New data recently published show that bortezomib given for induction and for maintenance after autologous stem-cell transplant (ASCT) improve the rate and the quality of responses and achieve superior progression-free survival (PFS) and overall survival (OS) versus a thalidomide-containing regimen (Sonneveld P, et al. J Clin Oncol. 2012 Jul 16. Epub ahead of print).
Results from the randomized phase 3 Dutch-Belgian Hemato-Oncology Group 65/German Multicenter Myeloma Group HD4 (HOVON-65/GMMG-HD64) trial were especially favorable in certain challenging subsets. “Patients with high-risk cytogenetics and those with renal impairment certainly benefited from this regimen,” noted lead investigator Pieter Sonneveld, MD, PhD, Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands, in an interview with Value-Based Care in Myeloma.
Nearly 50% with CR/nCR
The study randomly assigned 827 patients with newly diagnosed symptomatic multiple myeloma to receive induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD), followed by high-dose melphalan and ASCT. Maintenance (which was not randomized) consisted of thalidomide 50 mg for the VAD cohort once daily or bortezomib 1.3 mg/m2 for the PAD cohort once every 2 weeks for 2 years.
Complete responses (CRs) were observed in 24% of patients assigned to VAD and 36% of those assigned to PAD (P <.001). Overall, near CR (nCR) plus CR rates were 34% versus 49%, respectively (P <.001). After induction, all levels of response were superior in the PAD-receiving arm. The response rate for nCR plus CR after transplantation was 15% with VAD and 31% with PAD (P <.001), and during maintenance, an upgrade of response was observed in 24% of patients in the VAD arm and 23% of patients in the PAD arm.
Significant Differences in PFS and OS
At 41 months of follow-up, median PFS, which was the primary end point, was 28 months for patients in the VAD arm and 35 months for patients in the PAD arm. Even after adjusting for International Staging System stage, this represented a 25% reduction in the risk of progression with the bortezomib-based regimen (P = .001).
Median OS was not reached in either arm after 66 months of follow-up, but the 5-year OS was 55% with VAD and 61% with PAD. In the multivariate analysis, PAD exerted a 23% reduction in mortality risk that was statistically significant (P = .049).
Dr Sonneveld said, “Bortezomib during induction in a 3-drug combination is the standard, and this could be PAD, bortezomib plus cyclophosphamide/dexamethasone, or thalidomide/dexamethasone. Bortezomib during maintenance is tolerable and effective, and should be further explored.”
Significant Subgroup Differences
The study did not exclude patients with renal insufficiency, and 10% of all randomized patients had a serum creatinine >2 mg/dL. Bortezomib significantly improved outcomes in this subgroup, with median PFS of 30 months versus 13 months with VAD, and median OS of 54 months versus 21 months, respectively.
“Our subgroup analyses revealed that bortezomib was superior for CR/nCR, PFS, and OS in patients presenting with renal insufficiency, almost to the level of patients without organ failure,” said Dr Sonneveld. “Although the safety and efficacy of bortezomib in renal failure has been observed in phase 2 studies, this trial prospectively defines the benefit of bortezomib in these high-risk patients.”
A survival advantage was also seen for PAD among patients with deletion 17p13, whose median PFS was 22 months versus 12 months with VAD, and whose median OS was >54 months versus 24 months, respectively.
This finding “identifies a potential effective treatment option in this high-risk group,” the authors suggested, adding that the better outcome may be partly a result of longer administration of bortezomib. Better outcomes previously reported for bortezomib in patients with translocation t(4:14) were not confirmed.
Neurotoxicity Must Be Monitored
Bortezomib-emergent peripheral neuropathy was the prevalent toxicity during induction, preventing a number of patients from starting maintenance. Neuropathy grades 2 through 4 occurred in the first year among 40% of patients in the PAD arm and among 18% of patients in the VAD arm (P <.001). However, among patients who were able to begin maintenance treatment, more patients discontinued thalidomide maintenance than bortezomib because of toxicity.
In interpreting the toxicity data, the authors emphasized the importance of preventing neuropathy during induction, so that patients can receive the survival benefit of bortezomib during maintenance. They noted that prolonged administration of bortezomib every 2 weeks was feasible, but they predicted that the use of subcutaneous bortezomib might further improve tolerability.
In the interview, Dr Sonneveld commented, “The neurotoxicity observed in our trial was related to the twice-weekly administration that was the standard at that time. Now, subcutaneous administration, and, if needed, a once-weekly schedule during induction in patients who develop peripheral neuropathy would certainly reduce the frequency and severity of neuropathy.”