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This phase III, open-label, randomized, controlled study aimed to evaluate the benefit of adding continuous low-dose oral cyclophosphamide to bortezomib-dexamethasone in patients with primary relapsed/refractory multiple myeloma. Patients were randomized 1:1 to receive up to eight 3-week cycles of bortezomib (1.3 mg/m 2 ) and dexamethasone (20 mg; VD; n = 48) or bortezomib-dexamethasone plus oral cyclophosphamide (50 mg; VCD; n = 48). Median time to progression (primary endpoint) was slightly longer in the VD versus VCD group (12.6 vs 9.9 months, P = 0.192), and the hazard ratio for disease progression was in favor of VD (hazard ratio = 0.71, 95% confidence interval = 0.43-1.19, P = 0.196). The overall response rate was 74% with VD and 70% with VCD. Most adverse events were similar in frequency between arms; however, grade ≥ 3 peripheral neuropathy was more frequent in the VCD versus VD arm (15 vs 4%). Infection rate was higher in the VCD arm (64 vs 52%); however, grade ≥3 infection rates were comparable (19 vs 17%). Further trials are needed to determine whether addition of cyclophosphamide to VD at a different dose/schedule confers clinical benefit. This study was terminated prematurely, with insufficient sample size to adequately compare the arms; the results should, therefore, be considered descriptive. This trial is registered: EudraCT Number 2008-003213-27; ClinicalTrials.gov NCT00813150.

Purpose: Novel drugs including targeted approaches have changed treatment paradigms for multiple myeloma (MM) and may also have therapeutic potential in the poor-prognosis t(4;14) subset; t(4;14) results in overexpressed and activated fibroblast growth factor receptor 3 (FGFR3). Blocking this receptor tyrosine kinase (RTK) induces apoptosis in t(4;14)+ MM cells and decreases adhesion to bone marrow stromal cells (BMSC). Using combinations of novel drugs, we investigated potential enhancement of single-agent activities within the tumor cells, targeting of the marrow micromilieu, or circumvention of drug resistance in t(4;14)+ MM., Experimental Design: We tested effects on apoptosis and related signaling pathways in the t(4;14)+ MM subset, applying drug combinations including a FGFR3 tyrosine kinase inhibitor (RTKI), the proteasome inhibitor bortezomib, and dexamethasone., Results: RTKI, bortezomib, and dexamethasone were active as single agents in t(4;14)+ MM. RTK inhibition triggered complementary proapoptotic pathways (e.g., decrease of Mcl-1, down-regulation of p44/42 mitogen-activated protein kinase, and activation of proapoptotic stress-activated protein/c-Jun NH(2)-terminal kinases). Synergistic or additive effects were found by combinations of RTKI with dexamethasone or bortezomib. In selected cases of t(4;14)+ MM, triple combinations were superior to dual combinations tested. Prevention from MM cell apoptosis by BMSC or exogenous interleukin-6 was circumvented by drug combinations. In t(4;14)+, N-ras-mutated NCI-H929 cells, resistance to RTKI was overcome by addition of dexamethasone. Notably, the combination of RTKI and dexamethasone showed additive proapoptotic effects in bortezomib-insensitive t(4;14)+ MM., Conclusions: Combining novel drugs in poor-prognosis t(4;14)+ MM should take into account at least bortezomib sensitivity and probably Ras mutational status.

Abstract: Fifteen patients with advanced multiple myeloma were scheduled to receive bortezomib 1.3mg/m2 IV days 1, 4, 8, and 11 every 3 weeks for eight cycles in combination with dexamethasone. One patient (7%) achieved a complete response, 10 (67%) a partial response, and one (7%) a minor response (MR) resulting in an overall response rate (≥MR) of 80% (9/9 with ≥ 2nd untreated and 3/6 with refractory relapse). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters including deletion of chromosome 13. Adverse events, mainly myelosuppression, neuropathy and fatigue, were manageable. [Copyright &y& Elsevier]