Several oral presentations at this year’s American Society of Hematology (ASH) Annual Meeting & Exposition highlighted encouraging outcomes in the treatment of smoldering multiple myeloma (SMM), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM). Presentations included updated data on bispecific antibodies (bsAbs) and chimeric antigen receptor T (CAR T)–cell therapy, as well as several novel agents in development.
Adding daratumumab to lenalidomide, bortezomib, and dexamethasone (RVd) for patients with NDMM appears to improve treatment outcomes, according to the finding of a real-world comparison study. The study compared daratumumab-RVd (D-RVd) and RVd induction therapy, evaluating response rates and long-term survival for both standard- and high-risk patients. The cohort study included over a thousand patients treated with RVd and 326 patients treated with D-RVd induction therapy. Patients undergoing D-RVd showed an overall response rate (ORR) of 99.6% post-induction and an 86.5% rate of very good partial responses or better (≥VGPR). These rates were higher than the RVd cohort (97.1% ORR; 67.6% ≥VGPR). Although the median follow-up for the D-RVd cohort was shorter, a clear progression-free survival (PFS) advantage was observed for both standard- and high-risk groups. At the 2-year mark, PFS for D-RVd patients was 93%; it was 82% for those on RVd. Moreover, overall survival (OS) rates also favored the D-RVd group, particularly in high-risk patients, with 94% in D-RVd versus 79% in the RVd cohort. According to the researchers, “D-RVd is a highly effective induction regimen that can improve upon outcomes in a historical NDMM population treated with RVd in terms of depth of response and PFS benefit.”
The late-breaking abstracts session included results from the phase 3 PERSEUS trial, another study evaluating the D-RVd regimen for NDMM patients who were eligible for autologous stem cell transplantation (ASCT). The primary results demonstrated that adding subcutaneous daratumumab to RVd significantly improved patient outcomes. The trial included 709 patients aged 18–70 who were randomized to receive D-RVd followed by maintenance therapy with either D-R or R alone. At a median follow-up of 47.5 months, the D-RVd arm demonstrated an improved PFS compared to RVd alone, with an estimated 48-month PFS rate of 84.3% versus 67.7%. ORR (≥CR) and minimal residual disease (MRD) negativity were significantly higher (P<0.0001 for both) in the D-VRd group. Results were consistent across all subgroups, including in patients with high cytogenetic risk and International Staging System (ISS) stage III disease. According to the researchers, the safety profile remained consistent with known profiles for RVd, with no new safety concerns reported. From these results—in addition to data from the previous phase 2 GRIFFIN trial—the researchers concluded, “these data…demonstrate the consistent and clinically meaningful benefit of quadruplet (daratumumab) plus RVd followed by D-R maintenance versus triplet RVd followed by lenalidomide maintenance and support [this combination] as a new standard of care for transplant-eligible NDMM.”
The phase 3 IsKia study evaluated isatuximab, carfilzomib, lenalidomide, and dexamethasone (IsaKRd) versus KRd in 302 transplant-eligible NDMM patients. The MRD negativity rate (10-5) after consolidation (the study’s primary end point) was 77% with IsaKRd versus 67% with KRd (P=0.049). The benefit of MRD negativity from IsaKRd treatment versus KRd was consistent across all patient subgroups. MRD negativity rates and subgroup analysis favored IsaKRd following induction and after ASCT, as well. At a median follow-up of 20 months, PFS was no different between treatment arms. More patients experienced grade ≥1 hematologic and non-hematologic toxicities with IsaKRd (55% and 41%) than KRd (43% and 37%).
Results from the first interim analysis of the phase 2 EMN26 study indicate that iberdomide, a novel oral cereblon E3 ligase modulator, shows promise as a maintenance therapy following ASCT in NDMM patients. The multicohort study explored the safety and clinical activity of iberdomide in patients who had achieved a partial response or better post-ASCT. A total of 111 patients in 3 dosage cohorts (0.75, 1.0, or 1.3 mg) were enrolled, with 69 patients receiving ≥6 cycles of treatment (n=34 in 1.0-mg cohort; n=35 in 1.3-mg cohort; n=0 in 0.75-mg cohort [this cohort was added later]). The data showed a significant deepening of response across the cohorts, with a reported 48% response improvement in the 1.0-mg cohort and 45% in the 1.3-mg cohort—which was significantly higher than the null hypothesis of ≤20% improvement within 6 months. The most common grade ≥3 adverse events were neutropenia, infections, and fatigue/asthenia. According to the researchers, “iberdomide represents a novel effective post-ASCT maintenance strategy with a favorable safety profile and superior response improvement at 6 months than what has been observed with lenalidomide maintenance (26% at 6 months in the EMN02 study).”
