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Therapeutic Strategies in Myeloma

CE / CME

Therapeutic Strategies in Multiple Myeloma: Overview of Current and Emerging Treatment Options

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Nurses: 1.00 Nursing contact hour

Released: April 26, 2023

Expiration: April 25, 2024

Shaji K. Kumar
Shaji K. Kumar, MD
CME/CE Information

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Natural History of MM

Once we have exhausted these classes of therapies, the important question becomes: How do we manage MM in patients whose disease has become refractory to these commonly used agents? This is where newer therapies, particularly immunotherapies, have played a major role.

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Current Approved Options for Patients After ≥4 Prior Therapies

The currently approved options for patients after ≥4 prior therapies include selinexor, idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), and teclistamab, with response rates ranging from 26% to 98%.110,111

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Immunotherapy Era in Multiple Myeloma

There are 2 CAR T cell therapies approved for MM, ide-cel and cilta-cel, both of which have been approved for management of relapsed disease after ≥4 prior lines of therapy, as well as the bispecific antibody teclistamab that also targets the same antigen—BCMA. There are many immunotherapies in clinical trials that include antibody-drug conjugates (ADCs) such as belantamab mafodotin, which was initially FDA approved but subsequently taken off the market in the US following the results of the confirmatory phase III trial. Hopefully, there will be other phase III trials that will show benefit from this drug. In addition to the BCMA targeted CAR T cell therapy and bispecific antibody teclistamab, we also have other targets that are being explored in the context of both these immunotherapy platforms.112-114

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Phase II DREAMM-2: Response and DoR at 13 Mo of Follow-up, Belantamab Mafodotin 2.5 mg/kg

The ADC belantamab mafodotin was initially approved based on results of the randomized phase II DREAMM-2 study evaluating 2 different doses. This showed that there is an approximately 30% response rate with the use of belantamab mafodotin in this highly refractory patient population. However, belantamab mafodotin was associated with significant ocular toxicity that limited its use.115

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KarMMa: Study Design and Patients

KarMMa is the pivotal trial that led to approval of ide cel. In this study, patients with ≥3 prior lines of therapy who were refractory to a PI, an IMID, and an anti-CD38 mAb had lymphocytes collected for CAR T-cell manufacturing and many underwent bridging therapy, as needed. The modified CAR T cells were then infused.

The primary endpoint of this study was ORR, with secondary endpoints including complete response rate, safety, duration of response (DoR), PFS, OS, PK, MRD, QoL, and health economics and outcomes research (HEOR).116,117

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KarMMa: Efficacy

The use of ide-cel resulted in responses of upwards of 70% in this heavily pretreated patient population and a PFS that is a little less than 1 year (8.6 months).117

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CARTITUDE-1: Study Design and Patients

Subsequently, we have data from the phase Ib/II CARTITUDE study that looked at cilta cel in patients with ≥3 prior lines of therapy who were refractory to a PI, an IMID, and an anti-CD38 mAb. The primary endpoints were safety and to confirm the recommended phase II dose (phase Ib) and efficacy in phase II.118-120

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CARTITUDE-1: 2 Yr Post Last Patient Efficacy Results

This study demonstrated response rates of over 90% in patients with heavily pretreated MM and a median PFS reaching close to 2 years, so, quite exciting data in terms of efficacy.119-121

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CARTITUDE-1: CRS and Neurotoxicity

These therapies, particularly CAR T cell therapies, result in specific toxicities in the form of cytokine release syndrome (CRS) and neurotoxicity. These should be carefully monitored for and managed in this patient population.116,122

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MajesTEC-1: Phase I/II Study of Teclistamab for R/R MM After ≥3 Previous Lines of Therapy

Teclistamab is a BCMA targeted bispecific antibody that has shown response rates of approximately 60% in a very heavily pretreated patient population.110 Teclistamab is currently approved for treatment of patients who have received ≥3 prior lines of therapy.

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MajesTEC-1: Survival Outcomes With Teclistamab for R/R MM After ≥3 Previous Lines of Therapy

The median PFS with teclistamab for R/R MM after ≥3 previous lines of therapy was close to 1 year (11.3 months).110

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MajesTEC-1: Cytokine-Release Syndrome

The toxicity profile of teclistamab demonstrates a high rate of CRS, though it is mostly grade 1, which can be easily managed. High rates of infections were observed in clinical trials and this needs to be carefully monitored. Neurotoxicity is relatively uncommon with teclistamab.110,123

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Can We Sequence BCMA-Targeted Therapies?

One outstanding question is whether we can sequence these different BCMA targeted therapies. There are limited data from some of the phase III trials. Cilta cel is associated with a high response rate even in patients who have previously seen anti BCMA therapies. However, the response rate appears to fall off by about one third in patients who were previously exposed to BCMA-targeted therapies.124,125

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Comparing Options: Which BCMA Therapy To Choose?

At present, there is no ideal way to determine the best option among these different BCMA-targeted therapies for a given patient. For patients who are eligible for one of these BCMA-targeted therapies, these agents have shown high response rates with durability. For patients who may not be eligible for these BCMA-targeted therapies, alternative agents may include selinexor-based therapy, cyclophosphamide-based combinations, venetoclax-based combinations for those with t(11;14), or alkylator-based therapy.

Treatment selection needs to be taken in the context of what can be accessed, whether the patient receives therapy in the community setting or in a large referral center, and also, the need for toxicity monitoring.

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A 69-year-old female presents with fatigue and back pain and her primary medical history includes hypertension. She had Eastern Cooperative Oncology Group (ECOG) performance status of 1 and laboratory tests showed : hemoglobin of 9 g/dL, calcium of 8.7 mg/dL, creatinine of 1.6 mg/dL, beta-2 microglobulin at 5 mg/dL, albumin of 3.6 g/dL, LDH within normal limits, M-protein at 5.2 g/dL, IgG-kappa, and kappa FLC of 92 mg/L, and lambda FLC of 9.2 mg/L.


Plain films showed multiple lytic lesions and bone marrow biopsy revealed 50% plasma cells with no high-risk cytogenetic abnormalities. For first-line treatment, she received VRd followed by ASCT and lenalidomide maintenance (stopped after 18 mo due to AEs), but experienced progressive disease after 34 months. Subsequent lines of therapy included daratumumab/lenalidomide/dexamethasone (Dara-Rd), pomalidomide/cyclophosphamide/dexamethasone, and carfilzomib/dexamethasone (Kd).
Currently exam shows a progressive vertebral lesion and the patient desires aggressive treatment with the highest likelihood of response.


 

In your current clinical practice, what would you recommend for this patient after multiple relapses?

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