Dana-Farber Cancer Institute continues to lead the way in clinical research to further improve longevity and quality of life for our patients with multiple myeloma (MM). While CAR T-cell therapy has become a "game changer" in the therapeutic landscape, with an increasing number of patients benefiting from this highly efficacious immunotherapy due to the recent FDA approvals of ciltacabtage autoleucel (Carvykti) and idecabtagene vicleucel (Abecma) for patients in early lines of therapy, it is also clear that highly efficacious and well-tolerated non-cellular (drug) therapies are still needed, given the ongoing logistical barriers to CAR T-cell therapy for many of our patients, as well as the lack of curative signal seen thus far with this modality.
Within the relapsed/refractory multiple myeloma (RRMM) space, Dana-Farber has been a leader in the clinical development of the cereblon E3 ligase modulators (CELMoDs). Unlike the commercially available IMiDs such as lenalidomide and pomalidomide, 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. The most potent of these CELMoDs, mezigdomide, has been under study at Dana-Farber for the past several years under the leadership of Paul Richardson, MD. In the phase 1/2 study of mezigdomide-dexamethasone that was led by Dr. Richardson and published in the New England Journal of Medicine in August 2023, the overall response rate (ORR) of this combination in patients with triple class-refractory disease was 41% at the phase 2 dose, and responses were frequently seen in patients with extramedullary disease as well as high-risk cytogenetics. Active trials of mezigdomide in combination with other promising drugs, to include low-dose selinexor, are currently open and enrolling patients at Dana-Farber. The all-oral "seli-mezi" combination is of particular interest to us given the all-oral nature of this regimen as well as the unmet need for drug combinations that do not harm or exhaust T cells (and could perhaps even reinvigorate exhausted T cells), in the current era of T-cell-engaging bispecific antibodies and CAR T-cell therapy.
The anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC), belantamab mafadotin (bela maf), is also under active study at Dana-Farber, to include the phase 1/2 DREAMM-5 trial of bela maf in combination with multiple promising novel agents, as well as the phase 2 ISABELA investigator-sponsored trial of bela maf, isatuximab, pomalidomide, and dexamethasone in patients with at least one prior line of therapy. Lastly, the just-activated phase 1 trial of OPN-6602, an EP300/CBP bromodomain inhibitor that has demonstrated impressive pre-clinical activity by downregulating expression of IRF4 and MYC, further underscores Dana-Farber's commitment to studying promising new agents with novel mechanisms of actions for our patients in need.
Within the newly-diagnosed multiple myeloma (NDMM) space, the combination of isatuximab, lenalidomide, bortezomib, and dexamethasone is actively being studied in transplant-eligible patients. On the heels of this trial, Yuxin Liu, MD, is planning to open an investigator-sponsored trial of isatuximab plus iberdomide, bortezomib, and dexamethasone in patients with newly-diagnosed MM. Iberdomide, the other CELMoD currently under clinical development, is of great interest to us given its proven efficacy in patients with relapsed/refractory disease, as well as its favorable risk and toxicity profile in comparison to lenalidomide.
Lastly, the follow-up study to the landmark DETERMINATION trial ("DETERMINATION-2") is in the planning phase at Dana-Farber, with a goal of opening the trial nationwide later in 2025. This trial also plans to use the next-generation quad induction regimen of isatuximab-iberdomide-bortezomib-dexamethasone for transplant-eligible patients with NDMM, with a focus on tailoring consolidation and maintenance therapy according to both cytogenetic and functional (minimal residual disease (MRD)-based) risk status. As the emergence of quad induction as standard of care for patients with NDMM has produced a "tale of two cities" of sorts, with some patients (standard-risk and MRD-negative after induction) now able to enjoy long remissions without the use of high-dose melphalan with autologous stem cell transplant (HDM-ASCT), and others (high-risk and MRD-positive) still having an unmet need in this regard. In this spirit, DETERMINATION-2 will attempt to address the most important questions in both of these patient populations — long-term maintenance versus stopping therapy in standard-risk patients who have achieved sustained MRD-negativity, and conventional HDM-ASCT versus fixed-duration anti-BCMA bispecific antibody consolidation for high-risk and/or MRD-positive patients — with the goal of further improving patient outcomes. In addition, careful study of patient subgroups is planned as part of the trial to further aid in the tailoring of treatment decisions for individual patients.
As always, the multiple myeloma clinical research team at Dana-Farber continues to cherish both longstanding and new partnerships with referring community oncologists in New England and beyond, and greatly appreciates the trust placed in them to provide cutting-edge investigational therapies for their shared patients. This train of progress could not continue to move forward at full speed as it is without this collaborative spirit.
