Bortezomib Therapy Alone and in Combination with Dexamethasone for Patients with Previously Untreated Multiple Myeloma.

Abstract

Introduction: Bortezomib ± dexamethasone (dex) has demonstrated impressive activity in the treatment of relapsed and refractory myeloma. Bortezomib is currently approved in the U.S. for multiple myeloma patients who have received at least 1 prior therapy. We are conducting a phase 2 trial evaluating bortezomib alone or in combination with dex as first-line therapy in patients with myeloma. Methods: Eligible patients had measurable disease and a Karnofsky performance score (KPS) ≥ 50%. Bortezomib 1.3 mg/m2 was administered by IV bolus on days 1, 4, 8, and 11 of a 3-week cycle for a maximum of 6 cycles. Oral dex 40 mg was given to patients who achieved < partial response (PR) after 2 cycles or < complete response (CR) after 4 cycles. European Group for Blood and Marrow Transplantation criteria were used to assess response, with the addition of a near CR (nCR) category, defined as nondetectable M-protein by electrophoresis but positive immunofixation and normal bone marrow. Results: Fifty patients have been accrued to the study, and 40 are evaluable for response. Median age was 58 years, and 52% were men. The major myeloma subtypes were IgG (64%) and IgA (19%). The majority of patients were Durie-Salmon stage II (29%) or IIIA (43%). The major response rate (CR + nCR + PR) was 85%. The best response was observed after cycle 2 in 41%, after cycle 4 in 75%, and after cycle 6 in 85% of patients. Dex was added for 28 patients (70%): 17 patients at cycle 3, 10 patients at cycle 5, and 1 at cycle 6. An improved response after combination therapy was observed in 18 patients: 11 improved from MR to PR, 5 improved from stable disease (SD) to PR, 1 improved from SD to CR, and 1 improved from SD to minor response (MR). Twelve patients underwent stem cell transplantation, and all had complete hematologic recovery. Thirteen patients discontinued from the study: 9 due to adverse events, 2 due to progressive disease, and 2 withdrew. The most common adverse events (grade ≥ 2) were neuropathy (26%), fatigue (22%), constipation (17%), and neutropenia (14%). Two patients developed grade 4 events, 1 with neutropenia and 1 with thrombocytopenia. Conclusion: Bortezomib alone or in combination with dex was highly active in the first-line treatment of patients with myeloma. The combination of bortezomib + dex demonstrated additional benefit. Toxicities were manageable and reversible. Although experience has been limited to date, stem cell transplantation was successful in all attempts, indicating that bortezomib-based therapy should be further explored as an induction regimen before transplantation.

The Emerging Role of Targeted Therapy for Hematologic Malignancies: Update on Bortezomib and Tipifarnib

“…In a second phase II trial, bortezomib 1.3 mg/m 2 in the usual regimen was administered alone or with 40 mg of oral dexamethasone if patients did not achieve at least a partial response after two cycles, or had less than a complete response after four cycles [25]. For the 23 patients who completed the study and were evaluable, bortezomib was found to be highly active in the first-line treatment of multiple myeloma, with an overall major response rate of 83% (CR, 13%; nCR, 17%; PR, 53%) and minor response rate of 13%.…”

Update on Recent Developments for Patients with Newly Diagnosed Multiple Myeloma

“…The most common adverse events were neuropathy, fatigue, constipation, nausea, and neutropenia. Overall, adverse events were found to be predictable and manageable 2 …”

“…The success of bortezomib in the treatment of relapsed and refractory MM provides the rationale for its use in the treatment of newly diagnosed disease, both as single agent and in combination with conventional chemotherapy and autologous stem cell transplantation. In a Phase II study in patients with previously untreated MM, an overall response rate (ORR) of 90%, with a complete response (CR) plus near CR (nCR) rate of 19%, was achieved in 48 evaluable patients receiving bortezomib plus dexamethasone 2 . Dexamethasone was added in patients with less than a partial response (PR) after two cycles or less than a CR after four cycles.…”