Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM

Abstract

Key Points• The sequential and alternating administration of VMP and Rd have equal efficacy and toxicity.• The greatest benefit of this total therapy approach was observed for patients aged 65 to 75 years.Bortezomib plus melphalan and prednisone (VMP) and lenalidomide plus low-dose dexamethasone (Rd) are 2 standards of care for elderly untreated multiple myeloma (MM) patients. We planned to use VMP and Rd for 18 cycles in a sequential or alternating scheme. Patients (233) with untreated MM, >65 years, were randomized to receive 9 cycles of VMP followed by 9 cycles of Rd (sequential scheme; n 5 118) vs 1 cycle of VMP followed by 1 cycle of Rd, and so on, up to 18 cycles (alternating scheme; n 5 115). VMP consisted of one 6-week cycle of bortezomib using a biweekly schedule, followed by eight 5-week cycles of once-weekly VMP. Rd included nine 4-week cycles of Rd. The primary end points were 18-month progression free survival (PFS) and safety profile of both schemes. The 18-month PFS was 74% and 80% in the sequential and alternating arms, respectively (P 5 .21). The sequential and alternating groups exhibited similar hematologic and nonhematologic toxicity. Both arms yielded similar complete response rate (42% and 40%), median PFS (32 months vs 34 months, P 5 .65), and 3-year overall survival (72% vs 74%, P 5 .63). The benefit of both schemes was remarkable in patients aged 65 to 75 years. In addition, achieving complete and immunophenotypic response was associated with better outcome. The present approach, based on VMP and Rd, is associated with high efficacy and acceptable toxicity profile with no differences between the sequential and alternating regimens. This trial was registered at www.clinicaltrials.gov as #NCT00443235. (Blood. 2016;127(4):420-425) IntroductionMultiple myeloma (MM) is the second most frequent hematologic disease. Two-thirds of newly diagnosed patients are older than 65 years. 1Treatment options for this patient population have previously been limited to alkylators, but new up-front combinations based on novel drugs, with or without alkylating agents, have significantly improved outcomes.2 Findings from 6 randomized trials showed that melphalan, prednisone, and thalidomide (MPT) was better than melphalan plus prednisone in terms of response rate and progression-free survival (PFS), with increased overall survival (OS) reported in 3 out of 5 trials. To date, MPT has been considered a standard of care.3 Bortezomib plus melphalan and prednisone (VMP) is another standard of care for elderly MM patients based on the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial, in which VMP proved to be superior to melphalan and prednisone with an OS 4 benefit of 13 months. Moreover, bortezomib was subsequently optimized through weekly administration, which significantly improved tolerability but had no impact on the efficacy; this VMP "lite" is widely used in clinical practice.5 Concerning lenalidomide, the FIRST (Frontline Investigation of Lenalidomide plus dexamethasone vs Standard ...

How I treat extramedullary myeloma

“…A Spanish group recently reported the preliminary results of a phase 3 study evaluating the efficacy of an alternating VMP/Len-Dex sequence in de novo MM patients. 57 This strategy demonstrated a high CR/sCR rate and an encouraging median progression-free survival of 28 months in high-risk MM patients. In this study, the outcome of standard-risk and high-risk patients did not differ significantly.…”

Therapy for Relapsed Multiple Myeloma

“…Apart from its established use as the conditioning agent of choice before ASCT, it has been studied in combination with IMiDs 45,90–92 and PIs 46,93,94 both for induction of newly diagnosed myeloma and in the relapsed setting, the latter in combination with panobinostat. 95 It is reserved for patients who are not candidates for ASCT.…”

Analytical and clinical validation of a novel in-house deep-sequencing method for minimal residual disease monitoring in a phase II trial for multiple myeloma

“…This was the basis for the 18 cycles explored in the GEM10mas65 clinical trial (VMP+Ld combination), which yielded excellent clinical results. 12, 14 When we analyzed the molecular response in these elderly MM patients, we found that the proportion of patients achieving an MRD-negative status is significantly higher after 18 cycles of treatment (27% ( n =19) vs 11.5% ( n =8) after 18 and 9 cycles, respectively, P =0.04), confirming that a prolonged treatment improves the rate of molecular responses. Similar to the data obtained with other MRD methods, 7, 8, 15 the achievement of molecular responses measured by our NGS method is able to predict 3-year survival in patients enrolled in the GEM10 clinical trial.…”

“…Patients were enrolled in the phase 2 trial for newly diagnosed elderly MM patients PETHEMA/GEM2010MAS65 study (www.clinicaltrials.gov as #NCT01237249); patients were randomized to receive 9 cycles of bortezomib/melphalan/prednisone (VMP) followed by 9 cycles of lenalidomide/dexamethasone (Rd; sequential arm, n =38) vs 18 alternating cycles of VMP/Rd (alternating arm, n =35). 12 Nighty-five percent ( n =69) of the patients experienced a CR according to the International Myeloma Working Group (IMWG). 13 Median follow-up of the series was 3 years.…”