Comparison of VTD with VCD for the treatment of patients with NDMM

Induction treatment prior to autologous stem cell transplant (ASCT) aims to achieve the highest possible response rate, while avoiding toxicity and retaining the possibility of stem cell collection. For patients with newly diagnosed Multiple Myeloma (NDMM) the standard induction regimen, prior to ASCT, is a triple drug combination of either bortezomib-thalidomide-dexamethasone (VTD) or bortezomib-cyclophosphamide-dexamethasone (VCD). The IFM2013-04 clinical trial conducted by the Intergroupe Francophone du Myélome (IFM) was an open-label, phase 3 study to directly compare VTD with VCD in this patient set. In March 2016, the findings were published in Blood.

Treatment:

• Pts (340) were recruited between November 2013 and March 2015, across 56 centers of the IFM
• Age ≤ 65 years of age with untreated symptomatic MM
• Patients (170 in each treatment group) were randomized to receive:
• VTD - four 3-week cycles of:
  • bortezomib (1.3 mg/m²) subcutaneously (SC) on days 1, 4, 8, and 11
  • dexamethasone (40 mg) on days 1–4 and 9–12
  • thalidomide (100 mg/day) orally
• VCD - received four 3-week cycles of:
  • SC bortezomib and dexamethasone as above
  • Oral cyclophosphamide (500 mg/m²) on days 1, 8 and 15
• Patients proceeded to ASCT following induction therapy
• Primary endpoint was Very Good Partial Response (VGPR); secondary endpoints were complete response (CR) and overall response rate (ORR)

Key Findings:

• Intention to treat (ITT) population = 338 patients, 169 in each arm (2 pts were withdrawn after randomization)
• VGPR = 66.3% VTD vs. 56.2% VCD; (95% CI, 1-18%)
• CR rate = No significant difference
• ORR = 92.3% VTD vs. 83.4% VCD; (95% CI, 2-16%); P = 0.01
• Two percent progressed on treatment in each study group
• Per protocol (PP) analysis of VGPR rate = 70.7% VTD vs. 60.4% VCD; P= 0.05; (95%CI, 2-21%)
• CR rate = No significant difference
• ORR = 98.7% VTD vs. 90.3% VCD; (95% CI, 3.4-13.5%); P = 0.001
• Relative dose intensities:
  • bortezomib: 94.9% VTD and 96.4% VCD
  • dexamethasone: 92.4% VTD and 96.1% VCD
  • thalidomide: 89.9% VTD; cyclophosphamide: 94.5% VCD

Safety

• Safety set = 338 patients
• Any AEs = 63.9% VTD vs. 68.2% VCD; P=0.40
• Hematologic toxicity was higher with VCD than with VTD:
  • Thrombocytopenia: 4.7% VTD vs. 10.6% VCD; P = 0.04
  • Neutropenia 18.9% VTD vs. 33.1% VCD; P= 0.003
• Peripheral Neuropathy (PN) was significantly increased in the VTD arm: 7.7% vs. 2.9%; P = 0.05
• Grade 3 or 4 AEs were rare, no significant difference between VTD and VCD
• Death during induction therapy = 1.5%; 2 in the VTD arm (1 from infection and 1 pulmonary embolism) and 3 in the VCD arm (1 from progression to extramedullary myeloma and 2 from infections)
• Stem cell mobilization: 314 patients (93%)
  • VTD = 159 pts; VCD = 155 pts
  • Median number of CD34⁺ cells/kg collected: VTD = 10.7 x 10⁶; VCD = 9.2 x 10⁶; P = 0.05

The quality of the response to the induction regimen is a key prognostic indicator for PFS following ASCT. In this study the VGPR was 10.1% higher with VTD than VCD; the VGPR and PR were also significantly higher for VTD in both the ITT and PP datasets, and this was not related to relative dose intensity. Patients that underwent VTD induction also had a superior stem cell yield. Therefore, this study further promotes the use of a triple drug induction regimen combining a protease inhibitor (PI) and an immunomodulatory drug (IMiD) with dexamethasone, and promotes the preferential use of VTD over VCD. The use of lenalidomide instead of thalidomide (RVD) may further improve safety outcomes, while retaining the quality of the response.

Abstract

The Intergroupe Francophone du Myélome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.