A prospective randomized trial (VISTA) of 682 previously untreated symptomatic patients who were not candidates for stem cell transplantation because of age (one third of patients >75 years) compared bortezomib combined with melphalan and prednisone versus melphalan and prednisone alone. With a median follow-up of 26 months, the OS favored the bortezomib arm in the 3-year OS rates (72% vs. 59%, P = .03).[Level of evidence: 1iiA]
A prospective randomized study of 669 patients with relapsing myeloma, who had been treated previously with steroids, compared intravenous bortezomib with high-dose oral dexamethasone; with a median follow-up of 22 months, the median OS was 29.8 months for bortezomib versus 23.7 months for dexamethasone (HR = 0.77, P = .027), despite 62% of dexamethasone patients crossing over to receive bortezomib.[Level of evidence: 1iiA] Bortezomib-associated peripheral neuropathy is reversible in most patients after dose reduction or discontinuation.[21,46,47,48]
A prospective randomized trial (NCT00103506) of 646 previously treated patients compared bortezomib plus pegylated liposomal doxorubicin with bortezomib alone. With a median follow-up of 7 months, the combination was better in both median time to progression (9.3 mo vs. 6.5 mo, P < .001) and in OS (82% vs. 75%, P = .05).[Level of evidence: 1iiA]
Patients with unfavorable molecular cytogenetics did not show any difference in progression-free or OS compared with patients with more favorable risk factors when bortezomib was incorporated with induction therapy. The benefit from bortezomib appears to be maintained across risk groups.[50,51,52,53][Level of evidence: 3iiiD]
Because bortezomib is metabolized and cleared by the liver, it appears active and well tolerated in patients with renal impairment.
The VAD regimen has shown activity in previously treated and in untreated patients with response rates ranging from 60% to 80%.[54,55,56,57][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 complete response rate. An alternative version of VAD substitutes pegylated liposomal doxorubicin for doxorubicin, eliminates the need for an infusion, and provides comparable response rates.[58,59]Level of evidence: 3iiiDiv]
Evidence is not strong that any alkylating agent is superior to any other. All standard doses and schedules produce equivalent results. The two most common regimens historically have been oral MP and oral cyclophosphamide plus prednisone.[60,61,62]
Combinations such as those used in EST-2479, of alkylating agents and prednisone, administered simultaneously or alternately, have not proven to be superior to therapy with MP.[63,64,65,66][Level of evidence: 1iiA] A meta-analysis of studies comparing melphalan plus prednisone with drug combinations concluded that both forms of treatment were equally effective.[Level of evidence: 1iiA] Patients who relapsed after initial therapy with cyclophosphamide and prednisone had no difference in OS (median 17 mo) when randomly assigned to receive vincristine plus carmustine plus melphalan plus cyclophosphamide plus prednisone (VBMCP) or VAD.