Adverse events hinder thalomide treatment for multiple myeloma

SAN FRANCISCO -- Thalomide may not be the best partner for bortezomib(Drug information on bortezomib) (Velcade) in combination therapy for elderly multiple myeloma patients. Based on the results of a phase III clinical trial, bortezomib, prednisone, and thalidomide(Drug information on thalidomide) achieved equivalent outcomes when compared with a similar combination therapy using melphalan(Drug information on melphalan), but led to more serious adverse events, particularly thromboembolic complications.

Maria-Victoria Mateos, MD, of University Hospital of Salmanca in Spain, and the Spanish Myeloma Group wanted to determine the best treatment partner for a prednisone(Drug information on prednisone)-bortezomib treatment regimen for multiple myeloma: an alkylating medication (melphalan) or an immunomodulating agent (thalidomide).

The trial enrolled and randomized 260 elderly untreated multiple myeloma patients; 205 patients were available for evaluation after induction therapy. Patients in the bortezomib, melphalan, prednisone arm (VMP) received intravenous bortezomib 1.3 mg/m² twice weekly for one six-week cycle, followed by once weekly for five five-week cycles in combination with oral melphalan 9 mg/m² and prednisone 60 mg/m² once daily on days 1 to 4 of each cycle.

Those in the bortezomib, thalidomide, prednisone arm (VTP) received the same dosages of bortezomib and prednisone, but instead of melphalan, took an oral dose of 100 mg of thalidomide once daily (abstract 651).

The results showed no significant difference in response rates when the two regimens were compared. Overall response rate in both groups was 81%, and the complete response rate was also equivalent. The median time to first response was 1.6 months in both arms, and the median time to complete response was approximately 4.5 months with both treatment regimens. Only one patient in each arm progressed under induction treatment. Even when subgroups of patients were analyzed according to age, the presence of plasmocytomas or high-risk cytogenetics, the complete response rate continued to be similar in both treatment groups.

"We may need to explore other immunomodulatory drugs in this setting, such as lenalidomide," Dr. Mateos said.

However, when the researchers looked at toxicities, the two treatment regimens were clearly different. The overall serious adverse events in the VTP arm were much higher than in the VMP arm at 38% and 15%, respectively. Seventeen percent of patients in the VTP arm discontinued therapy because of these events versus 8% in the VMP arm. The number of deaths (4% in each arm) from toxicities was similar with both treatment regimens.

The VMP treatment caused more neutropenias (37% versus 21%) and thrombocytopenias (22% versus 12%) than the VTP regimen. But the rate of thromboembolic events was significantly higher with VTP than with VMP (4% versus <1%). Dr. Mateos noted that while grade IV infections can be prevented with prophylactic antibiotics, it was much more difficult to prevent thromboembolic events.

She also noted that the less intense dose of bortezomib in this study, when compared with the Spanish VISTA trial, resulted in a fairly low rate of grade IV neuropathy at 5% in the VMP arm and 9% in the VTP arm.

"This dose is better tolerated by elderly patients, but yields as many complete remissions. It's very effective but with lower toxicity, especially for frailer patients," Dr. Mateos said.