Bortezomib, low‐dose intravenous melphalan, and dexamethasone for patients with relapsed multiple myeloma

Abstract

Summary This multicenter phase I/II study investigated the maximum tolerated dose (MTD), safety, and efficacy of low dose intravenous (IV) melphalan in combination with bortezomib for patients with relapsed multiple myeloma (MM). Patients received bortezomib 1·3 mg/m2 on days 1, 4, 8, and 11 and escalating doses of IV melphalan (2·5–10·0 mg/m2) on day 2 of a 28‐day cycle for a maximum of eight cycles. Dexamethasone 20 mg was added for progressive or stable disease. Fifty‐three patients were enrolled. The MTD was defined at melphalan 7·5 mg/m2 and bortezomib 1·3 mg/m2. The overall response rate (ORR) was 68% (23% complete or near‐complete responses [CR/nCR]) whilst at the MTD (n = 33) the ORR was 76% (34% CR/nCR). After median follow‐up of 17 months, the median progression free survival was 10 months, rising to 12 months at the MTD (P < 0·05 vs. non‐MTD regimens). The median overall survival was 28 months, but was not yet reached at the MTD. Grade 3/4 adverse events included thrombocytopenia (62%), neutropenia (57%), infection (21%), and neuropathy (15%). Bortezomib and low‐dose IV melphalan combination therapy is a safe and highly effective regimen for patients with relapsed MM. These data suggest further investigation of this combination is warranted.

Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial

“…Bortezomib-based combinations are also being investigated with the aim of improving outcomes, with promising results to date. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] In conclusion, bortezomib continues to demonstrate superior survival to high-dose dexamethasone in patients with relapsed MM following 1 to 3 prior therapies, confirming the substantial activity of bortezomib as a single agent and further supporting its study both earlier in the disease course and in combination regimens. For personal use only.…”

A Phase I/II Trial Combining High-Dose Melphalan and Autologous Transplant with Bortezomib for Multiple Myeloma: A Dose- and Schedule-Finding Study

“…In conclusion, the efficacy of adding bortezomib to conventional chemotherapy is one that has been tested and confirmed in the context of standard dose therapy (22,23,37), but is not one that has been fully evaluated with high-dose melphalan and autologous transplant. Based on laboratory rationale for the use of proteasome inhibitors in conjunction with melphalan, this combination represents a novel way to improve efficacy, yet maintains a similar toxicity profile to high-dose melphalan alone, which has not been easily accomplished by adding radiation, additional chemotherapy agents, or radioimmunotherapy to the conditioning regimen for myeloma transplants.…”

Advances in treatment for relapses and refractory multiple myeloma

“…A second subanalysis of patients with impaired renal function revealed increased myelosuppression, particularly thrombocytopenia, in those patients with creatinine clearance \30 ml/min [61]. Based on these findings and pharmacokinetic studies done in healthy volunteers with varying degrees of renal failure without myeloma, dose adjustments were recommended for patients with a creatinine clearance less than 60 ml/min.…”

“…After Berenson reported a 50% response in previously treated patients who received bortezomib, melphalan, and prednisone [62], Popat et al [61] investigated a Phase I/II dose escalation of study of bortezomib, intravenous melphalan, and dexamethasone. In the study by Popat et al, patients had received a median of 3 lines of prior therapy, including 9% who had previously undergone autologous stem cell transplantation.…”

“…Bortezomib has since been combined with alkylating agents like cyclophosphamide and melphalan in phase I/II trials [19,[22][23][24][61][62][63][64][65][66].…”