Melphalan Safer than Thalidomide in Bortezomib-Regimen for Elderly Multiple Myeloma Patients

New Orleans, LA — In a plenary session at the 51^st ASH Annual Meeting, data from a randomized trial in elderly patients with multiple myeloma (MM) showed combining bortezomib (Velcade) and prednisone with the alkylating agent melphalan (VMP) is safer than adding thalidomide (VTP), an immunomodulatory drug, and just as effective. Maria-Victoria Mateos, MD, PhD, attending physician in hematology at Hospital Universitario de Salamanca in Spain, presented the results from the two-stage phase III trial conducted by the Spanish Myeloma Group.

Researchers randomized 260 patients (median age, 63 y) with newly diagnosed MM to receive 6 cycles of induction therapy with VMP (n = 125) or VTP (n = 128). This was followed by up to 3 years of maintenance therapy, with patients in each arm randomized to receive bortezomib combined with either thalidomide (VT) or prednisone (VP). Compared to the earlier VISTA trial, the Spanish Myeloma Group used a less intense dosing regimen for induction and maintenance therapy.

Dosing Regimens

Induction Therapy

VMP (n = 125)

VTP (n = 128)

N = 260 (253 evaluable)

6 Cycles

Bortezomib 1.3 mg/m² twice weekly (days 1, 4, 8, 11; 22, 25, 29, & 32) for five 5- wk cycles

Oral melphalan 9 mg/m² once daily (days 1-4 of each cycle)

Prednisone 60 mg/m² once daily (days 1-4 of each cycle)

Bortezomib 1.3 mg/m² twice weekly (days 1, 4, 8, 11; 22, 25, 29, & 32) for five 5- wk cycles

Thalidomide 100 mg daily

Prednisone 60 mg/m² once daily (days 1-4 of each cycle)

Maintenance Therapy

VP

VT

N = 178 (143 evaluable)

Bortezomib 1.3 mg/m² twice weekly (days 1, 4, 8, 11) every 3 mo

Thalidomide 50 mg daily

Bortezomib 1.3 mg/m² twice weekly (days 1, 4, 8, 11) every 3 mo

Prednisone 50 mg alternate days

Responses to induction therapy were rapid, with first response observed at a median of 1.6 months in both arms. Overall response rates were nearly identical in each arm, at 80% for the VMP group compared with 81% in the VTP group. Complete response (CR) was achieved at a median of 4.4 months in the VMP group compared with 4.9 months in the VTP group, with rates of 22% versus 27%, respectively. At a median follow-up of 22 months, the rate of progression-free survival (PFS) was 71% in the VMP arm versus 61% in the VTP arm, and overall survival in the VMP arm was 81% compared with 84% in the VTP group. Dr Mateos said the differences between the two treatment arms in PFS and OS were not significant. Only 2 patients in each study arm progressed during the induction phase. Researchers concluded that the regimens had similar efficacy.

The main differences were seen in toxicities. “In the melphalan group,” Dr Mateos said, “there was more neutropenia and the possibility of infections.” The rate of ≥grade 3 neutropenia in the VMP arm was 37%, with 7% of patients developing grade 3 infections; compared with a 21% rate of neutropenia in the VTP arm, with <1% of patients progressing to infection. Patients receiving VTP had a higher incidence of cardiac events ≥grade 3, however, including 5 cases of heart failure, 2 cases of atrial fibrillation, and 1 heart attack. Dr Mateos noted that these events were harder to treat than the neutropenia, and there were no reported cardiac events ≥grade 3 in patients taking VMP. The only other notable adverse event ≥grade 3 was peripheral neuropathy, observed in 5% of VMP patients and 9% of VTP patients.

After induction therapy, 178 patients were randomized to one of the maintenance therapy regimens, with 143 evaluable for efficacy. Maintenance therapy improved the rate of efficacy in both groups, bumping the rate of overall CR from a median of 25% to 42%. No significant differences in efficacy were noted between the two regimens, Dr Mateos said. The less intense maintenance regimen resulted in less toxicity, with 2 cardiac events in patients taking VT and 1 in patients on VP and lower rates of peripheral neuropathy in both groups. “In this study, we demonstrate that the combination of a reduced dosage for induction therapy followed by maintenance therapy may be a novel approach for treating this patient population,” Dr Mateos said.

Richard A. Van Etten, MD, PhD, director of Tufts Medical Center Cancer Center, Boston, Massachusetts, moderated the press conference. “We can say that in this trial, both regimens appeared effective but the melphalan-containing regimen had a better toxicity profile,” he said, noting that cardiac toxicity was a primary reason patients discontinue a thalidomide-containing regimen. ASH Abstract 3.