ORLANDO – For patients with newly diagnosed multiple myeloma, an intensive chemotherapy regimen with bortezomib, lenalidomide, and dexamethasone for induction followed by transplant and consolidation with the same regimen plus lenalidomide maintenance produced high rates of very good partial responses or better, with no major peripheral neuropathies, French investigators reported at the annual meeting of the American Society of Hematology.
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Primary results of the phase II IFM 2008 study showed that 80% of patients had at least a very good partial response (VGPR), and nearly 50% of patients had either a stringent complete response (sCR) or complete response (CR) according to international uniform response criteria, said Dr. Murielle Roussel from Hôpital Purpan in Toulouse, France.
There were no cases of grade 3 or 4 peripheral neuropathy, suggesting that the regimen is relatively safe, said Dr. Roussel on behalf of colleagues in the Intergroupe Francophone du Myélome (IFM).
"This intensive program compares favorably to the results obtained with long-term treatment with novel combinations without high-dose therapy. It is, as you know, the framework for the high-dose therapy arm in the IFM/DFCI 2009 joint trial challenging the role of up-front autologous stem cell transplant," she said.
Evidence from recent clinical trials conducted by the IFM and others suggest that a combination of bortezomib, lenalidomide, and dexamethasone (VRD) is a promising three-drug induction regimen prior to autologous stem cell transplants (ASCT). Consolidation therapy can enhance the depth of response, and maintenance can prolong its duration, supporting the choice of VRD as the backbone for the trial, Dr. Roussel said.
The investigators enrolled 31 patients aged younger than 65 years with newly diagnosed multiple myeloma from eight IFM transplant centers. The patients underwent induction therapy with three cycles of VRD, each lasting 21 days. The regimen included bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11), lenalidomide (25 mg/day for days 1-14), and oral dexamethasone (40 mg on day 1, 8, and 14).
Patients were assessed for response after the third cycle, and peripheral stem cells were mobilized and harvested. They then underwent intensification with melphalan 200 mg/m2 and ASCT. After a 2-month hematologic recovery period, the patients could then receive two cycles of VRD consolidation, followed by a year of lenalidomide maintenance, with the drug given at 10 mg/day for 3 months, with dose escalation up to 15 mg if the lower dose was well tolerated.
The primary study outcome was best achieved response 1 month after consolidation. Secondary end points included response rates after three cycles of VRD, the safety and tolerability of the combination in the setting of high-dose therapy, the feasibility of stem cell harvest, progression-free survival, overall survival, time to progression, and duration of response.
The combined CR and sCR rate after induction was 23%, and 62% of patients had a VGPR or better. Following transplant, those rates rose to 36% and 68%, respectively; after consolidation, they were 48% and 84%.
Common toxicities of all grades included thrombocytopenia in 97% of patients, and anemia and neutropenia each in 87%. Sensory peripheral neuropathy occurred in 68% of patients, erythroderma or skin rash in 32%, pneumonia in 16%, and varicella zoster viral infections in 13%.
In all, 39% of patients experienced grade 3 or 4 neutropenia leading to lenalidomide dose reduction in eight patients (26% of the total cohort). In addition, 13% of patients had grade 3 thrombocytopenia, and 6% had grade 3 anemia. There were no grade 4 thrombocytopenia or anemia cases, and no grade 3 or 4 sensory peripheral neuropathy. Grade 1 or 2 neuropathy requiring reductions of bortezomib dose occurred in seven patients.
From one to five stem cell collections (median, two) were required to obtain a sufficient number for ASCT. Five patients needed a second-line mobilizing agent, and investigators were unable to obtain enough cells from one patient with stable disease; this patient did not undergo autologous transplant.
The IFM-2008 study is sponsored by University Hospital Toulouse, with support from Celgene and Janssen-Cilag. Dr. Roussel disclosed receiving research funding and serving on the speakers bureaus of the companies.