Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.[10,51] In several retrospective, nonrandomized comparisons, bortezomib administered once weekly had significantly less grade 3 to 4 peripheral neuropathy (2%–8% vs. 13%–28%) with no loss of efficacy compared with standard biweekly administration.[52,53]
In a randomized, prospective trial, subcutaneous injections of bortezomib were compared with intravenous infusions in the usual schedule (days 1, 4, 8, 11). After a median follow-up of 1 year, grade 3 to 4 neurologic toxicity was reduced from 16% to 6% (P = .026) using the subcutaneous route, with no perceived loss of efficacy in terms of response. However, this study was not powered for noninferiority of response. New clinical trials are employing these changes of weekly treatment and subcutaneous route to improve the safety profile of bortezomib-containing regimens. In this trial, the bisphosphonates were continued until the time of relapse.
- A phase II trial of 257 patients who were heavily pretreated with bortezomib and lenalidomide showed a response rate of 24% and a median duration of response of 8 months.[Level of evidence: 3iiiDiv] Combinations of carfilzomib with lenalidomide and dexamethasone showed a 62% complete response (CR) or near CR in untreated patients.[Level of evidence: 3iiiDiv] Response rates around 50% were seen in 129 bortezomib-naïve patients wtih multiply-relapsed or refractory myeloma.[Level of evidence: 3iiiDiv]
Evidence (conventional-dose chemotherapy):
The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[58,59,60,61][Level of evidence: 3iiiDiv]
- No randomized studies support the widespread use of this regimen in untreated patients.
- This regimen avoids early exposure to alkylating agents, thereby minimizing any problems with stem cell collection (if needed) and any future risks for myelodysplasia or secondary leukemia.
- Disadvantages include the logistics for a 96-hour infusion of doxorubicin and a low CR rate.
- An alternative version of VAD substitutes pegylated liposomal doxorubicin for doxorubicin, eliminates the need for an infusion, and provides comparable response rates.[62,63][Level of evidence: 3iiiDiv]