Lenalidomide Maintenance Therapy Outperforms Observation in Newly Diagnosed Multiple Myeloma

Continuous lenalidomide therapy improves outcomes among patients with newly diagnosed myeloma who are not autologous stem cell transplant candidates, according to findings from the large phase III UK National Cancer Research Institute Myeloma XI clinical trial presented in a poster presentation (abstract 1854) at the 59th American Society of Hematology Annual Meeting and Exposition, held December 9–12 in Atlanta.

The findings support continued lenalidomide treatment until disease progression for this patient population, concluded Charlotte Pawlyn, PhD, of the Institute of Cancer Research in London, and coauthors.

“When long-term treatment with lenalidomide is administered the induction regimen used does not seem critical in older age groups and therapeutic choice can be driven by the side-effect profile and tolerability,” the research team reported.

Immunomodulators of the E3 ubiquitin ligase complex are effective antimyeloma agents and longer treatment is associated with improved disease control. Lenalidomide has previously been shown to involve a lower rate of toxicities than thalidomide, allowing longer treatment durations.

Triplet induction combination treatments induce deeper and longer remissions than doublet induction regimens, likely because they target different clonal populations, the authors noted. Among transplant non-eligible patients with myeloma, continuing lenalidomide in combination with dexamethasone offers improved outcome, but the optimal combination of immunomodulatory agents for induction and maintenance therapy are unclear.

The authors therefore compared triplet induction with lenalidomide vs thalidomide and maintenance lenalidomide vs observation. The randomized phase III Myeloma XI trial was a multicenter, open-label study of newly diagnosed patients. The study included both transplant-eligible and non-eligible patients. Patients with dialysis-dependent renal failure were not eligible to participate in the study.

For transplant non-eligible patients, patients were randomly assigned to undergo induction therapy with cyclophosphamide and dexamethasone plus attenuated doses of either lenalidomide (CRDa, 928 patients) or thalidomide (CTDa, 924 patients) for a minimum of 6 treatment cycles. Patients were then randomly assigned to lenalidomide maintenance therapy or observation. The primary endpoints were progression-free and overall survival. Secondary endpoints were toxicity and response.

The CRDa and CTDa study arms were well balanced for patient gender, age, performance score, paraprotein type, International Staging System (ISS) stage, cytogenetic risk, and risk category. 

At a median follow-up of 34.4 months, patients in the CRDa (lenalidomide) group saw better objective response rates than those assigned to the CTDa (thalidomide) group (51% vs 43%; P = .0003).

However, induction therapy survival rates were nearly identical between the two groups (progression-free survival hazard ratio [HR], 0.96; P = .48; overall survival HR, 0.92; P = .267).           

A similar proportion of patients in each group discontinued treatment because of toxicity (11% in CRDa vs 12% in CTDa). Grade 3 or higher neutropenia occurred in 34% of CRDa-assigned patients and 22% of CTDa patients. More CRDa patients also experienced grade 3 or higher thrombocytopenia (10% vs 2%) and anemia (16% vs 12%), the authors reported.

Lenalidomide maintenance outperformed observation (progression-free survival HR, 0.42; P < .0001). All subgroup analyses (for gender, age, performance status, ISS, and cytogenetic risk) favored lenalidomide maintenance over observation. Overall survival rates for maintenance therapy outcomes were not reported.

CRDa induction and lenalidomide maintenance represent the “optimum combination” regimens for prolonged progression-free survival, driven by the benefits of maintenance lenalidomide, the authors concluded.

Dr. Pawlyn disclosed honoraria and travel support payments from Celgene, which markets lenalidomide as Revlimid.