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Updates in the Management of Transplant-Ineligible Patients With Multiple Myeloma
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Key Takeaways
- Multiple myeloma affects older adults, with transplant-ineligible patients requiring alternative treatment strategies due to age and comorbidities.
- Trials like SWOG-S0777, MAIA, and ALCYONE have shown improved PFS and MRD negativity with quadruplet regimens, enhancing treatment efficacy.
Explore the latest advancements in treating transplant-ineligible multiple myeloma, highlighting new therapies and clinical trial outcomes for improved patient care.
Background
Multiple myeloma (MM) is a hematologic malignancy that affects plasma cells. In 2025, there will be an estimated 36,110 new MM cases in the United States. MM is currently the fourteenth most common cancer type and one of the most common hematologic malignancies.
Quadruplet regimens increase treatment options | Image credit: luchschenF | stock.adobe.com
The median age at diagnosis is 69 with most patients being between the ages of 65 and 74.1Although survival trends in MM have improved, patients 70 years of age and older have a lower 5-year survival rate compared with their younger counterparts. A 2023 study, found the age specific relative 5-year survival rate for MM patients 18 to 69 years of age to be 69% compared to 47% for those 70 to 79 years of age.2
Transplant-ineligible MM refers to a group of patients who are not suitable to undergo autologous stem cell transplant (ASCT). This may be due to a variety of factors, including advanced age, poor performance status, comorbidities, or other medical conditions. Transplant ineligibility encompasses a significant subset of newly diagnosed MM (NDMM). First line therapy for those with transplant-ineligible MM is dependent on a variety of factors, including patient specific factors, practice setting, and financial feasibility.1,2
In 2007, the SWOG-S0777 trial (NCT00644228) was initiated. It was a phase 3 trial that randomized 525 patients to receive bortezomib, lenalidomide, and dexamethasone (VRd) vs lenalidomide and dexamethasone (Rd). SWOG-S0777 included patients with NDMM who were not planning for immediate ASCT. The median progression-free survival (PFS) in the triplet regimen arm (VRd) was 43 months vs 30 months in the Rd treatment arm.3 Longer term follow up of the SWOG-S0777 trial continues to support the benefit of the triplet regimen with maintained PFS, overall survival (OS), and better depth of response. Despite improved efficacy, grade 3 or greater sensory neuropathy was reported in 26% of patients receiving VRd.4
The RVD Lite trial was a phase 2 study that aimed to decrease toxicity while maintaining efficacy. In contrast to SWOG-S0777, patients in RVD Lite received weekly bortezomib administered subcutaneously. Patients were eligible if they were over the age of 65 or ineligible for ASCT. The median age at study entry was 73 (range 65-91). Fifty patients were included in this study and the primary end point of overall response rate (ORR) after 4 cycles was 86%, with 66% achieving very good partial response (VGPR) or better. Peripheral neuropathy of any grade was reported in 62% and only 1 patient experienced grade 3 sensory neuropathy.5
The approval of daratumumab in 2015 significantly changed the treatment landscape for those with NDMM.6 MAIA (NCT02252172) was a randomized phase 3 trial that included 737 patients with NDMM who were transplant ineligible. Study participants were randomized to receive daratumumab, lenalidomide, and dexamethasone (D-Rd) vs Rd. The primary end point was PFS. At a median follow-up of 64.5 months, PFS was significantly longer in the D-Rd group with a median PFS of 61.9 months vs 34.4 months in the Rd arm (HR, 0.55; 95% CI, 0.45–0.67; P < 0.0001).7
The phase 3 ALCYONE trial (NCT02195479) included 706 transplant-ineligible patients with NDMM. Patients were randomized to receive daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone. The PFS at 78.8 months was 37.3 vs 19.7 months (HR, 0.43; 95% CI, 0.36-0.52; P<0.0001) in the D-VMP and VMP treatment arms, respectively.8 This supports the use of the quadruplet daratumumab-containing regimen over VMP alone.
The treatment landscape for patients with transplant-ineligible MM has continued to evolve, with the approval of several new therapies in the frontline setting. This article will review these newly approved regimens in addition to ongoing clinical trials.
