Lenalidomide, doxorubicin hydrochloride and dexamethasone versus bortezomib, lenalidomide, and dexamethasone prior to scheduled stem cell transplant in newly diagnosed myeloma.

Abstract

8001 Background: In younger, medically fit patients (pts) with newly diagnosed (ND) multiple myeloma (MM), autologous stem cell transplant (SCT) remains a standard of care. Prior to SCT, induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks amongst the most effective treatments. VRD + SCT proved superior over VRD alone in a randomized, controlled trial (RCT). We found encouraging efficacy and low toxicity with RAD (RD and adriamycin) + SCT and decided to compare RAD versus VRD induction in an RCT. Methods: The DSMM XIV study was set up according to a double 2x2-factorial design to enroll NDMM pts up to 65 years (yrs). Post-induction (PI) CR rate was the efficacy endpoint for the initial study phase. We hypothesized CR rate with RAD would be non-inferior to an estimated 20% CR with VRD. The study was powered to confirm non-inferiority of RAD at a 10% margin with a one-sided α level of .05. Minimal residual disease (MRD) was analyzed by eight-color flow cytometry (EuroFlow standards) on marrow samples. Results: 476 pts were randomized between 05/2012 and 06/2016, 469 of whom (median age 55 (range, 32–65) yrs) received at least one dose of study drug. 18.3% of pts had ISS stage III MM and 17.2%, elevated LDH. 11.3% of pts had del17p; 11.1% had t(4;14); and 4% had t(14;16). 232 pts were randomized to 3 four-week RAD cycles and 237 to 3 three-week VRD cycles, respectively. 89.7% of RAD versus 93.2% of VRD pts completed all induction cycles. PI CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD versus 13.0% (90% CI, 8.9-18.0) with VRD, (P = .697). 72/317 pts (22.7%) with paired baseline/PI samples achieved negative MRD at a median sensitivity level of 6.73x10-6. 47 (20.3%) RAD versus 35 (14.8%) VRD pts experienced treatment-emergent SAEs (P = .144). Treatment-related induction mortality was 0% in either arm. Conclusions: To the best of our knowledge, this is the first RCT to compare two lenalidomide-based triplets prior to SCT. The endpoint was met with comparable PI CR rates for RAD and VRD, respectively. Tolerability was encouraging in both arms. Follow-up data is needed to analyze time-dependent endpoints. Clinical trial information: NCT01685814.

Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma

“…These data are supportive of other studies reporting undetectable MRD after induction, including a pattern of deepening response also seen in a phase 2 IFM study of VRD induction and consolidation. 21,27 However, differences in methodology, sensitivity, and populations analyzed may limit MRD comparisons across trials.…”

“…Although VRD has been studied in multiple clinical trials, the schedule and dosing are not identical (supplemental Table 1, available on the Blood Web site). [20][21][22][27][28][29][30][31][32] Since dose intensity can have an impact on the depth of response and there are no significant overlapping toxicities between bortezomib and lenalidomide, a VRD regimen using 25 mg lenalidomide for 21 days in 4-week cycles (instead of the 14 days in 3-week cycles used in the IFM2009 and SWOG S0777 trials) was selected to maximize induction response and obtain a greater long-term benefit posttransplant. This VRD regimen was tested in the Spanish Myeloma Group's phase 3 trial.…”

Clinical perspectives on the optimal use of lenalidomide plus bortezomib and dexamethasone for the treatment of newly diagnosed multiple myeloma

“…The DSMM XIV study, evaluating induction with RVd (given as three 21-day cycles) compared with lenalidomide, doxorubicin, and dexamethasone (RAD), followed by response-adapted SCT (autologous or allogeneic) and lenalidomide maintenance, was designed to confirm the noninferiority of RAD for the induction phase primary end-point of CR rate. 41 In the RVd versus RAD arms, the rates of ≥CR were similar (13.0% vs . 11.8%), but there were nonsignificant trends toward higher rates of ≥VGPR (46.3% vs .…”

“…Most commonly, RVd was administered in 21-day cycles, with lenalidomide 25 mg on days 1-14 and bortezomib 1.3 mg/m 2 (IV or SC) on days 1, 4, 8, and 11; some studies used dexamethasone 40 mg once weekly, 29 , 30 and others split the dose to 20 mg on days of and after bortezomib (“partnered dosing”, totaling 80 mg/week). 32 , 33 , 37 , 41 , 43 Importantly, although weekly dexamethasone may be more convenient for some patients, the severity of bortezomibinduced PN may be mitigated by partnered dosing. 60 …”