Bortezomib Plus Thalidomide Treatment of Newly Diagnosed Patients with Multiple Myeloma - Efficacy and Neurotoxicity: Results of a Multicenter Study.

Introduction: The standard first-line treatment for patients with multiple myeloma (MM) has been melphalan plus prednisone (MP). However, complete responses (CRs) are rare. As single agents, bortezomib (V) and thalidomide (T) achieved responses in <50% of newly diagnosed MM patients, whereas combinations of V or T with dexamethasone (D), designated VD and TD, demonstrated response rates of 85% and 63%, respectively. We examined the anti-MM activity and neurotoxicity of VT, a steroid-free regimen.

Methods: In this phase II study in 30 untreated MM patients, bortezomib 1.3mg/m² was administered intravenously on days 1, 4, 8, and 11 of a 21-day cycle for up to 8 cycles. Thalidomide 100mg was administered orally at bedtime on days 1 through 21 for up to 8 cycles. Response was assessed with European Group for Blood and Marrow Transplantation (EBMT) criteria. Newly diagnosed MM patients (including Phase IB, II and III according to the International Myeloma Working Group [IMWG] criteria) were eligible if they were 18–80 years of age, had anticipated life expectancy >6 months, and had an age-adjusted creatinine clearance of ≥15 mL/min within 14 days before enrollment.

Results: Median age was 56.6 years (range, 30–77), albumin was <3.5g/dL in 18 patients (60%), b2-microglobulin was ≥3.5mg/L in 20 patients (66%), and hemoglobin was ≥100g/L only in 9 patients (30%). International Staging System I/II/III were 3%/50%/47% respectively; all patients had stage III MM according to the IMWG criteria. There were 26 patients (87%) who completed at least two cycles of therapy and were evaluable for response; 18 (60%) completed the planned 8 cycles. Treatment was discontinued in 4 patients due to renal failure. Rates of overall response (ORR), CR, near CR (nCR), partial response (PR), and stable disease (SD) are summarized in Table 1. Median time to response was 35.6 days (range, 7–60). The best response occurred within the first 4 cycles in 96% of patients. Side effects were predictable and manageable. The main toxicities were hematologic (53%), fever (47%), gastrointestinal (40%), fatigue (37%), and peripheral neuropathy (36%). Grade 3 nonhematologic adverse events included 4 patients (15%) with renal failure associated with tumor lysis syndrome, 1 patient (4%) with peripheral sensory neuropathy and motor neuropathy that improved with VT dose reductions, and 1 patient (4%) with hypotension. One patient (4%) experienced Grade 4 thrombocytopenia. One patient (4%) died due to acute renal failure. No deep vein thromboses occurred in this study, compared with a reported incidence of thromboembolic events between 15–20% with TD-containing regimens.

Conclusions: VT produced very high ORR and CR in the treatment of newly diagnosed MM patients. No DVTs occurred with this steroid-free combination without any use of anticoagulant drugs. The rate of peripheral neuropathy was lower than expected. This is a very effective regimen with manageable toxicity.