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Bispecifics, Steroid-Free Regimens, Screening, and Early Interventions: Much to Learn in Myeloma

December 10, 2022
Victoria Vardell, MD, and Manni Mohyuddin, MD

Dr. Manni Mohyuddin (@ManniMD1) hails from Peshawar, Pakistan, and attended Aga Khan University in Karachi. He is an assistant professor in the Division of Hematology and Hematologic Malignancies at Huntsman Cancer Institute at the University of Utah in Salt Lake City, and recently served as an abstract reviewer for the Outcome Research category. He specializes in plasma cell dyscrasias and hematopoietic stem cell transplantation. In his downtime, Dr. Mohyuddin is an avid cyclist, a novice skier, and an obsessive book reader. “If I were not a hematologist,” he said, “I would have gone into politics … and actually tried to do good!”

Dr. Victoria A. Vardell is a native of Sandpoint, Idaho. She completed undergrad at the University of Wyoming and medical school at Creighton University in Omaha. She is currently an internal medicine resident at the University of Utah in Salt Lake City, where she will begin her hematology and oncology fellowship at the Huntsman Cancer Institute next year. Her clinical interests include malignant hematologic disorders, especially multiple myeloma. Dr. Vardell’s hobbies include mountain biking, trail running, snowboarding, and skiing.

It is a great privilege to care for patients with multiple myeloma (MM) today, and the future certainly is bright based on this year’s annual meeting program. As a junior faculty member specializing in the treatment of patients with MM and a resident preparing to embark on a hematology-oncology fellowship with a particular interest in MM, we acknowledge that we are probably more thrilled than most. Nevertheless, the breathtaking progress in MM is a testament to the incredible ongoing preclinical and clinical work; the oral sessions this year represent a small sample of the exciting research going on in this space.

Teclistamab was the first bispecific antibody approved for patients with MM by the Food and Drug Administration in October 2022, and it certainly won’t be the last. Correspondingly, an entire oral session is dedicated to bispecifics in MM at 12:15 p.m on Saturday, December 10 (Room R02-R05, Ernest N. Morial Convention Center)! Bispecific antibodies are poised to create a new therapeutic landscape in the treatment of MM as data continues to build up. This session includes updated results on elranatamab, which showed particularly noteworthy activity in patients who previously received B-cell maturation antigen (BCMA) –targeted therapy. As these drugs move to earlier settings and challenge the status quo of established regimens, which have a long track record of safety and efficacy, the risk of infection needs close attention. Additionally, an update on teclistamab/daratumumab and lenalidomide, a novel combination that is being tested in a new randomized study, is also provided. Although the numbers are small, the toxicity is nontrivial (70% with grade 3 neutropenia, and febrile neutropenia in 12.5%). Moving beyond BCMA as a target, we will have results on talquetamab, a G protein–coupled receptor, class C, group 5 member D (GPRC5D) antibody and a promising potential option for patients with MM progressing on BCMA-directed immune therapies.

There is obviously a lot to look forward to when it comes to chimeric antigen receptor T-cell (CAR-T) therapy in MM. Data continue to mature for some of the other products, but most importantly we anticipate providing better patient access to these therapies, as highlighted in sobering work by Dr. Samer Al Hadidi (905. Outcomes Research—Lymphoid Malignancies: Poster II, Sunday, December 11, Hall D, Ernest N. Morial Convention Center), in which a third of patients on waiting lists for CAR-Ts died without receiving the product. Moreover, if you have seen patients following this therapy, you are aware that cytopenias following CAR-Ts are a major concern. (They have indeed been aptly named “cartopenias” by Dr. Vibha Taneja and colleagues.) In what is perhaps the best effort to date to understand this process in patients with MM, we look forward to a large analysis on the natural history, incidence and risk factors for cytopenias following CAR-T therapy. Don’t miss this at the session “Clinical and Epidemiological: Relapsed and/or Refractory Myeloma (RRMM)” taking place Saturday, December 10, at 2:30 p.m.

Dexamethasone is a huge nuisance for our patients with MM. It is thus incredibly reassuring to learn about a phase III trial in frail patients with newly diagnosed MM that omitted dexamethasone, comparing daratumumab-lenalidomide to lenalidomide-dexamethasone, being presented on Sunday, December 11 (New Orleans Theater C, Ernest N. Morial Convention Center). From an efficacy standpoint, the omission of steroids did not decrease response rates, and we eagerly await the quality-of-life analysis. Hematologic toxicities were worse with daratumumab-lenalidomide than with lenalidomide-dexamethasone; however, infection risks were similar. Additional trials omitting steroids would be a victory for patients.

Secondary malignancies remain a concern with lenalidomide therapy, and we have important updates on the long-term follow-up of the Myeloma XI trial — a large study from the United Kingdom that continues to provide us with gems. It appears that the incidence of a secondary primary malignancy at seven years was 12.2 percent for patients receiving lenalidomide maintenance, compared to 5.8 percent in those under observation. Hematologic secondary malignancies were most common in those treated with lenalidomide (whether in induction or maintenance), though MM-related deaths were lower in those receiving lenalidomide. The granularity provided in this oral session on Monday, December 12 (abstract 754, New Orleans Theater C, Ernest N. Morial Convention Center), will be essential in understanding this nuanced study and will aid in our patient counselling for maintenance therapy.

Moving beyond MM, the most instrumental study ever to be performed on monoclonal gammopathy of undetermined significance (MGUS) is a population-based screening study (> 75,000 individuals) in Iceland that assessed the value of screening the general population for plasma cell dyscrasias (iSTOPMM). At the precursor state oral session on Saturday, December 10 (Room R02-R05, Ernest N. Morial Convention Center), a model derived from this dataset will be presented that can potentially help omit bone marrow biopsies for a majority of patients with MGUS (abstract 107). Other work being presented from this stellar Icelandic group also highlights a link between rheumatologic disorders and MGUS, potentially dispelling a long-held common notion.

An oral session on Saturday, December 10 (Room 278-282, Ernest N. Morial Convention Center), presents an update on the GEM-CESAR trial of patients with high-risk smoldering MM treated with carfilzomib/lenalidomide/dexamethasone (KRd), autologous stem cell transplantation, consolidation with two cycles of KRd, and then maintenance therapy with lenalidomide. With only 23 percent of patients maintaining measurable residual disease (MRD) negativity four years post-transplant (if one considers sustained MRD negativity a surrogate for a “cure”), this study raises more questions than answers when it comes to early intervention for smoldering MM. Will certainly be a riveting discussion.

The highlighted sessions cover the full gamut of plasma cell dyscrasias, from screening interventions for MGUS, to omission of steroids (YAY), to curative (or not?) approaches for smoldering MM, to many new bispecific drugs and a better understanding of toxicities from other therapies. This is only a small sample of the fascinating research being presented at the meeting, and we hope you are as excited as we are to learn more about them!

Dr. Vardell and Dr. Mohyuddin indicated no relevant conflicts of interest.

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