No abstract

In a recent phase 3 trial, bortezomibmelphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this posthoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P > .999), and 3-year overall survival rate was 88% and 89%, respectively (P ‫؍‬ .54). The complete response rate was 30% in the onceweekly and 35% in the twice-weekly group (P ‫؍‬ .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P ‫؍‬ .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P < .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P < .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179. (Blood. 2010;116(23): 4745-4753)

PURPOSE We investigated the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included bortezomib, thalidomide, and dexamethasone (VTD) in patients with multiple myeloma (MM) responding to autologous stem-cell transplantation (auto-SCT). PATIENTS AND METHODS Patients achieving at least very good partial response who had an available molecular marker based on the immunoglobulin heavy-chain rearrangement received four courses of treatment every month: four infusions per month of bortezomib at 1.6 mg/m(2), thalidomide at 200 mg/d, and dexamethasone at 20 mg/d on days 1 to 4, 8 to 11, and 15 to 18. Patients were studied with tumor-clone-specific primers by qualitative nested PCR and RQ-PCR. Results Of 39 patients enrolled, 31 received the four VTD courses. Immunofixation complete responses increased from 15% after auto-SCT to 49% after VTD. Molecular remissions (MRs) were 3% after auto-SCT and 18% after VTD. Median time to maximum response was 3.5 months. So far, no patient in MR has relapsed (median follow-up, 42 months). VTD consolidation induced an additional depletion of 4.14 natural logarithms of tumor burden by RQ-PCR. Patients with a tumor load less than the median value after VTD had outcomes better than those who had tumor loads above the median value after VTD (at median follow-up: progression-free survival, 100% v 57%; P < .001). CONCLUSION To the best of our knowledge, this study is the first to document the occurrence of persistent MRs in a proportion of MM patients treated without allogeneic transplantation. Moreover, the major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs.

In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination, bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m 2 , 1.3 mg/m 2 , or 1.6 mg/m 2 ) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m 2 on days 1 through 5 and prednisone at 60 mg/m 2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The maximum tolerated dose of bortezomib was 1.3 mg/m 2 . Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%) achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5 patients), fatigue (1), vasculitis (1), and peripheral neuropathy ( IntroductionMultiple myeloma (MM) is a malignant plasma cell proliferative disorder that accounts for more than 16 000 deaths each year in Europe. 1 In the last 50 years, several combination chemotherapy regimens have been tested, but no regimen was better than the original melphalan and prednisone (MP) regimen. 2 During the last 10 years, high-dose melphalan with hematopoietic stem cell support was the only option that significantly increased the rate of complete response (CR) and extended event-free and overall survival. 3,4 Oral low-dose melphalan in elderly patients and high-dose melphalan in younger patients, therefore, became the standard of care. However, new drugs, such as thalidomide, lenalidomide, and bortezomib, are changing the therapeutic scenario of MM. 5 Thalidomide, in combination with dexamethasone or chemotherapeutic agents, showed in vivo additive or synergistic activity, and often induced high rates of profound tumor regression, similar to those achieved after high-dose chemotherapy. [6][7][8][9][10] The response rate of relapsed myeloma to thalidomide ranges from 25% to 35%. 5,6 When thalidomide is used in combination with corticosteroids, the response rate increases to about 50% and to approximately 70% in combination with alkylating agents. 5,7,8 In 2 independent randomized studies, the combination of MP plus thalidomide (MPT) not only increased the CR rate, but also significantly prolonged event-free and overall survival in comparison with the original MP. 9,10 In the French study, MPT was also superior to a reduced intensity autologous transplantation procedure. 9 These findings are now changing the treatment paradigm of elderly patients with myeloma.Bortezomib is the first proteasome inhibitor to enter into clinical use. Preclinical...