Dose Definition for Intravenous Cyclophosphamide in Combination with Bortezomib/Dexamethasone for Remission Induction in Patients with Newly Diagnosed Multiple Myeloma.

This study was designed to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and efficacy of intravenous cyclophosphamide (CY) in combination with the proteasome inhibitor bortezomib and high-dose dexamethasone (DEX) for remission induction in younger patients with newly diagnosed multiple myeloma (MM). Patients ≤ 60 years were enrolled to receive three 3-week treatment cycles with bortezomib 1.3 mg/m²/dose on days 1, 4, 8, and 11 in combination with DEX 40 mg/day orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY intravenously on day 1 at either 600, 900, 1200, or 1500 mg/m² - the optimal dose had to be defined. Recommended concomitant medication included bisphosphonates, antacids, prophylactic antiviral treatment, prophylaxis against pneumocystis pneumonia, and oral non-absorbable antifungal medication. In addition, antiemetics, cytokines, and intravenous immunoglobulins were allowed. DLT was defined using the National Cancer Institute common terminology criteria for adverse events, version 3.0 as grade 4 hematologic toxicity, ≥ grade 3 non-hematologic toxicity (except emesis, vomiting, and alopecia), ≥ grade 3 peripheral neuropathy, and ≥ grade 2 peripheral neuropathy with pain. MTD was defined as the highest dose studied for which the incidence of DLT was ≤ 33%. Thirty patients completed 78 treatment cycles. Twenty seven patients were evaluable for CY dose definition. Start dose level for CY was 1200 mg/m². Since no patient experienced a DLT the dose level was increased to 1500 mg/m². On this dose level a DLT occurred in 2/3 patients (67%). Therefore the dose level was decreased again to 1200 mg/m² with 4/12 (33%) of patients experiencing DLT. On the next lower dose level a DLT was observed in 8% (1/12). Thus, the MTD for CY in combination with bortezomib and DEX based on cycle 1 was defined as 900mg/m². Dose-limiting toxicities included leukopenia (n=5), neutropenia (n=1), and pneumonia (n=1). No patient died. Other adverse events not reaching dose-limiting intensity included thrombocytopenia, gastrointestinal irritations, fatigue, neuropathy and one patient with herpes zoster. Median time to best response was 63 days. The overall response rate (EBMT criteria) to up to three cycles of this combination was 87%, with 3 complete responses, 20 partial responses and 3 minor responses. No patient experienced progressive disease. Bortezomib combined with DEX and CY is a highly effective treatment for newly diagnosed MM. Recommended phase II/III dose of CY in this combination is 900 mg/m². This schedule is currently being evaluated as pretransplant induction in newly diagnosed MM in a prospective trial of the Deutsche Studiengruppe Multiples Myelom (DSMM).