Results from the OPTIMUM/MUKnine trial suggest that risk of early relapse is increased in patients with ultra-high-risk (UHiR) MM with multi-hit tumors and a SKY92 high-risk signature, even with aggressive treatment. The study included UHiR MM patients characterized by ≥2 high-risk cytogenetic abnormalities (HRCAs) and/or the SKY92 high-risk signature or primary plasma cell leukemia. Patients underwent intensive therapy, including with Dara-CVRd, V-ASCT, and extended Dara-VR(d) consolidation. Despite this, a subset of participants relapsed within the first 18 months. In an exploratory analysis, the baseline characteristics of patients who experienced early relapse were compared against those who did not. Lower platelet levels were more common in the early relapse group, and a majority were at ISS stage 2. By contrast, only one out of 29 ISS stage 1 patients faced early relapse.
The presence of del(17p) was also significantly associated with early relapse, with 50% of these patients relapsing early. Of note, most patients with del(17p) myeloma relapsing early also had a SKY92 high-risk signature, whereas the majority of patients with del(17p) myeloma who did not relapse early were SKY92 standard risk. Regarding MRD status at the end of induction, the presence of soft tissue plasmacytomas was the only clinical factor associated with an insufficient response; ISS stage was not. Most patients identified as SKY92 high risk alone remained MRD-positive. The results highlight the “utility of integrated molecular diagnostics, including gene-expression risk profiling, to support clinical decision-making in the era of advanced frontline combination therapies.”
Also in high-risk patients, diffusion-weighted magnetic resonance imaging (DW-MRI) outperformed positron emission tomography (PET-CT) in detecting residual focal lesions post-ASCT. Most NDMM patients achieve deep responses during first-line therapy but end up relapsing due to focal lesions acting as reservoirs for relapsed disease. However, the best imaging modality for tracking focal lesions remains unclear. PET-CT and DW-MRI were evaluated at multiple predefined time points to track resistant lesions in 170 NDMM patients. The findings indicated that DW-MRI outperformed PET-CT. Though both imaging modalities initially identified focal lesions in most patients, DW-MRI showed a substantially higher detection rate post-ASCT, finding lesions in 53 patients compared with only 12 detected by PET-CT. Patients without focal lesions at baseline as determined by both PET-CT and DW-MRI remained negative post-ASCT. In addition, with the exception of 1 patient, focal lesions after ASCT were persistent from initial diagnosis. About two thirds of persistent post-transplant lesions were located in the humeri or femora—which was unexpected given that myeloma is considered a disease of the axial skeleton, according to the researchers.
HSCT is a standard of care for eligible MM patients and has been shown to improve survival. A comprehensive examination of the National Cancer Database from 2004 to 2020 of 43,653 patients recommended for HSCT found a refusal rate of approximately 2%. Those who underwent HSCT after induction chemotherapy had a median OS of 124 months compared to 95 months for those who declined. The research identified several factors influencing HSCT refusal:
According to the researchers, HSCT refusal rates have increased over the years, potentially due to the emergence of novel therapies and anti-CD38 immunotherapy, providing alternative treatment options.
An international study from the Worldwide Network for Blood & Marrow Transplantation was conducted between 2013 and 2017 and included 61,725 patients to estimate how age influences post-transplant survival and relapse rates. The study found that <1% of patients >75 receive an ASCT, pointing to a potential age bias in treatment selection. In addition, the use of conditioning with melphalan 200 mg/m2 was predominant among younger patients, with a shift to a lower dose of 140 mg/m2 in patients >75. As expected, OS and PFS were lower in older age groups. However, the incidence of relapse did not significantly vary with age, suggesting that disease course post-transplant is relatively consistent across age groups. Non-relapse mortality was significantly higher with advancing age, though it remained very low even in patients >75.
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Jointly provided by the MMRF and RedMedEd.
This educational activity is supported by educational grants from AbbVie Inc., Bristol Myers Squibb, and GSK and sponsorship from Genzyme Corporation and Legend Biotech USA Inc.
