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Phase I/II Study of Oral Cyclophosphamide, Prednisone, and Velcade in Patients with Relapsed/Refractory Myeloma
By Donna E. Reece, MD

This Phase I/II study of oral cyclophosphamide, prednisone, and Velcade included a new dosing schedule for Velcade: days 1, 8, and 15 at 1.5 mg/square meter on a 28-day schedule. The overall response rate was 84%, with 38% CR/VGPR. There was no significant peripheral neuropathy, and patients tolerated the regimen well. It is now the standard relapse protocol in Canada.


A Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone for Relapsed/Refractory Multiple Myeloma. Session Type: Poster Session, Board #765-III

Donna E. Reece, Giovanni Piza, Suzanne Trudel, Mariela Pantoja, Christine Chen, Joseph R. Mikhael, Vishal Kukreti, Keith Stewart Princess Margaret Hospital, University Health Network, Toronto, ON, Canada

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 2-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)
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
*Community acquired pneumonia without neutropenia; ** protocol amended to exclude G-CSF for 2 weeks before study entry.

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: 1) 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; 2) preliminary response rates at this dose level include 4/6 (67%) CR/near CRs and 1/6 (17%) PR.
Abstract #3536 appears in Blood, Volume 108, issue 11, November 16, 2006

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