CEPHEUS
CEPHEUS (NCT03652064) was a phase 3 randomized trial that evaluated the quadruplet regimen daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) alone in patients with NDMM. Patients included in this study were transplant-ineligible or transplant-deferred. There were 395 patients who were randomized to receive D-VRd (n=197) or VRd (n=198) and the median age was 70 years, with over 55% of patients aged 70 or older. Approximately 28% of patients had International Staging System (ISS) Stage 3 disease, and 13% presented with high-risk cytogenetics.9
The primary end point was minimal residual disease (MRD) negativity rate, which was defined by the percentage of patients that achieved a complete response (CR) or better and were MRD-negative at a sensitivity threshold of 10-5. MRD was evaluated at baseline; time of suspected CR; 12, 18, 20, 24, 30 and 36 months after the first dose; and then yearly for patients with a confirmed CR.Secondary end points included rate of CR or better, PFS, and sustained MRD-negativity rate (≥12 months).9
After a median follow-up of 58.7 months (0.1-64.7 months), the primary end point was met in 60.9% versus 39.4% (p < 0.001; odds ratio [OR] 2.37; confidence interval [CI], 1.58-3.55) in the D-VRd and VRd groups, respectively. MRD negativity at 10-6 also favored the D-VRd group, with 46.2% versus 27.3% in the VRd group (p=0.0001; OR, 2.24; 95% CI, 1.48-3.40). Results of the secondary end points also favored D-VRd, with 12 months or greater MRD sustained in 48.7% in the D-VRd group vs 26.3% in the VRd group (p < 0.0001; OR 2.63; 95% CI, 1.73-4.00). Median PFS was not reached in the D-VRd group and was 52.6 months in the VRd group. Lastly, CR or better was 81.2% vs 61.6% in D-VRd and VRd groups respectively (odds ratio, 2.73; 95% CI, 1.71- 4.34; p < 0.0001).9
Grade 3 or 4 treatment emergent adverse events (TEAEs) reported in 20% or more of patients included thrombocytopenia (28.4% D-VRd vs 20% VRd), neutropenia (44.2% D-VRd vs 29.7% VRd), and infection (40.1% D-VRd vs 31.8% VRd). The results of the CEPHEUS trial demonstrate that the addition of daratumumab to VRd enhances the depth of response. This improvement translated into a notable increase in PFS and further supports the use of MRD negativity as a predictor of PFS outcomes in NDMM.9
IMROZ
The addition of isatuximab to VRd in patients with transplant-ineligible NDMM was evaluated in IMROZ (NCT03319667). A total of 446 patients were randomized 3:2 to receive isatuximab-VRd vs VRd alone. The median age in both treatment arms was 72 with 69.4% and 69% of patients over the age of 70 in the isatuximab-VRd and VRd arms, respectively. At baseline, stage 3 R-ISS was identified in 10.9% (isatuximab-VRd) and 11.6% (VRd); and in the isatuximab-VRd arm, high risk cytogenetics was present in 15.1% vs 18.8% in the VRd arm. PFS was the primary end point and was defined as the time from randomization to the first documented disease progression. Secondary end points including CR or better, MRD-negativity as assessed by 10-5, VGPR or better, and OS were also evaluated.10
At 60 months, PFS as assessed by independent review was 63.2% in the isatuximab-VRd arm vs 45.2% in the VRd arm (hazard ratio [HR], 0.60; 98.5% CI 0.41 to 0.88; p < 0.001). A higher CR rate was seen in patients receiving isatuximab-VRd vs VRd, with CR rates of 74.7% and 64.1%, respectively. VGPR or better was also higher in the isatuximab-VRd arm (89.1%) compared to the VRd arm (82.9%; OR,1.73 [95% CI, 0.99–3.01]). Sustained MRD negativity for at least 12 months was observed in 46.8% of patients receiving isatuximab-VRd, versus 24.3% receiving VRd (OR 2.7; 95% CI: 1.799–4.141). The estimated 60-month OS rate was 72.3% for isatuximab-VRd and 66.3% for VRd (HR for death 0.78; 99.97% CI, 0.41 to 1.48). The HR of 0.78 suggests a 22% reduction in the risk of death for the isatuximab-VRd arm compared to VRd alone.10
Treatment discontinuation resulting from adverse events occurred in 22.8% of those receiving isatuximab-VRd and 26% in the VRd arm. Grade 3 or greater adverse events occurring in 20% or more of patients in both treatment arms included lymphopenia (60.1% Isa-VRd vs 53% VRd), neutropenia (54.4% Isa-VRd vs 37% VRd), and thrombocytopenia (30% Isa-VRd vs 27.6% VRd). Including COVID-19 related deaths, the incidence of death from an adverse event for the isatuximab-VRd and the VRd groups was 11% and 5%, respectively. Death from any cause and death from disease progression were both lower in the isatuximab-containing arm compared to VRd, with incidences of 26.2% vs 32.6% and 4.9% vs 12.2%, respectively. IMROZ concluded that the addition of isatuximab to VRd resulted in improved PFS, supporting the use of this quadruplet regimen in patients who have transplant-ineligible NDMM.10
BENEFIT
