.

Multiple Choice Questions

Earn 1 hpcsa or 0.25 sacnasp cpd points – online quiz.

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License .

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Multiple myeloma--a case-control study

Affiliation.

1 Department of Mathematics, Statistics and Epidemiology, Imperial Cancer Research Fund, London, UK.
PMID: 3395559
PMCID: PMC2246387
DOI: 10.1038/bjc.1988.118

A total of 399 patients with multiple myeloma and an equal number of match controls were interviewed about factors possibly related to the causes of their disease. Factors studied included occupation, chemical exposure, radiation exposure, prior diseases, immunizations, chronic infections and markers for defects in immune regulation. A strong risk associated with agriculture/food processing was observed (RR = 1.8, P = 0.002). The risk could not be restricted to those exposed to animals or meat products, or those exposed to pesticides. Significant excesses were also noted for reported exposures to chemicals and gases/fumes, but no specific agent or group of agents could be identified. Cases had fewer tonsillectomies above the age of 10 (P = 0.01). A large excess of shingles (herpes zoster) was observed in cases (P less than 0.001), but most of the excess cases occurred within 10 years of diagnosis, suggesting this was a preclinical manifestation of disease rather than a cause of it.

Age Factors
Agriculture
Food-Processing Industry
Herpes Zoster / complications
Middle Aged
Multiple Myeloma / etiology*
Occupational Diseases / etiology
Risk Factors
Tonsillectomy
Virus Diseases / complications

IMAGES

Multiple Myeloma
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Case Study Multiple Myeloma -1.docx
(PDF) MULTIPLE MYELOMA PRESENTING AS ORAL CAVITY LESION
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COMMENTS

