Isatuximab 500mg/25ml solution for infusion vials

Abstract CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65–79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10 −5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10 −5 were reported in 35 patients (26%, 95% confidence interval (CI) 19–34) in IsaRd versus 71 (53%, 95% CI 44–61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89–5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10 −5 and 10 −6 , and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10 −5 , the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 .

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Background: This meta-analysis evaluates the efficacy and safety of isatuximab, an anti-CD38 monoclonal antibody, in combination regimens for newly diagnosed (NDMM) and relapsed/refractory multiple myeloma (RRMM). Methods: We systematically searched major databases for randomized controlled trials (RCTs) comparing isatuximab-based therapy with standard regimens up to September 2025. Efficacy and safety analyses were performed separately for NDMM and RRMM populations using random-effects models. Efficacy outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), very good partial response (VGPR) or better, and minimal residual disease (MRD) negativity rate. Safety was assessed by grade ≥ 3 adverse events. Results: In NDMM patients, isatuximab significantly improved PFS (HR = 0.66, 95% CI: 0.52–0.84, p = 0.001) and MRD negativity rates (RR = 1.28, 95% CI: 1.13–1.45, p < 0.001), but not OS (HR = 1.01, p = 0.937), ORR (RR = 1.02, p = 0.49), or VGPR or better (RR = 1.10, p = 0.13). In RRMM patients, isatuximab significantly improved PFS (HR = 0.61, 95% CI: 0.50–0.74, p < 0.001) and showed strong trends favoring OS (HR = 0.81, 95% CI: 0.65–1.00, p = 0.051) and ORR (RR = 1.30, 95% CI: 0.79–2.16, p = 0.303), while significantly increasing MRD negativity (RR = 4.37, 95% CI: 0.60–31.68, p = 0.144). A trend toward improved OS was observed in RRMM (HR = 0.81, p = 0.051). In NDMM, PFS benefit was significant for standard-risk but not high-risk cytogenetics. Safety analysis showed an increased risk of grade ≥ 3 adverse events RRMM (RR = 1.18, p < 0.001) but not in NDMM (RR = 1.08, p = 0.064), primarily driven by neutropenia (NDMM RR = 1.96, p = 0.003; RRMM RR = 1.77, p = 0.039) and pneumonia in NDMM (RR = 1.80, p = 0.001). Conclusion: Isatuximab-based regimens significantly improve PFS and depth of response with a manageable safety profile, supporting its use across MM settings, though efficacy in NDMM may vary by cytogenetic risk.

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PURPOSE: The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity. METHODS: , next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS). RESULTS: Among 125 patients with HRNDMM (TE-intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for ≥1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm. CONCLUSION: Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.

Abstract licence: CC BY-NC-ND

Previously, addition of isatuximab (Isa) to standard-of-care lenalidomide-bortezomib-dexamethasone (RVd) in transplant-eligible patients with newly diagnosed multiple myeloma in the GMMG-HD7 trial (ClinicalTrials.gov identifier: NCT03617731 ) resulted in a significant increase of minimal residual disease negativity (MRD–) rates after induction therapy. A total of 662 patients were randomly assigned to receive induction therapy with Isa-RVd (n = 331) or RVd (n = 329), followed by single or tandem autologous stem-cell transplant and second random assignment to maintenance with lenalidomide alone or Isa-lenalidomide. We report updated results for part 1 from first random assignment to post-transplant. As of January 31, 2024, MRD– rates continued to deepen after transplant (66% Isa-RVd v 48% RVd). Isa-RVd induction therapy significantly prolonged progression-free survival (PFS) compared with RVd regardless of maintenance therapy (hazard ratio, 0.70 [95% CI, 0.52 to 0.95]; P = .0184). Weighted risk set estimator analysis accounting for second random assignment followed by maintenance with only lenalidomide confirmed a statistically significant benefit for Isa-RVd followed by lenalidomide maintenance versus RVd followed by lenalidomide maintenance (stratified weighted log-rank test P = .016). In conclusion, after 18-week induction therapy followed by transplant without consolidation therapy, adding Isa to RVd resulted in a significant PFS benefit, regardless of maintenance strategy.

Abstract licence: CC BY-NC-ND