A Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone for Relapsed/Refractory Multiple Myeloma.

Abstract Bortezomib (btz) has established efficacy in relapsed/refractory multiple myeloma (MM) patients (pts). Combinations of btz and other agents can produce even higher response rates. We have reported that oral cyclophosphamide (CY) + prednisone (P) produced partial remissions (PR) in 41% and a median progression free survival (PFS) of 18.6 mos in MM pts who had progressed after ASCT. We now report a phase I trial adding btz to CY + P in 27 patients with relapsed/refractory MM. CY was given p.o. once weekly on days 1, 8, 15, and 22 of a 28 day cycle while P 100 mg was given every other morning. CY was given before btz on appropriate days. A total of 8 cycles was planned. The median age was 59 yrs (48–74); 16 were male. Ig subtypes were: IgG (19 pts), IgA (4 pts), kappa light chain (4 pts). The median number of prior regimens was 2 (1–6); all had undergone prior ASCT and 59% had received thalidomide and/or lenalidomide. The median pretreatment β2-microglobulin was 228 nm/L (114–875), albumin 38 g/L (30–46) and creatinine 86 nmol/L (58–153). The dose escalation scheme and toxicity with cycle 1 is shown below: Table 1. Dose levels and toxicity Dose Level N CY dose (mg/m2) Btz dose (mg/m2) Gr 3–4 Toxicity (cycle 1) *Community acquired pneumonia without neutropenia; ** protocol amended to exclude G-CSF for 2 weeks before study entry. 1 6 150 0.7 d 1,8,15 2 CAP* 2 3 300 0.7 d 1,8,15 0 3 3 300 1.0 d 1,8,15 1 ↓ PO4 4 6 300 1.0 d 1,4,8,11 1 ↓ANC**; 1 ↑ AST/ALT 5 6 300 1.3 d 1,4,8,11 1 N/V 6 3 300 1.5 d 1,8,15 0 All the above toxicities above were gr 3 except for 1 transient episode of gr 4 hypophosphatemia. Dose limiting toxicity was not seen. The median number of protocol cycles given per pt was 7 (1–8); 1 pt chose to continue therapy and has received 15 cycles. Toxicities in cycles 2–8 were generally mild. Episodes of infection included shingles (5), gr 3 respiratory infection (6) and febrile neutropenia (2). A total of 168 cycles have been administered; the dose of CY was reduced in 5 cycles due to neutropenia (↓ANC) (3), thrombocytopenia (1) or increased AST/ALT (1), while the btz dose was decreased in 4 cycles due to gr 2 peripheral neuropathy (PN) (1) or ↓ANC (3). 12 pts have completed all 8 cycles, 5 are on therapy and 7 have progressed after a median of cycles 3 (1–7). 3 stopped protocol therapy (physician choice in 1 pt with minimal response, gr 2 PN in 2 pts (after 7 cycles at dose levels 2 and 5) including the pt with prior btz dose reduction. 14/15 pts treated at dose levels 4–6 (effective btz doses) were evaluable for response after receiving at least 2 cycles. Best response was CR/nearCR in 6 (43%) and PR in 7 (50%) for an overall response rate of 93%. The median follow-up is 12 mos (1–20). 6 pts have progressed after stopping therapy. The median PFS is 11 mos, while the median overall survival (OS) has not been reached. The actuarial 1 year OS and PFS are 83% (95% CI 61–93%) and 47% (95% CI 24–68%), respectively. 7 of 10 planned additional pts have entered the phase II portion of the trial at dose level 6. 3 have completed at least 2 cycles; 2 are in CR/near CR while one is in PR. We conclude: Btz 1.5 mg/m2 can be given safely on a convenient weekly schedule days 1, 8 and 15 of a 28 day cycle in combination with full dose oral CY + P in relapsed/refractory MM pts; preliminary response rates at this dose level include 4/6 (67%) CR/near CRs and 1/6 (17%) PR.

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