In 2022, the COVID-19 pandemic continues to impact the practice of medicine and the dissemination of treatment advances presented in scientific forums. Adapting to the changes, societies such as the American Society of Clinical Oncology (ASCO), the European Hematology Association (EHA), the International Myeloma Workshop, and the American Society of Hematology (ASH) have adopted hybrid formats, including virtual meetings that delivered cutting-edge research in the advancement of oncology care. Recognizing the challenges of the virtual format in terms of reach and impact, we are bringing the Year in Review series that seeks to disseminate the presented treatment advances to clinicians in a timely and effective manner.
This edition of Year in Review is focused on multiple myeloma (MM), a disease for which there have been significant treatment advances that have resulted in major changes in patient outcomes. Several new treatments have been approved and novel classes of agents continue to be investigated, particularly in the relapsed/refractory (RR) setting; below is a quick review of some of the topics discussed in this issue, with a focus on recent advances and potentially practice-changing developments in MM.
Immunomodulating agents and proteasome inhibitors have long been regarded as core components of the treatment algorithm of MM. The anti-CD38 monoclonal antibodies, daratumumab and isatuximab, represent transformative advances in the management of MM, and are now also considered integral components of the antimyeloma armamentarium. Research continues to further optimize their use.
In the frontline setting, the pivotal phase 3 MAIA trial demonstrated survival benefit with daratumumab plus lenalidomide/dexamethasone (D-Rd) compared with lenalidomide/dexamethasone (Rd) in patients ineligible for autologous stem-cell transplantation (ASCT) with newly diagnosed multiple myeloma (NDMM). Quadruplet induction therapy with daratumumab plus carfilzomib/lenalidomide/dexamethasone, ASCT, and minimal residual disease (MRD) response–adapted daratumumab plus carfilzomib/lenalidomide/dexamethasone consolidation therapy yielded high MRD negativity rates in patients with NDMM, but also added a note of caution to the concept of therapy discontinuation as patients experienced relapse. Simulation modeling data in patients with transplant-ineligible NDMM support using the first-line lenalidomide/dexamethasone regimen in the first-line setting instead of reserving it for later lines of therapy since achieving longest progression-free survival in first line appears to ultimately confer overall survival benefit.
For isatuximab, the pivotal ICARIA-MM study demonstrated that its addition to pomalidomide/dexamethasone led to significant improvements in efficacy outcomes compared with pomalidomide/low-dose dexamethasone alone in patients with RRMM who have received ≥2 previous therapies, including lenalidomide and a proteasome inhibitor. The ongoing phase 3 GMMG-HD7 trial results also demonstrated superior MRD negativity rates after induction with isatuximab plus a bortezomib/lenalidomide/dexamethasone regimen that was not accompanied by new safety signals or early discontinuations.
Patients with RRMM who received immunomodulating agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies have poor outcomes with subsequent treatments, underscoring the clinical need for active agents in this setting. B-cell maturation antigen (BCMA) and G protein–coupled receptor family C group 5 member D are novel targets that are being investigated in MM, with several chimeric antigen receptor (CAR) T-cell therapies, bispecific antibodies, or antibody–drug conjugates directed toward these antigens developed and in various stages of clinical testing. The anti-BCMA antibody–drug conjugate belantamab mafodotin is approved for the treatment of patients with RRMM, based on results of the DREAMM-2 study that continued to demonstrate deep and durable responses with longer 13-month follow-up. While the safety profile with belantamab mafodotin monotherapy was manageable, incidence of belantamab mafodotin–associated corneal events is unique to this class of agents and occurred frequently, early in treatment, and in many cases without symptoms, which may be managed with dose modifications and supportive care. Recognizing that hematologists/oncologists may be unfamiliar with the management of belantamab mafodotin–associated corneal events, specific management guidelines have been developed to guide practicing clinicians.
The BCMA-directed ciltacabtagene autoleucel CAR T-cell therapy continued to produce responses with longer follow-up in heavily pretreated patients with RRMM (CARTITUDE-1 trial), with manageable safety, which extended to patients with MM who had 1 to 3 previous lines of therapy and were lenalidomide-refractory (CARTITUDE-2 cohort A), with a manageable safety profile. The BCMA-directed idecabtagene vicleucel CAR T-cell therapy also showed an overall favorable clinical benefit–risk profile in heavily pretreated, triple-class–exposed patients with RRMM. In addition, the BCMA-targeted CD3-engaging bispecific molecules elranatamab (MagnetisMM-1 study), teclistamab (MajesTEC-1 study), as well as the G-protein–coupled receptor family C group 5 member D–directed bispecific antibody talquetamab (MonumenTAL-1 study) alone or in combination with daratumumab (TRIMM-2 trial) were well-tolerated and resulted in promising antimyeloma activity.
Recognizing that the management of patients with RRMM requires a systematic approach, the International Myeloma Working Group developed evidence-based clinical practice recommendations for the treatment of RRMM, with the goal to help guide real-world clinical practice and improve patient outcomes. Preferred and alternative treatment options for patients in first relapse or in second or higher relapse were outlined based on clinical considerations of lenalidomide refractoriness and exposure to daratumumab-based regimens.
We are pleased to present the highlights of these topics and more!
Sagar Lonial, MD, FACP
Chair and Professor
Department of Hematology and Medical Oncology
Anne and Bernard Gray Family Chair in Cancer
Chief Medical Officer
Winship Cancer Institute