According to the Surveillance, Epidemiology, and End Results Program registry, approximately 36,000 patients are annually diagnosed with multiple myeloma (MM) in the US, with 13,000 deaths. In newly diagnosed, transplant-eligible MM patients, median progression-free survival (PFS) with a triplet (VRD) induction, autologous hematopoietic stem cell transplantation (autoHCT), and lenalidomide (Len) maintenance was 67.5 months (>5.5 years), and five-year overall survival (OS) was >80% in the recently published DETERMINATION trial in NEJM in June 2022. There has been steady progress in the treatment of MM since that publication. Several studies of exciting developments in the areas of induction and maintenance therapy for newly diagnosed MM (NDMM), and cellular therapy for relapsed/refractory MM were reported at the recently concluded American Society of Hematology (ASH) Meeting in San Diego, CA. This article will highlight a few of these abstracts.
Quadruplet-Based Induction
In an updated analysis from the German Myeloma Group’s trial (GMMG-HD7), they evaluated the impact of adding the anti-CD38 monoclonal antibody, Isatuximab, to VRD (Isa-VRD) on the secondary endpoint of PFS. The trial included 662 patients that were randomized between Isa-VRD and VRD, followed by high-dose melphalan and autoHCT in both arms, followed by a second randomization to maintenance between Isa-Len or Len alone. After a median follow-up of 47 months, three-year PFS was significantly better in the Isa-VRd arm (83% versus 75%, HR: 0.70, p=0.0184). This improvement in PFS was seen across all subgroups except for patients with poor performance status and high-risk cytogenetics. This study is consistent with what has been seen with another trial of quadruplet versus triple induction (Perseus trial), which also showed a longer PFS with Daratumumab (Dara)-VRD quadruplet, confirming a quadruplet-based induction as the new standard of care for transplant-eligible NDMM patients.
Maintenance Therapy with Daratumumab + Lenalidomide
The phase 3 Auriga trial evaluated the impact of adding daratumumab (Dara) to post-transplant Len maintenance in NDMM patients who had achieved >VGPR post autoHCT and were MRD +ve at 10-5 by next generation sequencing (NGS). The primary endpoint was conversion rate to MRD -ve at 10-5 after 12 months of maintenance therapy. Overall, 200 patients were randomized to Dara-Len versus Len alone. The MRD -ve conversion rate at 12 months was significantly better across all subgroups (<65, >65, Black, White, standard-risk and high-risk). Grade 3-4 adverse events (AEs) were higher in Dara-Len in patients <65, Black and White subgroups. With a 32.3-month follow up, PFS was longer with Dara-Len across the same subgroups. This trial makes the case for adding Dara to Len as maintenance after an autoHCT in NDMM patients, who are MRD +ve and have not received Dara as part of their induction. However, it is difficult to adopt this approach when most patients in the U.S. are given Dara as part of their induction.
Discontinuation of Maintenance Therapy with Sustained MRD Negativity
The current practice for post-transplant maintenance in NDMM is to use len maintenance until disease progression. With the availability of more sensitive methods of disease monitoring, such as next generation flow cytometry (NGF) and advanced imaging, including whole body MRI and PET/CT, there is an effort to identify patients who can safely stop maintenance after a fixed duration therapy, after achieving a sustained MRD -ve status by NGF and advanced imaging. In a prospective study from the Kapodistrian University in Athens, 194 NDMM received induction with a bortezomib-based triplet (VCD, VTD or VRD), an autoHCT, and three years of Len maintenance. If patients had three consecutive MRD -ve results, and no evidence of disease on PET/CT, their maintenance was discontinued. Overall, 51 (26.3%) patients achieved BM and PET/CT imaging MRD -ve status and discontinued Len maintenance. With a median follow-up of 32.5 months, 23/25 (92%) patients who discontinued Len remained MRD -ve. The authors conclude that MRD negativity after three years of maintenance may allow safe discontinuation of maintenance, although this requires confirmation in a large, randomized trial. SWOG1803/BMTCTN 1706 is currently studying this approach in the U.S.
Ide-cel vs. Cilta-cel in Relapsed/Refractory MM
Dr. Hansen and colleagues presenting on behalf of the U.S. MM Immunotherapy Consortium compared the safety and efficacy of the two FDA-approved chimeric antigen receptor (CAR)-T cells, ide-cel and cilta-cel, for relapsed/refractory (MM RRMM) in a standard of care setting. Overall, 641 (ide-cel: 386, cilta-cel: 255) patients underwent leukapheresis for CAR-T production and 586 (ide-cel: 350, cilta-cel: 236) received the actual CAR-T infusion. With a median follow up of 12 to 13 months for both ide-cel and cilta-cel, patients treated with cilta-cel had a significantly higher incidence of grade >3 cytokine release syndrome (CRS), infections and delayed neurotoxicity. In terms of efficacy, patients treated with cilta-cel had significantly higher CR rate, and significantly longer PFS and OS. They conclude that cilta-cel has higher efficacy with a higher incidence of certain toxicities.
Anito-cel, the Newest anti-BCMA CAR-T Cell
Results from iMMagine-1, a phase 2 registration trial evaluating anito-cel, the newest anti-BCMA CAR-T cell, were also presented at the meeting. In this trial, 58 patients with RRMM with >3 prior lines of therapy received anito-cel after LD Rx. The primary endpoint was overall response rate (ORR). The final ORR was 95%, CR rate was 62%, and 92% of the evaluable patients achieved MRD -ve status at 10-5. With a median follow up of 10.3 months, six-month PFS and OS were 90% and 95%, respectively. Any grade CRS was seen in 84%, mostly grade 1, and any grade early neurotoxicity in 9%. There was no delayed neurotoxicity, cranial nerve palsy, Guillain-Barre syndrome, or Parkinsonian-like symptoms. These results show deep and durable responses in a heavily pretreated population without the toxicity seen with other anti-BCMA CAR-T products so far.
In summary, several papers from this meeting underscore the rapid growth of therapeutic options for MM patients, with an ongoing steady improvement in their outcomes and survival.
Dr. Quazilbash has no financial interests or conflicts of interest to report.
Illustration by April Brust
