Evaluating the Efficacy and Toxicity of Two Lenalidomide Dose Regimens for the Treatment of Older Relapsed Multiple Myeloma Patients with Co-Morbidities: A Multi-Site Study at the Veteran's Administration Hospitals

Background: Lenalidomide 25 mg once daily, 3 weeks on and 1 week off, with weekly dexamethasone is considered standard treatment for patients with multiple myeloma, although patients with comorbidities treated with this regimen frequently require dose reductions due to toxicity. We investigated the use of a lower initial lenalidomide dose in an effort to assess dose-associated toxicity as well as efficacy.

Methods: This multi-center, open-label randomized trial included relapsed multiple myeloma patients randomized in a 1:1 ratio to receive lenalidomide 25 mg (Arm A) or lenalidomide 15 mg (Arm B) orally once daily for 21 days of each 28 day cycle. Both groups also received dexamethasone 40 mg once weekly. Patients continued the treatment until disease progression, with dose reductions or cessation of lenalidomide or dexamethasone as needed for toxicity. The primary objective of the trial was to monitor dose reductions and toxicities and compare response rates based on IMWG criteria and event-free survival in each arm.

Results: A total of 33 relapsed multiple myeloma patients were treated on this clinical trial at 6 different Veteran's Administration Hospitals in the United States, with 16 patients randomized to the lenalidomide 25 mg group (Arm A) and 17 patients to lenalidomide 15 mg group (Arm B). All patients were male, with a median age of 70.5 years (range 53 to 87) and an average of 6 comorbid conditions; including, but not limited to, 64% with cardiovascular disease, 55% with urologic/renal dysfunction (33% with renal dysfunction), 36% with metabolic disorders and 33% with respiratory disorders. Patients were taking an average of 12 medications with significant risk of polypharmacy. We observed significantly higher frequency of dose reductions with the lenalidomide 25 mg dose compared to 15 mg dose (10 vs 4; p= 0.03). Of those requiring lenalidomide dose reductions the median number of comorbid conditions was 6.5 (mean 7.5). The majority of lenalidomide dose reductions were due to Grade III serious adverse events, such as infection, fatigue, rash and cytopenias. Four patients developed a venous thromboembolism. Five patients in each arm required dose reductions in dexamethasone. With a median follow-up of 10 months, 4 patients remain on study. The remainder of patients withdrew from the trial, most frequently due to disease progression, adverse events, or worsening of comorbid conditions. Only one death occurred, which was unrelated to the patient's multiple myeloma. Twenty-five patients (76%) achieved at least a partial response with treatment, including 12 patients in Arm A and 13 patients in Arm B. Overall there were 3 complete responses (2 in Arm A and 1 in Arm B), which all occurred at a lenalidomide dose of 15 mg. The event-free survival was similar between both groups (at 18 months: 62% in Arm A and 59% in arm B, p= 0.82).

Conclusions: In older individuals with multiple comorbidities, lenalidomide 15 mg is associated with less frequent toxicities and dose reductions without significantly affecting response rates or event-free survival. These results provide the rationale for a lower initial lenalidomide dose for relapsed multiple myeloma patients with multiple comorbidities.