Older patients with newly diagnosed myeloma had no loss of efficacy and significantly less toxicity with reduced-intensity induction therapy followed by maintenance, results of a multicenter Spanish study showed.
Two regimens based on less frequent dosing of bortezomib (Velcade) led to major responses in 80% of patients during induction therapy and to complete response rates of about 40% after maintenance therapy, Maria-Victoria Mateos, MD, of University Hospital of Salamanca, and co-authors concluded in an article reported online in The Lancet Oncology.
The incidence of severe neurotoxicity declined by more than 50% and gastrointestinal toxicity by about 80% compared with historical results with twice-weekly dosing, they found.
The combination of melphalan and prednisone has constituted standard therapy for older patients with myeloma for more than 30 years. Clinical trials showed that adding thalidomide or bortezomib improved efficacy compared with the two-drug regimen.
However, studies also have shown that VMP leads to high rates of severe peripheral neurotoxicity and gastrointestinal toxicity. Mateos and co-authors designed a trial aimed at maintaining the efficacy of bortezomib-based treatment and reducing the toxicity.
Investigators at 63 Spanish centers enrolled patients ages 65 and older with newly diagnosed myeloma. All patients received one six-week cycle of bortezomib given twice a week, plus prednisone, and were randomized to either melphalan or thalidomide. The first cycle of therapy was followed by five additional five-week cycles of once-weekly bortezomib, plus prednisone and randomized therapy.
Patients who completed induction therapy were randomized to bortezomib plus either prednisone or thalidomide for as long as three years.
The primary endpoint was response rate during induction and maintenance.
The trial began with 260 patients, 178 of whom completed all six cycles of induction therapy and were randomized to the two induction regimens.
During induction, 81% of patients in the VTP group had partial responses or better, as did 80% of the VMP group. Complete response rates were 28% with VTP and 20% with VMP, a nonsignificant difference.
Combining bortezomib with melphalan and prednisone (VMP) proved safer than the combination of bortezomib, thalidomide, and prednisone (VTP).
VTP was associated with twice as many serious adverse events (31% versus 15%, P=0.01) and a significantly higher discontinuation rate (17% versus 12%, P=0.03).
Grade 3+ toxicity included infection in 1% of VTP patients and 7% of VMP patients, cardiac events (8% versus 0), and peripheral neuropathy (7% versus 9%). Gastrointestinal toxicity occurred in 4% of patients in both groups.
The complete-response rates after maintenance therapy increased to 42% with bortezomib-thalidomide and 39% with bortezomib-prednisone.
Peripheral neuropathy occurred in 2% of the prednisone group and 7% of the thalidomide group. No grade 3+ hematologic toxicity occurred in either group.
Median follow-up was 32 months. The patients had a median progression-free survival of 31 months and a median time to progression of 35 months. The three-year overall survival was 70%. Results were similar in both treatment groups.
“This regimen could represent a platform for further refinement of an optimized treatment of elderly patients with multiple myeloma,” the researchers wrote.
In an accompanying commentary, S. Vincent Rajkumar, MD, of the Mayo Clinic in Rochester, Minn., said the findings have immediate applicability to clinical practice and provide “important answers about how new agents such as bortezomib can be incorporated effectively in the overall treatment strategy.”
At least three other regimens have demonstrated efficacy in randomized trials involving older patients with myeloma, Rajkumar continued. Deciding how to choose among the options will not be simple.
“As exciting as the advances are, we are faced with the challenge of selecting from treatments with significantly different side-effect profiles and route of administration with the benefit of randomized trials,” Rajkumar wrote.
“For now, the choice of a particular regimen in elderly patients with myeloma will need to be made by baseline comorbidities, cytogenetic risk factors, drug availability, and physician preference.”
Mateos disclosed relationships with Millennium, Celgene, Ortho-Biotech. Several co-authors disclosed multiple relationships with commercial interests.
Rajkumar reported that he had no relevant disclosures.