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Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma
Daratumumab‑resistant multiple myeloma with extramedullary disease successfully treated with combination elotuzumab, pomalidomide and dexamethasone: A case report, Oncology Letters, 27, 6, (2024 ...
Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple
Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with direct on-tumor 5-8 and immunomodulatory 9-11 mechanisms of action. Daratumumab has been approved for use in combination with ...
Multiple Myeloma: 2022 update on Diagnosis, Risk-stratification and
DISEASE OVERVIEW. Multiple myeloma accounts for 1% of all cancers and approximately 10% of all hematologic malignancies. 1,2 Each year over 32,000 new cases are diagnosed in the United States, and almost 13,000 patients die of the disease. 3 The annual age-adjusted incidence in the United States has remained stable for decades at approximately 4 per 100,000. 4 Multiple myeloma is slightly more ...
Multiple myeloma-associated light chain amyloidosis... : Medicine: Case
How to cite this article: Lee IH, Kim CY, Kang S, Ahn DJ, Kim MK. Multiple myeloma-associated light chain amyloidosis involving heart, kidneys, and peripheral nerves: a case report. Med Case Rep Study Protoc. 2021;2:8(e0128). Informed written consent was obtained from the patient for publication of this case report. This study was approved by ...
Tecvayli Produces Promising Results in Multiple Myeloma
The MajesTEC-1 trial enrolled 165 adults with relapsed or refractory multiple myeloma who had previously been treated with at least three types of drugs commonly used to treat multiple myeloma. Half of the study participants had received five previous lines of therapy, and 82% had a previous stem cell transplant.
A multidisciplinary case report of multiple myeloma with renal and
Multiple myeloma (MM) is a malignant neoplasm associated with kidney involvement in nearly half of the patients. Cast nephropathy, monoclonal immunoglobulin deposition disease (MIDD), and light chain (AL) amyloidosis are the most common monoclonal immunoglobulin-mediated causes of renal injury. Cardiac involvement is also present in MM, characterized by restrictive cardiomyopathy generated by ...
Patient Case Studies and Panel Discussion: Plasma Cell Neoplasms
Patient Case Study 2: Active Multiple Myeloma. In the second case study, a 53-year-old man presented with persistent swelling and pain around the left shoulder for several months. A small mass was detected on his left clavicle on physical examination. Medical history showed hypertension, schizoaffective disorder, and chronic hepatitis B, and a ...
Early-onset multiple myeloma: an illustrative case report
Objective: This case study describes a patient diagnosed with early manifestations of multiple myeloma and illustrates relevant aspects of differential diagnosis and the use of laboratory, radiologic, and advanced imaging techniques to aid in establishing the diagnosis and issues of management. Clinical features: A 36-year-old male student experienced midback pain that occurred primarily at ...
Case Study: Supportive Care in Multiple Myeloma
Of note, denosumab is also significantly more expensive with a severalfold difference in price. Case study submitted by Arun Singavi, MD, of Medical College of Wisconsin, Milwaukee, Wisconsin. Resources. Snowden JA, Ahmedzai SH, Ashcroft J, et al. Guidelines for supportive care in multiple myeloma 2011. Br J Haematol. 2011;154:76-103.
CAR T therapies in multiple myeloma: unleashing the future
The ongoing clinical trial CARTITUDE-1 (NCT03548207) investigates the use of cilta-cel in patients with multiple myeloma who have received multiple prior therapies. This study served as the basis ...
Multiple Myeloma
The patient's condition became rapidly worse, and on the basis of his clinical picture and roentgen studies the diagnosis of multiple myeloma was established. He died 1 week later on July 26, 1944 ...
A case study progression to multiple myeloma
Abstract. Multiple myeloma consistently is preceded by precursor states, which often are diagnosed incidentally in the laboratory. This case report illustrates the clinical dilemma of progression from precursor to full malignancy. The article also discusses future directions in management and research focusing on myelomagenesis.
Case Presentation: A 74-Year-Old Woman with Relapsed/Refractory
Sagar Lonial, MD: Let's start this next discussion with another case. Dr Joseph? Nisha Joseph, MD: This is a 74-year-old woman who initially presented with anemia and hypercalcemia after presenting to a primary care physician with acute onset severe rib pain after sneezing. She was subsequently diagnosed with IgG kappa myeloma. Her marrow showed 30% to 40% clonal plasma cells, FISH ...
Lung Involvement in Multiple Myeloma
Pulmonary parenchyma is an uncommon site of extramedullary involvement in multiple myeloma; only isolated cases with histological proofs have been reported in the literature. One study described 13 cases with lung involvement of multiple myeloma, of which six had pneumonia, two had mass lesions, two had multiple nodular lesions, and three had ...
Clinical features and diagnosis of multiple myeloma: a population-based
Objectives Patients with multiple myeloma (MM) experience significant delays in diagnosis due to non-specific symptomatology. The aim of this study was to characterise the frequency and timing of clinical features in the primary care setting prior to MM diagnosis. Design Population-based cohort study. Setting Electronic health records data of approximately 17 million patients (2006-2016 ...
PDF International Myeloma Foundation
International Myeloma Foundation | IMF |Multiple Myeloma Information
Early detection of multiple myeloma in primary care using blood tests
Background Multiple myeloma is a haematological cancer characterised by numerous non-specific symptoms leading to diagnostic delay in a large proportion of patients. Aim To identify which blood tests are useful in suggesting or excluding a diagnosis of myeloma. Design and setting A matched case-control study set in UK primary care using routinely collected data from the Clinical Practice ...
Multiple myeloma Case Study
A 59 year old male presents to the medical out patient department with a one month history of progressively increasing fatigue and backache. Acknowledgement. This case study was kindly provided by Dr Monica Mercer, MBChB from Immunopaedia. History. For the last month the patient has been feeling exhausted for no apparent reason and due to this ...
Multiple myeloma--a case-control study
Multiple myeloma--a case-control study Br J Cancer. 1988 May;57(5):516-20. doi: 10.1038/bjc.1988.118. Authors J Cuzick 1 ... A total of 399 patients with multiple myeloma and an equal number of match controls were interviewed about factors possibly related to the causes of their disease. Factors studied included occupation, chemical exposure ...

Case Presentation: A 68-Year-Old Man With Multiple Myeloma

EP: 1 . Case Presentation: A 68-Year-Old Man With Multiple Myeloma

Teclistamab Shows Promise for People with Heavily Pretreated Multiple Myeloma

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Strong treatment responses, concerns about infection risk

Pros and cons of CAR T-cell therapy versus bispecific antibodies

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A multidisciplinary case report of multiple myeloma with renal and cardiac involvement: a look beyond amyloidosis

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Case Presentation: A 74-Year-Old Woman with Relapsed/Refractory Multiple Myeloma