Phase 1b Study of Isatuximab in Combination With Bortezomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed, Transplant-ineligible Multiple Myeloma Patients
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ABSTRACT:
SUBMITTER: Ocio E
PROVIDER: S-EPMC9894356 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:AbstractIn newly diagnosed transplant-ineligible patients with myeloma, daratumumab has improved outcomes when added to the standard-of-care regimens. In a randomized trial, we tested whether similar improvements would be observed when daratumumab was added to the bortezomib, cyclophosphamide, and dexamethasone (VCD) regimen. Transplant-ineligible patients with untreated myeloma were randomized to receive VCD or VCD plus daratumumab (VCDD). A total of 121 patients were randomized: 57 in the VCD arm and 64 in the VCDD arm. Baseline characteristics were balanced between the 2 arms. The median progression-free survival (PFS) was 16.8 months (95% confidence interval [CI], 15.3-21.7) and 25.8 months (95% CI, 19.9-33.5) in the VCD and VCDD arms, respectively (hazard ratio, 0.67; log-rank test P = .066). In a preplanned analysis, it was demonstrated that the daratumumab-containing arm showed a significant improvement in PFS from 18 months onward, based on estimates at fixed time points after randomization. The proportions of patients who were progression-free at the following time points were: 18 months, 48% vs 68% (P = .0002); 24 months, 36% vs 52% (P = .0001); and 30 months, 27% vs 41% (P < .0001) in the VCD and VCDD arms, respectively. The best overall response and very good partial response rate were significantly higher in the daratumumab arm compared with the VCD and VCDD arms, respectively (65% vs 86%, P = .007; and 28% vs 52%, P = .009). Seventy-two percent of the VCDD patients completed the 9 cycles of induction therapy with no grade 3 or 4 peripheral neuropathy adverse events. This study supports VCDD as an option for the initial treatment of transplant-ineligible patients with myeloma. This trial was registered at the Australian New Zealand Clinical Trials Registry (ACTRN12617000202369).
| S-EPMC11296246 | biostudies-literature
Project description: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 .
| S-EPMC11333283 | biostudies-literature
Project description: Not available
| S-EPMC10430979 | biostudies-literature
Project description:This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D-VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4-8 induction cycles of bortezomib 1·5 mg/m2 , cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split-first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty-six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12-month progression-free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment-emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D-VCd was well tolerated, split-first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1-year PFS rate was 87%.
| S-EPMC6593455 | biostudies-literature
Project description:Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.
| S-EPMC8462404 | biostudies-literature
Project description:Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10-5 sensitivity). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).
| S-EPMC10264885 | biostudies-literature
Project description:Bortezomib, lenalidomide, and dexamethasone (VRD), and bortezomib, doxorubicin, and dexamethasone (PAD), are commonly used in induction regimens for patients with newly diagnosed multiple myeloma (NDMM) in China. This real-world study enrolled 390 patients, 195 receiving VRD and 195 receiving PAD induction. The primary endpoint was progression-free survival (PFS) and stringent complete remission/complete remission. Across the entire cohort, VRD demonstrated significantly improved five-year overall survival (OS) (74% vs. 59%, p = 0.0024) and five-year PFS (67% vs. 37%, p = 0.0018) compared to PAD. Notably, the median OS and PFS were not reached for VRD-treated patients, while they were 77 months (60-not reached [NR]) and 46 months (36-NR), respectively, for PAD. In patients with standard-risk cytogenetics, VRD showed superior five-year OS (83% vs. 58%, p = 0.0038) and PFS (78% vs. 48%, p = 0.0091) compared to PAD. However, these differences were not statistically significant in high-risk patients. For transplanted patients, VRD was associated with superior five-year OS (91% vs. 67%, p = 0.014) and PFS (79% vs. 47%, p = 0.015) compared to PAD. In non-transplanted patients, VRD showed a trend towards improved five-year OS (p = 0.085) and PFS (p = 0.073) compared to the PAD group. In conclusion, VRD displayed superior OS and PFS outcomes in standard-risk patients and those who underwent transplantation. These findings suggest potential advantages of VRD over PAD in real-world clinical settings for NDMM treatment. However, due to the imbalance in transplantation rates between the VRD and PAD groups, limitations in testing for high-risk cytogenetic abnormalities (HRA), and the difference between the received cycles and salvage therapies, the conclusions of this study should be interpreted with caution.
| S-EPMC11386351 | biostudies-literature
Project description:Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10-5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.
| S-EPMC7441167 | biostudies-literature
Project description: Not available
| S-EPMC4916300 | biostudies-literature
Project description:In the phase 3 MAIA study of patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd). We present a subgroup analysis of MAIA by frailty status. Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit, intermediate, non-frail (fit + intermediate), or frail. Of the randomized patients (D-Rd, n = 368; Rd, n = 369), 396 patients were non-frail (D-Rd, 196 [53.3%]; Rd, 200 [54.2%]) and 341 patients were frail (172 [46.7%]; 169 [45.8%]). After a 36.4-month median follow-up, non-frail patients had longer PFS than frail patients, but the PFS benefit of D-Rd versus Rd was maintained across subgroups: non-frail (median, not reached [NR] vs 41.7 months; hazard ratio [HR], 0.48; P < 0.0001) and frail (NR vs 30.4 months; HR, 0.62; P = 0.003). Improved rates of complete response or better and minimal residual disease (10-5) negativity were observed for D-Rd across subgroups. The most common grade 3/4 treatment-emergent adverse event in non-frail and frail patients was neutropenia (non-frail, 45.4% [D-Rd] and 37.2% [Rd]; frail, 57.7% and 33.1%). These findings support the clinical benefit of D-Rd in transplant-ineligible NDMM patients enrolled in MAIA, regardless of frailty status.
| S-EPMC8979809 | biostudies-literature