Elsevier Global Medical News. 2009 Dec 7, JS MacNeil
NEW ORLEANS (EGMN) - Melphalan showed itself to be a better partner than thalidomide for induction bortezomib in a randomized phase III trial with important implications for the treatment of elderly patients with multiple myeloma.
Investigators from the Spanish Myeloma Group modified the intensity of what has come to be known as the VISTA regimen in the trial. Instead of receiving bortezomib (Velcade) twice a week as part of a combination regimen, 260 patients (median age, 75 years) were given the bortezomib component once a week during the induction phase. To consolidate response, the design added a maintenance regimen that combined bortezomib with either thalidomide or prednisone for up to 3 years.
The result was reduced toxicity with no loss in efficacy, Dr. Maria-Victoria Mateos of the Hospital Universitario de Salamanca (Spain) reported Dec. 6 in a plenary presentation at the annual meeting of the American Society of Hematology.
The rate of serious peripheral neuropathy, in particular, had been 17% in the earlier VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) trial, which established bortezomib, melphalan, and prednisone (VMP) as an induction regimen. Dr. Mateos reported that it fell to 5% with the modified VMP regimen and to 9% with an induction regimen of bortezomib, thalidomide, and prednisone (VTP). In the maintenance phase that was added to both the VMP and VTP arms, peripheral neuropathy was 2% and 5%, respectively.
Toxicity drove the conclusion favoring the alkylating agent melphalan over immunomodulatory thalidomide, Dr. Mateos said. The investigators saw almost no difference in efficacy between VMP and VTP. Overall response rates were 80% and 81%, respectively. There were slightly more complete responses in the VTP arm (20% with VMP vs. 27% with VTP).
The toxicity profiles were "clearly different," however. The VMP regimen produced more grade 3 or higher neutropenia (39% vs. 22% with VTP; P = .008) and thrombocytopenia (27% vs. 12%; P = .0001), which resulted in more grade 3 or higher infections (7% vs. fewer than 1%; P = .01).
Although no grade 3 or higher cardiotoxicity was observed with VMP, cardiac events occurred in 8% of patients on VTP (P = .001). These included five cases of cardiac failure, two of atrial fibrillation, two of hypotension, one heart attack, and one atrial valve blockage. Each arm of the trial had seven deaths, but five in the VMP arm resulted from infections and five in the VTP arm were from cardiac complications.
Because neutropenia and infections are more easily addressed than cardiac complications, the investigators concluded that melphalan was superior to thalidomide as a partner for induction bortezomib.
The investigators did find an advantage for thalidomide vs. melphalan in the maintenance arms. This was true regardless of whether patients received induction with VMP or VTP, Dr. Mateos said. At a median follow-up of 15 months, median progression-free survival had not been reached with bortezomib plus thalidomide, but was 23 months with bortezomib plus melphalan (hazard ratio, 1.7; P = .05).
In both induction arms, patients benefited from maintenance, which increased the complete response rate from 23% after induction therapy to up to 42% after maintenance.
Moreover, a subgroup analysis found that the complete response rate was "almost identical" when 27 patients with high-risk cytogenetic abnormalities were compared with standard-risk patients. At 2 years after the first randomization, 55% of standard risk patients and 58% of high-risk patients had not progressed. Dr. Mateo reported. Overall survival at 2 years was 77% and 74%, respectively.
"They set out to answer specific questions, and they answered them really well," Dr. Richard A. Van Etten, director of the Tufts Medical Cancer Center in Boston, commented in an interview after a press briefing that he moderated. "For elderly patients, this really sets the standard."
Melphalan is not used in younger patients because it is stem-cell toxic, he explained. Older patients often are not candidates for stem cell transplantation.
In her introduction of Dr. Mateos at the plenary session, Dr. Donna Weber of the University of Texas M.D. Anderson Cancer Center in Houston observed this is the first trial to compare one novel agent to another novel agent in untreated patients with multiple myeloma. "It is time to answer some of the burning questions, particularly in patients who are elderly, and Dr. Mateos and colleagues herald a new era" in which some of these questions might be answered, she said.
In the current study, which randomized 260 patients between April 2005 and October 2008, the modified protocol called for six cycles of induction therapy followed by up to 3 years of maintenance therapy. One arm received bortezomib 1.3 mg/m² twice weekly for one 6-week cycle, followed by once weekly dosing for five 5-week cycles in combination with oral melphalan 9 mg/m² and prednisone 60 mg/m² once daily on days 1-4 of each cycle. The same combination of bortezomib and prednisone was used in the VTP arm, but thalidomide 100 mg daily was substituted for melphalan.
During the maintenance phase, patients in both arms received bortezomib 1.3 mg/m² twice weekly (days 1, 4, 8, and 11) every 3 months in combination with either continuous thalidomide 50 mg daily (VT) or prednisone 50 mg on alternate days (VP).
A total of 253 patients could be evaluated for response to the induction regimen. Along with similar response rates, no significant differences between the VMP and VTP groups were observed in progression-free survival or overall survival; the latter was 81% with VMP and 84% with VTP.
Of 178 patients who were randomized to maintenance therapy, 143 were evaluable for efficacy.
For the entire cohort at a median follow-up of 24 months, Dr. Mateos reported median progression-free survival to be 33 months and a 3-year overall survival rate of 75%.
The approach of using VMP but adding maintenance is very attractive and "probably will give you the opportunity of going back and treating with bortezomib or also using another IMiD [thalidomide analogue] at the time of relapse instead of using everything up front," Dr. Jésus F. San Miguel, the principal investigator of the VISTA trial and the new study, said in an interview. "I would like very much using the best combination up front, but the best combination should be the most effective and not the most expensive."
The conclusions are "really clear and important," added Dr. San Miguel of Hospital Universitario de Salamanca. "The modification of the regimen is associated with a significant reduction in toxicity, and the second message is the addition of thalidomide is not superior to the melphalan; and the melphalan is cheaper, and the toxicity is lower," he said.
The next question to be addressed, Dr. Mateos said, will be how a maintenance regimen containing lenalidomide (Revlimid) would compare with thalidomide.
Dr. Mateos disclosed that she received honoraria and served on the speakers bureau of Janssen-Cilag and Celgene Corp.