A 4-Drug, Weekly Combination Regimen of Bortezomib, Cyclophosphamide, Liposomal Doxorubicin, and Dexamethasone for Initial Treatment of Multiple Myeloma

Combination regimens have been highly effective in multiple myeloma. Based on our results with the combination of bortezomib, cyclophosphamide, dexamethsone (Bensinger et al Br J Haematol 2010), we added liposomal doxorubicin to assess whether we could improve response as well as evaluate a weekly combination regimen at our academic center and network affiliated sites in the community. The trial is registered as NCT00849251.

We initially evaluated the regimen in the relapsed setting for toxicity and found it to be well tolerated in 6 patients, then moved to newly diagnosed patients, with the intent that the regimen would serve as induction chemotherapy in preparation for autologous stem cell transplant for transplant-eligible patients. The dosing was bortezomib 1. 6 mg/m² IV, cyclophosphamide 300 mg/m² IV, and dexamethasone 40 mg po, days 1, 8, 15, and a single dose of liposomal doxorubicin 30 mg/m² on day 8 per 28 day cycle. Patients received a maximum of 4 cycles of therapy and the primary endpoints were safety and response at the end of treatment.

A total of 31 out of the planned 45 patients (both newly diagnosed and relapsed) were enrolled, as the trial was ended early due to inability to obtain liposomal doxorubicin (Doxil®) for a period of 6 months. One of the relapsed patients was administratively withdrawn after the cycle 1 day 1 treatment. For the remaining 5 relapsed patients who received 2–4 cycles of treatment, the responses were 1 VGPR that was only immunofixation positive, 1 PR and 3 stable disease (SD). For the 24 patients with newly diagnosed MM who completed 1–4 cycles of treatment, there were 2 complete remissions (CRs), 5 VGPRs (2 of which were only immunofixation positive), 11 PRs, and 6 SD for an overall (CR+VGPR+PR) response rate of 75%. Five patients did not complete 4 cycles of therapy, one due to massive pulmonary embolism, one because of need for radiation for intractable back pain during cycle 2 despite marked serological response, and 3 due to stable disease with plateau in response. Of the 25 patients who received BCDD as initial therapy, there have been 3 deaths to date, one due to massive pulmonary embolism on day 13 of the first cycle of treatment, without known history of hypercoagulable risk, one at 7. 7 months of unknown cause, and one at 15. 3 months of progressive disease, resulting in an estimated overall survival of 86% at 2 years from start of therapy. Median follow-up among the 22 survivors is 16. 6 months (range, 8. 1 to 26. 8 months). One patient with a known central line associated deep venous thrombosis in the relapsed group did not exhibit progression of thrombosis off warfarin during therapy. After enrollment of the first 9 patients, an amendment was filed for subsequent patients to receive aspirin prophylaxis, or if at high risk by criteria suggested by Palumbo et al for prophylaxis for MM patients on imids, with low molecular weight heparin or warfarin. Other adverse events that were attributed to investigational regimen include grade 3 hand/foot syndrome (2), infection without neutropenia (1), urinary tract infection (1), and gastrointestinal hemorrhage due to Mallory-Weiss tear (1). Twenty-one patients who completed therapy went on to successful mobilization and collection of peripheral blood stem cells, and autologous or tandem autologous (2) or tandem autologous-minimal myeloablative allogeneic stem cell transplant (7). Two of the 21 patients have died (one at 2. 1 months after first autologous transplant from unknown cause, and one at 9. 8 months from progressive disease). Median follow-up after first autologous transplant among the 19 survivors is 13. 4 months (range, 1. 1 to 20. 4 months).

The 4 drug BCDD regimen exhibited a 75% overall response rate after 4 cycles, with no progression during treatment, was able to be administered weekly in an outpatient setting of both academic and community hematologists and oncologists, and successfully prepared patients for autologous stem cell transplant.

Becker:Millennium: Research Funding. Bensinger:Millennium: Research Funding.