Advancing the Standard of Care for Newly Diagnosed and Relapsed/Refractory Multiple Myeloma

Dana-Farber Cancer Institute has long been at the forefront of therapeutic advances for patients with multiple myeloma (MM). Over the course of the past two decades, Dana-Farber has led in the development of many of today's standard-of care MM drugs and regimens, and this in turn has led to significant improvements in prognosis and quality of life for many patients.

Although MM is now a highly treatable disease, it unfortunately remains incurable, and further advances are necessary to address the currently unmet needs of our patients, and ultimately find a cure. Certainly, the FDA approval of Abecma (idecabtagene vicleucel), our first commercially available anti-BCMA CAR T-cell therapy, has been a notable win for the MM community over the past year, and as Adam Sperling, MD, PhD, describes separately in this edition of Advances in Hematologic Malignancies, other immune effector cell therapies being studied at Dana-Farber may serve to further brighten the horizon. However, a number of promising non-cellular therapies are also in various stages of clinical development here, as well, and 2022 promises to be a busy year for our clinical research team in this regard.

Within the relapsed/refractory MM (RRMM) space, a new class of orally available drugs, the cereblon E3 ligase modulators (CELMoDs) have demonstrated an impressive degree of efficacy in early phase trials. Unlike the commercially available IMiDs, the CELMoDs were specifically designed to engage the cereblon E3 ligase with maximal efficiency, leading to rapid degradation of Ikaros and Aiolos, as well as enhanced immune stimulatory and direct apoptotic effects compared to the IMiDs. CC-220, now known as iberdomide, was the first CELMoD to enter the clinic at Dana-Farber, and has since demonstrated encouraging activity as well as tolerability in an ongoing phase 1/2 multicenter study (NCT02773030), with a 26% ORR in combination with dexamethasone at the RP2D in a lenalidomide- and pomalidomide-exposed and triple class-refractory population. More recently, our patients have been treated on this study with iberdomide-based triplet regimens with encouraging results so far, and a phase 3 trial of daratumumab-iberdomide-dexamethasone versus daratumumab-bortezomib-dexamethasone (the EXCALIBUR study) is expected to open here later this year.

A more recently developed and even more potent CELMoD, known for now as CC-92480, is also currently in clinical trials at Dana-Farber and other select centers. In a recent phase 1 study, the results of which were presented by Dana-Farber MM Clinical Program Leader and Director of Clinical Research, Paul Richardson, MD, at the 2020 ASCO Annual Meeting, the combination of CC-92480 plus dexamethasone achieved an ORR of 55% at the recommended phase 2 dose and schedule in a largely triple class-refractory population, with impressive responses seen even in patients with extramedullary disease. On the heels of this study is a phase 1/2 trial of CC-92480 in combination with various approved MM agents (NCT03989414), with enrollment opportunities expected to increase this year.

Other investigational MM therapies currently under study at Dana-Farber include next-generation anti-CD38 monoclonal antibody constructs (NCT04000282) and antibody-drug conjugates (NCT03215030), belantamab mafadotin-based combination regimens (NCT04126200), CD47-blocking/macrophage-activating mAb therapy (NCT04445701), FcRH5-targeting and T-cell-engaging bispecific antibody therapy (NCT03275103), and venetoclax-based therapy for patients with t(11;14) (NCT03314181). Dana-Farber is also part of the MMRC-led MyDRUG study, which aims to improve upon the efficacy of IMiD and PI-based triplet therapy with the addition of targeted agents selected based on genomic profiling of the patient's MM (NCT03732703). Lastly, trials evaluating T-cell-engaging bispecific antibodies targeting BCMA are planned to open this year, as well.

Within the newly diagnosed MM (NDMM) space, the addition of anti-CD38 mAb therapy to IMiD-PI-dexamethasone triplet regimens has led to the achievement of unprecedented depths of response and rates of MRD negativity for transplant-eligible patients with MM, leading to a new era of "quad" therapy as a reasonable standard of care in this population. Multiple studies to date have demonstrated the value of daratumumab in this context, perhaps none more so than the GRIFFIN study of Dara-RVd versus RVd, the updated analysis of which was presented by Dana-Farber MM Clinical Director, Jacob Laubach, MD, MPP, at the 2021 ASH Annual Meeting. As GRIFFIN has since closed to accrual and met its endpoint, we have now shifted focus to evaluating the role of daratumumab-based quad therapy in the transplant-ineligible population via the ongoing Alliance trial of daratumumab plus dose-reduced lenalidomide, ixazomib, and dexamethasone (NCT04009109), as well as that of isatuximab, an anti-CD38 mAb with direct tumoricidal capability that was recently approved for patients with RRMM, in combination with triplet backbone regimens for transplant-eligible patients with NDMM (NCT04430894, NCT04653246).

Although the cloud of COVID-19 continues to hang over us all, perhaps this will be the year that it lifts. Regardless, the Jerome Lipper Multiple Myeloma Center at Dana-Farber remains motivated and inspired to press on in the fight against MM in partnership with our treasured patients, and together we will continue to improve outcomes and advance the standard of care.

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