Bortezomib, Intravenous Cyclophosphamide and Dexamethasone (VelCD) for Previously Untreated Multiple Myeloma: An Interim Analysis of the German DSMM XIa Trial

Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). However, 40% of pts fail to achieve remission to standard cytotoxic regimens obviously necessitating improvement. Bortezomib (Vel) is considered the most potent single agent MM therapy. Bortezomib-containing induction treatments have already been shown to be superior to vincristine, adriamycine, and dexamethasone.

Methods. As previously reported, 30 pts were included in the dose finding study to determine the optimum dose of intravenous cyclophosphamide (C) in conjunction with Vel and dexamethasone (D). Here we report on the results of the planned interim analysis with an additional 70 pts up to 60 years of age with untreated MM. They were enrolled between 03/2006 and 03/2008 to receive a maximum of 3 three-week cycles of induction treatment with Vel 1.3 mg/m2 IV d1,4,8,11; D 40 mg/d d1,2,4,5,8,9,11,12; and C 900mg/m2 IV d1 before scheduled ASCT as a consolidation. Primary study objective is response rate (≥ PR) to VelCD before ASCT according to the stringent EBMT criteria.

Results. Data from the first consecutively completed 100 pts (mean age, 52 years; 78% stage III) from 22 German centers were analyzed. Molecular cytogenetic analysis was available for 79% with the most frequent cytogenetic abnormalities being 13q− (34%), 17p− (14%) and t[4;14] (8%). All 100 pts (84% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate was 79% with 11% CR and 68% PR + VGPR; only 2 subjects (2%) progressed. Typically VAD induces app. 60% response. Additionally, response by cytogenetic risk group was assessed. Response was documented in 73.5% of the subjects with 13q−, in 100% with t(4;14) and in 57.1% with 17p−. 42 SAEs were reported: 18 pts had a SAE associated with Vel, 17 had a SAE associated with C, and for 10 pts SAE associated with D was established. One patient died due to gastric hemorrhage possibly related to dexamethasone. This is a remarkably low rate of early deaths (1%) in this setting. 53% of the patients experienced grade 3 + 4 AE with leucopenia (34%), thrombocytopenia (6%), neutropenia (5%), anaemia (4%), nausea (3%) and bone pain (3%) being the most frequent. Infections of grade 3 and 4 have been reported in 2% and a low incidence of grade 3 (2%) but no grade 4 paraesthesia occurred while 13% of pts developed peripheral neuropathy (only of grades 1 and 2).

Conclusion. This analysis demonstrates Bortezomib combined with D and intravenous C is a highly effective treatment regimen regardless of cytogenetic risk factors for newly diagnosed MM with acceptable toxicity. Given the importance of high-quality response prior to ASCT, VelCD is considered a very active induction regimen.

Table 1. Response to study therapy (intent-to-treat set, n=100)

Table 2. Response by result of cytogenetic analysis (intent-to-treat set, n=100)