Comparing Bortezomib-Based Triplet Combinations for Newly Diagnosed Multiple Myeloma

The first head-to-head trial of bortezomib-based triplet combination therapies for patients with newly diagnosed multiple myeloma (MM) found that induction with a combination of bortezomib, thalidomide, and dexamethasone (VTD) led to higher overall response rates (ORR) than the combination of bortezomib, cyclophosphamide, and dexamethasone (VCD), with more patients in the VTD arm achieving at least a very good partial response (VGPR; the study’s primary endpoint).

VTD and VCD are two of the most commonly used induction regimens for MM patients prior to autologous hematopoietic cell transplantation (AHCT), as both have been effective in phase II and phase III trials. Results from this prospective, open-label, randomized, phase III study, by Philippe Moreau, MD, from the University Hospital in Nantes, France, and colleagues, may provide physicians with more information to guide their treatment selections for transplant-eligible MM patients.

The 338 patients in this study were enrolled from 56 centers in the Intergroupe Francophone du Myélome between November 2013 and March 2015.

Patients were eligible for inclusion if they:

  • Were ≤65 years old
  • Had untreated symptomatic MM with measurable paraprotein in the serum (>1 g/dL) or urine (>0.2 g per 24 hours)
  • Had an Eastern Cooperative Oncology Group performance status of 0-2
  • Had adequate renal function

Patients were then randomized (stratified by baseline International Staging System category and by cytogenetics by fluorescence in situ hybridization analysis) to receive four cycles of either:

  • VTD: 3-week cycles of bortezomib 1.3 mg/m2 administered subcutaneously on days 1, 4, 8, and 11; dexamethasone 40 mg on days 1-4 and 9-12; thalidomide 100 mg/day administered orally (n=169)
  • VCD: 3-week cycles of bortezomib 1.3 mg/m2 administered subcutaneously on days 1, 4, 8 and 11; dexamethasone 40 mg on days 1-4 and 9- 12; cyclophosphamide 500 mg/m2 administered orally on days 1, 8, and 15 (n=169)

All patients then proceeded to AHCT after induction therapy. Patients who received at least one dose of therapy were included for intent-to-treat (ITT) and safety analyses, and those who completed all four cycles were included in the per protocol (PP) analysis.

In addition to VGPR, secondary endpoints included complete response (CR), ORR, safety, and the quality of stem cell harvest following induction. Blood and 24-hour urine samples were analyzed at baseline and after the four cycles of treatment.

Both the ITT and PP analyses indicated that more patients in the VTD arm achieved VGPR than in the VCD arm: 66.3 percent versus 56.2 percent (p=0.05) and 70.7 percent vs. 60.4 percent (p=0.05), respectively. While there were no significant differences in CR rate between the two treatment cohorts in both the ITT and PP analyses, the ORR rate was significantly higher in the VTD group compared with the VCD group in both the ITT and PP analyses: 92.3 percent versus 83.4 percent (p=0.01) and 98.7 percent versus 90.3 percent (p=0.001), respectively. (See TABLE 1 for the response to treatment in each group.)

“These differences were not the result of dose attenuation or the use of a ‘VCD-light’ regimen since the dose of cyclophosphamide that was administered in our trial was higher than that reported in [previous retrospective studies] or in other VCD regimens reported previously,” Dr. Moreau and colleagues noted. “The dose intensity in both arms was high, and greater than 90 percent for each drug.”

Overall, the rate of serious grade ≥3 adverse events did not differ between the two groups. However, hematologic toxicity was higher in the VCD arm, with patients experiencing significantly increased rates of grade 3/4 anemia, thrombocytopenia, and neutropenia, while patients in the VTD arm experienced severe PN more frequently than patients in the VCD cohort (TABLE 2).

Most of the study population (93%; n=314) underwent stem cell mobilization per study protocol (159 in the VTD cohort and 155 in the VCD cohort). Though the quality of the stem cell harvest was high in both arms, the authors observed, VTD induction was associated with a superior stem cell yield (number of CD34+ cells/kg collected: 10.7 x 106 in the VTD arm vs. 9.2 x 106 in the VCD arm [p=0.05]).

“The 10 percent difference in terms of both partial response and VGPR in favor of VTD strongly suggest that the combination of a proteasome inhibitor plus an immunomodulatory drug plus dexamethasone is the best option prior to intensive therapy and AHCT,” Dr. Moreau and co-authors concluded.

The study’s findings are limited by the lack of progression-free survival and overall survival data collected. Also, the study protocol did not include recommendations about post-AHCT therapy, leaving subsequent consolidation and maintenance therapy at the discretion of the treating physician.


Reference

Moreau P, Hulin C, Macro M, et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 March 21. [Epub ahead of print]

Table 1. Response to Induction
  VTD VCD p Value
Intent-to-treat analysis n=169 n=169
≥CR 13% 8.9% 0.22
≥VGPR 66.3% 56.2% 0.05
≥PR 92.3% 83.4% 0.01
Per protocol analysis n=157 n=154
≥CR 14% 9.1% 0.17
≥VGPR 70.7% 60.4% 0.05
≥PR 98.7% 90.3% 0.001
VTD = bortezomib/thalidomide/dexamethasone; VCD = bortezomib/cyclophosphamide/dexamethasone; CR = complete response; VPGR = very good partial response; PR = partial response

Table 2. Safety Profile of Induction Therapies
  VTD(n=169; Grade 3/4 Events) VCD(n=169; Grade 3/4 Events) p Value
Any adverse event 63.9% 68.2% 0.40
Anemia 4.1% 9.5% 0.05
Neutropenia 18.1% 33.1% 0.003
Infection 7.7% 10.1% 0.45
Thrombocytopenia 4.7% 10.6% 0.04
Thrombosis 1.8% 1.8% 0.99
Cardiac disorders 1.2% 0% 0.16
Peripheral neuropathy 7.7% 2.9% 0.05
Peripheral neuropathy grade 2-4 21.9% 12.9% 0.008
VTD = bortezomib/thalidomide/dexamethasone; VCD = bortezomib/cyclophosphamide/dexamethasone

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