Updated Results of a Phase 2 Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVd-lite) in Transplant-Ineligible Multiple Myeloma

Abstract

PURPOSE: This updated analysis examined survival outcomes after 60 months of follow-up in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with the 3-drug regimen of modified lenalidomide-bortezomib-dexamethasone (RVD lite) in this population. METHODS: RVD lite was administered over a 35-day cycle. Lenalidomide 15 mg was given orally days 1-21; bortezomib 1.3 mg/m2 once weekly subcutaneously (SC) on days 1, 8, 15, and 22; dexamethasone 20 mg orally day of and after bortezomib for 9 cycles followed by 6 cycles of consolidation. Eligibility requirements included ECOG performance status ≤ 2 and acceptable hepatic, renal, and hematologic function. Primary objective was to evaluate overall response rate (ORR). Secondary objectives included evaluation of safety, progression free survival (PFS), overall survival (OS), and the pharmacokinetic (PK) profile of intravenous (IV) and SC bortezomib. RESULTS: Fifty-three eligible patients enrolled between 4/17/13 and 7/25/15; 50 received at least one dose of therapy. As previously reported, the median age at study entry was 72 years (range 65-91). ISS stage was I in 19 (38%), II in 17 (34%), and III in 14 (28%) pts. Fatigue was the most commonly reported toxicity occurring in 37 (74%) and was mostly grade 1 or 2 in 29 (58%). Other grade 3 or greater toxicities included hypophosphatemia in 17 (34%), neutropenia in 7 (14%), and rash in 5 (10%) pts. Low grade peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. There were statistically significant improvements in scores of physical functioning (p=0.013), future perspective (p=0.023) and disease symptoms (p=0.001). Patients reported fewer symptoms across all symptom domains with the exception of diarrhea. The ORR was 86% and 66% of patients achieved a very good partial response (VGPR) or better. The median time to response was 1.1 months. At a follow-up of 61 months, median PFS was 41.9 months (95% CI, 31.2 - ∞) and median OS not reached. The 5-year overall survival was 61.3%. Sixty-six percent of patients received lenalidomide maintenance. CONCLUSIONS: RVD lite is a well-tolerated and highly effective regimen in the transplant-ineligible population with robust PFS and OS. Our data demonstrate that the benefits of more effective combination strategies observed in younger, fitter, transplant-eligible patients can be effectively used in older, transplant-ineligible patients with modifications in dose and schedule, without compromising efficacy. Disclosures O'Donnell: Celgene: Consultancy; Sanofi: Consultancy; BMS: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Yee:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Huff:Karyopharm, Sanofi, MiDiagnostics: Consultancy; Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Schlossman:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Munshi:Celgene: Consultancy; Takeda: Consultancy; Abbvie: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Oncopep: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder . Richardson:Bristol-Myers Squibb: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding. Raje:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Celgene Corporation: Consultancy; Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy.

Effect of initial treatment on health‐related quality of life in patients with newly diagnosed multiple myeloma without immediate stem cell transplant intent: results from the Connect® MM Registry

“…Improved FACT‐MM total score and FACT‐MM TOI were observed in the RVd group versus the Vd/VMP groups; however, the difference was non‐significant. Although different instruments were used to assess HRQoL, our present findings are similar to previous reports of improved HRQoL with the RVd induction regimen among clinical trials in patients with MM 25–27 . In young (≤65 years) patients with NDMM from the Phase III IFM/DFCI 2009 trial (ClinicalTrials.gov Identifier: NCT01191060) who did not receive SCT, domains from the EORTC QLQ‐C30 and EORTC QLQ‐MY20 instruments that were suboptimal at baseline were significantly improved ( P < 0·05) at the end of induction with RVd treatment 27 .…”

“…In another Phase II trial of transplant-ineligible patients with MM, a modified regimen of RVd (RVd lite) significantly improved physical functioning (P = 0Á013), future perspective (P = 0Á023) and disease symptoms (P = 0Á001) compared with baseline. 26 Similarly, global health status, as assessed by EORTC scores, improved compared with baseline, although the difference was not statistically significant. Collectively, RVd has not been associated with significant impairments in patient-reported HRQoL and may be associated with improved MM-related symptoms.…”

“…This study also identified improvements from baseline in global HRQoL, physical functioning, role functioning, pain and disease symptoms following RVd treatment. In another Phase II trial of transplant‐ineligible patients with MM, a modified regimen of RVd (RVd lite) significantly improved physical functioning ( P = 0·013), future perspective ( P = 0·023) and disease symptoms ( P = 0·001) compared with baseline 26 . Similarly, global health status, as assessed by EORTC scores, improved compared with baseline, although the difference was not statistically significant.…”

“…Although different instruments were used to assess HRQoL, our present findings are similar to previous reports of improved HRQoL with the RVd induction regimen among clinical trials in patients with MM. [25][26][27] In young (≤65 years) patients with NDMM from the Phase III IFM/DFCI 2009 trial (ClinicalTrials.gov Identifier: NCT01191060) who did not receive SCT, domains from the EORTC QLQ-C30 and EORTC QLQ-MY20 instruments that were suboptimal at baseline were significantly improved (P < 0Á05) at the end of induction with RVd treatment. 27 This study also identified improvements from baseline in global HRQoL, physical functioning, role functioning, pain and disease symptoms following RVd treatment.…”

Approaches and Challenges in the Management of Multiple Myeloma in the Very Old: Future Treatment Prospects

“…Grade ≥3 toxicities included hypophosphatemia, neutropenia and rash with minimal grade 3 peripheral neuropathy. Because RVd-lite is well-tolerated and highly effective, it is an attractive alternative for transplant-ineligible patients unable to tolerate the standard VRd regimen ( 72 ) without compromising efficacy.…”