The BENEFIT trial (NCT04751877) is a phase 3, randomized, multicenter study assessing the efficacy and safety of combining isatuximab with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) compared to isatuximab, lenalidomide, and dexamethasone (IsaRd) in transplant-ineligible NDMM patients. There were a total of 270 patients randomized and the primary end point was MRD-negativity rate at 10-5 18 months following randomization. Secondary end points included response rates, MRD assessment rates, safety, and survival.11
At 18 months, MRD negativity rate at 10-5 occurred in 106 (39%) of patients. The MRD negativity rate was significantly longer in the Isa-VRd arm vs the IsaRd arm, with 53% compared to 26%. OR for MRD negativity was 3.16 for recipients of Isa-VRd compared to IsaRd (95% CI 1.89-5.28, P < 0.0001), indicating that MRD negativity was 3.16 times more likely in the Isa-VRd arm than the IsaRd arm. MRD negativity rates in the subgroup analysis were consistently better in the Isa-VRd arm, including those over the age of 75, ISS stage 3, and those with high-risk cytogenetics. Rates of CR or better were 58% (Isa-VRd) and 31% (IsaRd; OR 2.97 [95% CI 2 to 5], P < 0.0001).11
Grade 2 or greater TEAEs that occurred in 20% or more patients in either treatment arm included neutropenia (40% Isa-VRd vs 45% IsaRd), lymphopenia (33% Isa-VRd vs 24% IsaRd), diarrhea (29% Isa-VRd vs 22% IsaRd), non-respiratory infections (36% Isa-VRd vs 28% IsaRd), and respiratory infections (35% Isa-VRd vs 40% IsaRd). Peripheral neuropathy of any grade occurred in 52% and 28%, and grade 2 or greater nervous system disorders were seen in 41.5% and 22.2% of the Isa-VRd and IsaRd arms, respectively. The BENEFIT trial demonstrated that the addition of isatuximab to VRd in transplant-ineligible NDMM patients resulted in improved outcomes, including MRD-negativity and CR rates.11
Future Directions
DREAMM-9 (NCT04091126) is a phase 1, randomized, dose-optimization study evaluating belantamab mafodotin, a B-cell maturation antigen-directed antibody-drug conjugate, plus VRd in ASCT-ineligible NDMM patients. As of March 2024, 108 patients were enrolled across 8 cohorts and the median age was 74, with 44% of patients being 75 years or older. An interim analysis found an ORR of 90% (71%-100%) and a CR of 63% (30%-92%) across all cohorts. Grade 3 or greater ocular events occurred in the greatest proportion for those in cohorts 1 through 3 (cohort 1 [1.9 mg/kg Q3/4W]; 83% [10]; cohort 2 [1.9 Q6/8W], 92% [11]; cohort 3 [1.4 mg/kg Q3/4W], 85% [11]), and the lowest rates were observed in cohort 7 (1.4 mg/kg for 1 dose and then 1.0 mg/kg Q9/12W), 7% [1] and cohort 8 (1.0 mg/kg Q12W), 20% [2].12
CARTITUDE-5 (NCT04923893) is an ongoing phase 3, randomized, open-label, multicenter study comparing induction therapy with VRd plus a single dose of ciltacabtagene autoleucel vs VRd induction plus Rd maintenance. The primary end point is PFS, with secondary end points including sustained MRD-negative CR, OS, CR or better, and safety, among others. This study aims to evaluate the efficacy and safety of ciltacabtagene autoleucel as frontline therapy in patients with NDMM for whom ASCT is not planned as initial therapy.13
Lastly, the MajesTEC-7 trial (NCT05552222) is a phase 3, randomized, multicenter study designed to evaluate the efficacy and safety of teclistamab in combinationwith daratumumab and lenalidomide (Tec-DR) and talquetamab in combination with daratumumab and lenalidomide (Tal-DR) versus daratumumab, lenalidomide, and dexamethasone (DRd) in patients with NDMM who are ineligible for or not intended for ASCT.The trial will evaluate PFS and 12-month MRD-negative CR or better.14
Results from these trials could expand first-line therapy options in patients with transplant-ineligible NDMM.
Conclusion
As the treatment paradigm for transplant-ineligible NDMM continues to evolve, there remain unanswered questions. As new regimens are approved, regimen sequencing and treatment algorithm becomes an important conversation, especially after first-line therapy. Patients over the age of 75 account for 32.9% of all new MM diagnosis, and between 2018 and 2022 patients over the age of 84 comprised 8.4% of new cases.1 Many of these trials did not include patients over the age of 80, which misses a percentage of transplant-ineligible NDMM patients.
The approval of quadruplet regimens in the first line setting increases treatment options. Despite the benefits that are seen in these regimens, triplet therapy may still be adequate for some patients. Safety data from the BENEFIT trial identified higher rates of grade 2 or greater peripheral neuropathy in the Isa-VRd arm (27%) vs IsaRd arm (10%).11 Higher rates of grade 3 or greater neutropenia (54.4% vs 37%) and leukopenia (31.6% vs 16.6%) were also observed in the Isa-VRd arm compared to the VRd arm in the IMROZ trial.10 As quadruplet therapy becomes more of a treatment standard in the front-line setting, treatment tolerability may be difficult for certain patients. Choosing the appropriate first-line option for transplant-ineligible NDMM patients is determined by a variety of factors, including comorbidities, cytogenetic risk, frailty, and financial feasibility.
