The effectiveness and safety of Revlimid in newly diagnosed myeloma has rapidly been investigated and demonstrated. Revlimid in combination with dexamethasone is now listed as a recommended option for initial therapy in transplant candidates in the National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines for multiple myeloma. The combination of Revlimid plus melphalan and dexamethasone is a promising approach for use in patients not eligible for transplant.

In combination with dexamethasone. Results from the first Phase II study evaluating Revlimid in combination with dexamethasone in newly diagnosed, previously untreated, symptomatic myeloma demonstrate that the combination is highly active. (Rajkumar et al. Blood. 2005;106(13):4050-4053.) In the study, patients received treatment for four 28-day cycles, during which Revlimid (25 mg) was taken orally on days 1 to 21 and dexamethasone (40 mg) was taken orally on days 1 to 4, 9 to 12, and 17 to 20. Dose adjustments were permitted based on toxicity. All patients received low-dose aspirin to prevent DVT. Patients could go off treatment after 4 cycles of therapy to pursue stem cell transplant, but treatment beyond 4 cycles was permitted. Adequate stem cells were collected in all patients who proceeded to stem cell transplant.

Thirty-one of 34 patients achieved an objective response with the oral regimen, including 2 (6%) achieving a CR and 11 (32%) meeting the criteria for both very good PR and near CR, resulting in an overall objective response rate of 91%. This response rate compares favorably with those previously reported with the combination of thalidomide and dexamethasone.

The side effect profile was similar to that seen with dexamethasone alone in a recent randomized trial conducted by ECOG. Forty-seven percent of patients experienced Grade 3 or higher nonhematologic toxicity; major toxicities are noted in the table below.

Updated response data from this trial, as well as new data on time-to-progression (TTP) and survival were reported at the ASH meeting in 2006. (Lacy et al. Blood. 2006;108(11). Abstract 798.) The data show that this oral regimen is highly effective and durable both as primary therapy or as induction therapy prior to transplant, with low disease progression rates at 2 years (see table below).

The most common Grade 3/4 events were fatigue (21%) and neutropenia (21%). Aspirin was effective prophylaxis for deep vein thrombosis; one patient developed pulmonary embolism.

In combination with melphalan and prednisone (R-MP). Previously, the addition of thalidomide to the standard melphalan-prednisone regimen (MPT) was shown to significantly increase response rate and event-free survival when used as initial treatment in elderly patients not eligible for transplant. (Palumbo A, Bringhen S, Caravita T, et al. Lancet. 2006;367;825-831.) The addition of Revlimid to MP (R-MP) also appears to be a promising approach for this patient population, according to results of a dose-ranging Phase I/II study presented at ASH in 2006. (Palumbo et al. Blood. 2006;108(11). Abstract 800.) The rates of CRs and very good PRs achieved approach those obtained with stem cell transplant with less toxicity.

Patients in this study were older than 65 years of age and were treated with 9 courses of Revlimid (5-10 mg/day for 21 days every 4-6 weeks) plus MP (melphalan 0.18-0.25 mg/kg and prednisone 2 mg/kg for 4 days every 4-6 weeks) at four different dose levels. Patients then received maintenance Revlimid (10 mg/day for 21 days for 21 days). All patients received ciprofloxacin and aspirin as prophylaxis.

The maximum tolerated doses were identified as 0.18 mg/kg melphalan for 4 days and 10 mg/day Revlimid for 21 days. Response rates and preliminary survival data compare favorably with those previously reported for MPT. Overall, 48% of patients achieved a CR or VGPR (CR = 18%, VGPR = 30%). Responses were not correlated with chromosome 13 deletion, suggesting that this combination may overcome the poor prognosis associated with this deletion. Grade 3/4 toxicities were mainly low blood counts.

Similar preliminary findings with combination MP and Revlimid (MPR) were seen in a Phase I/II study being conducted at the Mayo Clinic in elderly patients with newly diagnosed myeloma, results of which were also reported at ASH in 2006. (Roy et al. Blood. 2006;108(11). Abstract 3558.)

A Phase III trial of Revlimid in combination with melphalan and prednisone (MP) in newly diagnosed patients aged 65 years and older is now enrolling patients in Europe and Australia.