Monique Hartley-Brown, MD, MMSc
Attending, Jerome Lipper Multiple Myeloma Center
Department of Medical Oncology
Dana-Farber Cancer Institute
This edition of Year in Review is focused on multiple myeloma (MM), a disease for which the treatment landscape has seen tremendous growth resulting in major favorable changes in patient outcomes. New treatments have been approved and novel classes of agents continue to be investigated, particularly in the relapsed/refractory multiple myeloma (RRMM) setting. We are providing this Year in Review series to disseminate the latest information on treatment advances in 2022 to clinicians in a timely and effective manner. 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.
Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have long been regarded as core components of the treatment algorithm for MM. Anti-CD38 monoclonal antibodies, namely daratumumab (dara) and isatuximab, entered the MM therapeutic landscape in the past decade and have illustrated clinically impactful and transformative advances in the management of MM. Both dara and isatuximab are now considered integral components of the MM treatment paradigm.
In the frontline setting, long-term outcomes from the pivotal phase 3 MAIA trial continue to demonstrate a superior progression-free survival (PFS) and overall survival (OS) benefit with dara plus lenalidomide/dexamethasone (D-Rd) compared with lenalidomide/dexamethasone in patients ineligible for autologous stem-cell transplantation (ASCT) with newly diagnosed MM. The 2022 updated post hoc analysis of the MAIA trial, evaluating patients receiving D-Rd for ≥18 months compared with those receiving D-Rd for <18months, showed a significant OS benefit for the D-Rd group (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.1-0.25; P <.0001). The median follow-up was 56.2 months, with results also illustrating favorable PFS outcomes (HR, 0.57; 95% CI, 0.43-0.76; P <.0001). These results supported D-Rd treatment for ≥18 months to achieve deep clinical responses. The GRIFFIN and LYRA studies are both phase 2 trials evaluating dara in a quadruplet regimen. Updates from the GRIFFIN phase 2 trial of dara plus lenalidomide, bortezomib, and dexamethasone (RVd), from the patient-reported outcome (PRO) perspective, have shown favorable PROs in the dara-containing arm. With the prior data illustrating the dara-RVd arm as clinically superior in PFS and minimal residual disease (MRD) negativity rates compared with the RVd arm, this aligns PROs with clinically significant results in patients with standard-risk disease. A sobering take-home from the GRIFFIN trial results is the poor PFS and MRD negativity outcomes seen in the high-risk patient population. Updated results from ASH 2022 support continued use of dara-RVd in transplant-eligible standard-risk patients with newly diagnosed MM (NDMM). The LYRA phase 2 study evaluated dara plus cyclophosphamide, bortezomib, and dexamethasone in patients with NDMM and RRMM. On evaluation, all arms containing dara were favorable in comparison to the non–dara-containing arms. Beneficial outcomes were seen in complete response or better, very good partial response or better, and overall response rate (ORR).
Results from the DETERMINATION trial demonstrated superior PFS outcomes with lenalidomide (R) plus bortezomib/dexamethasone (Vd) treatment, ASCT, and R maintenance in the upfront setting compared to RVd alone. This trial showed the longest PFS to date compared to RVd alone (without early ASCT) in this setting. The lack of OS benefit in delaying ASCT further confirmed clinical benefit of R maintenance and the use of ASCT to deepen response and extend PFS, with the caveat that upfront versus delayed ASCT remains an area of discussion between physicians and their MM patients.
The final OS analysis of the pivotal ICARIA-MM study continues to demonstrate that isatuximab added to pomalidomide/dexamethasone (Pd) leads to significant improvements in OS versus Pd alone in patients with RRMM who have received ≥2 previous therapies, including lenalidomide and a PI. Updated PFS and depth of response from the IKEMA trial of isatuximab plus carfilzomib/dexamethasone (Kd) versus Kd alone demonstrated the longest PFS seen when using a PI backbone in the RRMM setting. The updated analysis at a median follow-up of 44 months was unprecedented, with a median PFS of 35.7 months in the isatuximab-containing arm versus 19.2 months in the non-isatuximab arm, translating to the longest PFS seen in the RRMM setting for patients exposed/refractory to PIs and/or IMiDs in frontline therapy. Moreover, the interim analysis of the GMMG-CONCEPT trial also demonstrated rapid and deep responses with isatuximab, carfilzomib, lenalidomide, and dexamethasone, which will potentially translate into durable responses based on the ongoing trial and potential results. It is worthy to note the first-in-human phase 1 trial of subcutaneous administration of isatuximab via an on-body delivery system showed tolerability and safety and efficacy similar to intravenous isatuximab. This is a novel application for subcutaneous administration of isatuximab which unlocks a unique opportunity for real-world access and use of this medication for patients with MM in remote community oncology centers.
Patients with RRMM who have relapsed beyond IMiDs, PIs, and anti-CD38 monoclonal antibodies, known as triple refractory disease, have notably poorer survival outcomes. This is an area of unmet need, wherein subsequent treatments and more active novel MM therapeutic agents are needed in this setting. Novel cereblon E3 ligase modulators (CELMoD) are being investigated as promising agents in MM treatment post–triple exposed/refractory MM disease. B-cell maturation antigen (BCMA) and G protein–coupled receptor family C group 5 member D–targeted novel therapies are currently being investigated in RRMM, 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. Of note, in 2022, 2 CAR T-cell therapies were commercially FDA-approved, namely idecabtagene vicleucel and ciltacabtagene autoleucel, as well as 1 bispecific antibody, teclistamab. Results of the pivotal phase 2 trial CARTITUDE-2 resulted in FDA approval for this agent in patients with >4 lines of therapy, including IMiD, PI, and anti-CD38 monoclonal antibody. There are trials evaluating this agent in early RRMM patients, defined as relapse occurring within 12 months or less. The ASH 2022 update presenting ciltacabtagene in early RRMM relapse showed remarkable efficacy signal with an ORR of 100% (95% CI, 82.4-100) in 19 patients, median follow-up of 13.4 months, and 15/16 patients with MRD negativity at 10-5. These results warrant further evaluation of ciltacabtagene autoleucel in early relapse and in earlier lines of therapy. The CELMoD agent iberdomide demonstrated clinically meaningful activity in heavily pretreated RRMM patients in a phase 1/2 study. Additionally, the BCMA-directed CD3-engaging bispecific molecules elranatamab (MagnetisMM-3 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) were well tolerated and demonstrated promising antimyeloma activity, hence the recent FDA approval in October 2022 for teclistamab in patients with RRMM.
With all of these novel therapies and an increasing number of FDA-approved therapies for treatment of RRMM, it is exciting to consider the future curative therapy being on the horizon for MM. We are pleased to present the highlights of these topics and more!
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