VMPT emerges as new standard for older MM patients

Multiple myeloma cells

CHICAGO—The Italian Multiple Myeloma Network, GIMEMA, has confirmed that a 4-drug combination followed by maintenance is superior to the current best standard therapy—bortezomib-melphalan-prednisone (VMP)—for elderly patients with multiple myeloma (MM).

The addition of thalidomide (T) to VMP “dramatically increased the response rate,” according to Antonio Palumbo, MD, of the University of Torino in Italy, from a complete response (CR) rate of 24% with VMP to 38% with VMPT.

Dr Palumbo noted that 90% of the improvement occurred within the induction period. “This tells us that 24 months of treatment is not needed to increase the CR rate,” he said.

He presented the phase 3 results at the annual meeting of the American Society for Clinical Oncology held recently here.

Investigators enrolled 511 patients, median age 75 years, and  randomized them to receive VMP plus thalidomide (VMPT) followed by bortezomib plus thalidomide (254 patients) or VMP without maintenance (257 patients).

Initially, the VMPT arm consisted of induction with nine 6-week cycles including bortezomib 1.3 mg/m² on days 1, 4, 8, 11, 22, 25, 29,  and 32 in cycles 1-4 and days 1, 8, 22, and 29 in cycles 5-9; melphalan 9 mg/m2 and prednisone 60 mg/m² on days 1-4 and thalidomide 50 mg on days 1-42, followed by maintenance bortezomib 1.3 mg/m² every 15 days and thalidomide 50 mg per day.

The VMP arm consisted of bortezomib, melphalan and prednisone at the same doses and schedules without maintenance. In March 2007, the protocol was changed to once-weekly bortezomib infusion.

 
At 3 years, progression-free survival (PFS) was 40% in patients from the VMP group compared to 54% in the VMPT group. “With the best treatment available today, PFS usually is around 2 years. This 4-drug combination plus maintenance is moving the expected remission duration to 3 years,” said Dr Palumbo.

Investigators found no difference in overall survival (OS) because the follow-up is too short, but Dr Palumbo predicted the median OS would be about 6 years. “For elderly patients, this is a major improvement. A few years ago median OS was 3 years,” he said.

Grade 3-4 hematologic adverse events were as expected, with about a 30%-35% risk of severe neutropenia, about 20% risk of thrombocytopenia, and about 10% risk of anemia in both groups.

Nonhematologic adverse events included about 5% peripheral neuropathy and about 10% infection in both groups, but there was a higher risk of cardiologic events in the 4-drug group due to the addition of thalidomide. Deep-vein thrombosis was less than 5%.

The drop-out rate (15%) is half of the usual discontinuation rate, he noted.

The move to once-weekly bortezomib infusions did not affect CR or PFS at 2 years while the risk of peripheral neuropathy was reduced from 14% to 2% and discontinuation rates dropped from 16% to 4%. “Once-weekly bortezomib does not change efficacy and is a major improvement in the safety profile in this combination,” he said.

Dr Palumbo and colleagues concluded that “the 4-drug combination with maintenance is the best available treatment option today for elderly MM patients and should become the new standard of care.”