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Managing Multiple Myeloma in the Relapsed Setting: Expert Perspectives on Recent Advances

Sagar Lonial, MD

Professor and Chair
Department of Hematology and Medical Oncology
Chief Medical Officer
Winship Cancer Institute of Emory University
Atlanta, Georgia

Sagar Lonial, MD: consultant/advisor/speaker: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Novartis, Takeda; researcher: Bristol-Myers Squibb, Janssen, Novartis, Takeda; board member with stock: TG Therapeutics.

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Thomas G. Martin, MD

Clinical Professor of Medicine
Associate Director,
Myeloma Program
University of California, San Francisco Medical Center
San Francisco, California

Thomas G. Martin, MD: consultant: GlaxoSmithKline; researcher: Amgen, Janssen, Sanofi, Seattle Genetics.

View ClinicalThoughts from this Author

Released: November 2, 2022

Key Takeaways

  • In early relapse, key considerations include whether patients are truly refractory to prior therapy or if relapse occurred off treatment and there is possibly still sensitivity.
  • Patients with disease progression on one class of BCMA-directed therapy may respond to a different class of BCMA-directed therapy.

In this commentary adapted from a discussion between Sagar Lonial, MD, and Thomas G. Martin, MD, they address important clinical nuances about the management of patients with relapsed/refractory multiple myeloma (MM).

Considerations With MM Early Relapse

Sagar Lonial, MD:
Updated data from the RVD 1000 series show that for fit patients with MM, median progression‑free survival (PFS) for all patients is 67 months, with median expected overall survival (OS) more than 10 years. For the high‑risk patient cohort, a median PFS of 40 months and a median OS of 78 months demonstrate there is still room for improvement. But it is a new day in 2022 when considering expectations for a patient with newly diagnosed MM. During the past 20 years, MM management has evolved from proteasome inhibitor–based regimens to immunomodulatory drug (IMiD)–based regimens with lenalidomide and pomalidomide as backbone agents. Today, the anti‑CD38 antibodies daratumumab and isatuximab, or SLAMF7 antibody elotuzumab, provide the third component of a therapeutic backbone. We can often expect longer remissions in patients using CD38‑directed therapy than we were getting with initial therapies, particularly in patients not previously exposed to anti-CD38 antibodies. Many practitioners are moving toward CD38‑directed therapy regimens at first relapse. In my mind, the real question is in a CD38‑naive or nonresistant patient at first relapse, whether an anti-CD38 antibody should be combined with an IMiD or a proteasome inhibitor. We want to choose regimens that have high responses and can provide a longer PFS, particularly in early relapse when a patient still has sensitive disease.

Thomas G. Martin, MD:
In early relapse, it has to be considered whether patients are refractory to prior therapy or whether they were off treatment and then relapsed and may still have sensitivity. There are so many choices now that options causing any toxicity can potentially be eliminated. The most debilitating toxicity for patients with MM is neuropathy, which is less common with anti-CD38 antibodies compared with other agents. Choosing the next therapy line also depends on the goals for the patient. Some people who had a long initial first remission may be able to get a deep remission with their second regimen. For fit patients, I aim to use the best triplet possible based on durable response and tolerability.

Sagar Lonial, MD:
Some patients have higher- risk MM, with genetically defined cytogenetic abnormalities such as del17p or t(14;16), or are refractory to prior therapies. There may be the potential to consider personalized medicine options when genetic drivers are present. The BOSTON trial evaluated selinexor, a nuclear export combination inhibitor, in combination with bortezomib and dexamethasone, and the median PFS was 13.95 months with the triplet. There was also a lower incidence of neuropathy when selinexor was combined with bortezomib. The data demonstrate that this combination is safe and tolerable. Subgroup analysis revealed greater benefit in the del17p subgroup. This finding needs to be confirmed in additional studies, but it is interesting to consider when thinking about how to manage a very resistant or potentially high‑risk MM patient. The BELLINI trial of venetoclax, which targets BCL2 in MM, demonstrated PFS improvement when adding venetoclax to bortezomib and dexamethasone in patients with positive t(11;14) and high BCL2 expression. This benefit did not translate to an OS improvement in the entire patient cohort. Venetoclax is off-label for MM, and trials are continuing to investigate its role in the  t(11;14) subset of patients. 

Sequencing BCMA Therapies

Thomas G. Martin, MD:
Before the last couple of years, it was difficult to treat the triple-class refractory population, and the expected survival was less than a year. Where we are right now is the MM immunotherapy era, which some say started with the anti-CD38 antibodies, but I say it starts with BCMA-targeted therapies. BCMA is expressed on mature and malignant plasma cells and can be targeted in several ways. An antibody–drug conjugate (ADC) such as belantamab mafodotin-blmf binds to BCMA and gets internalized, and then the payload gets released into the cell and kills the cell. CAR T‑cells are a gene therapy including a gene that expresses a receptor for BCMA on the cell surface and has an intracellular signaling domain that activates the T‑cell.  Bispecific antibodies where one arm binds to BCMA and the other arm activates CD3 on the T-cell surface such as teclistamab are emerging alternatives. Teclistamab was approved by the European Union in August 2022 and received accelerated approval by the FDA in October 2022.

Currently, options with FDA approval for use after 4 prior lines of therapy include selinexor and dexamethasone, belantamab mafodotin, idecabtagene vicleucel, and ciltacabtagene autoleucel. Overall response rates and median OS are much higher with CAR T‑cell therapy. So how do we choose between all the agents? I consider venetoclax as an option for high-risk patients with t(11;14). If there is a slot, and the patient is a candidate, CAR T‑cell therapy with ciltacabtagene autoleucel or idecabtagene vicleucel is offered. Selinexor and dexamethasone or belantamab is an alternative in this setting. The optimal sequence of BCMA-targeted therapeutics is not well understood.

Sagar Lonial, MD:
Patient preference and tolerance for adverse events are considerations in this setting. There are patients who do not want to be hospitalized under any circumstance, so belantamab mafodotin may be offered in that context. There are questions about sequencing from a practical perspective as well. There have been patients who progressed on CAR T-cell therapy and then responded to either a BCMA-directed bispecific antibody or an ADC, or the reverse. Understanding mechanisms of resistance is very important. If I retreat with a BCMA‑directed therapy, I assess to make sure that there is still tumor BCMA expression. The absence of BCMA expression is rare, but it can happen, particularly in high‑risk patients.

Thomas G. Martin, MD:
The availability of bispecific antibodies will help further individualize therapy. Within the population of patients waiting for CAR T-cell therapy, some may be more optimal candidates than others. With the availability of BCMA bispecific antibodies, we can better individualize therapy and maximize opportunities for CAR T-cell therapy candidates. Hopefully, extended remission durations will improve patient quality of life.

Your Thoughts
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