SAN DIEGO, CA—Lenalidomide-dexamethasone (Len-dex) induction therapy, followed by lenalidomide maintenance therapy, significantly prolonged time to progression (TTP), as compared to no treatment (standard of care), as per results of a Phase 3 randomized, multicenter trial of smoldering multiple myeloma (SMM) patients at high-risk of progression to symptomatic disease. The data was presented at the 53rd American Society of Hematology Annual Meeting and Exposition.

SMM is a disorder of plasma cells (PCs) characterized by a serum monoclonal component (MC) ≥30g/L and/or 10% or more PC in the bone marrow. Risk factors for predicting high-risk of progression to symptomatic disease include: >10% of PCs in bone marrow; serum MC >30g/L; >95% aberrant PCs by immunophenotyping; abnormal free-light chains; reduction in uninvolved immunoglobulins; evolving MM; and abnormal MRI studies. María-Victoria Mateos, MD, PhD, of Hospital Clinico Universitario, Salamanca, Spain, and colleagues studied patients who were determined to be high risk if they had both >PC 10% and MC >30g/L; if patients had only one of the two risk factors, there must have been a proportion of abnormal PCs within the total PCs bone marrow compartment by immunophenotyping of 95% plus immunoparesis.

Patients were randomized to receive a Len-dex induction dose followed by lenalidomide maintenance or no treatment. Induction therapy for those patients receiving Len-dex included lenalidomide 25mg on Days 1–21 with dexamethasone 20mg on Days 1–4 and 12–15 (total dose of 160mg) of a 28-day cycle for nine cycles. Maintenance dosing until progression of disease included lenalidomide 10mg on Days 1–21 every two months, which was amended in May 2010 to monthly dosing. Treatment was stopped at two years per an August 2011 amendment.

A total of 124 patients were recruited. Of this, 118 were evaluable (the remaining six did not meet inclusion criteria). After a median follow-up of 32 months (range 12–49), nine patients receiving Len-dex progressed to symptomatic disease; four of these patients progressed during maintenance therapy, while five progressed after early discontinuation of the trial (non-health related reasons for discontinuation). Twelve patients developed biological progression during maintenance therapy; the addition of dexamethasone was able to control the disease without having elevated calcium, renal failure, anemia, or bone lesions (median of 11 months).

In patients who received no treatment, 37 out of 61 patients (59%) progressed to active multiple myeloma. The estimated hazard ratio was 6.0 (95%CI: 2.9–12.6; P<0.0001); there was a median time to progression of 25 months for the no treatment arm versus the median not reached in the treatment arm (P<0.0001). Of the 28 patients, 13 developed bone lesions. Three deaths occurred in the study, one in the Len-dex and two in the no-treatment arms (P=0.6). The estimated three-year overall survival (OS) from the inclusion in the trial was 98% for the Len-dex arm and 82% for no-treatment arm (P=0.05). This difference was more evident when OS was evaluated from the moment of diagnosis (HR: 6.7, 95% CI: 0.7–57; P=0.03).

There were no Grade 4 adverse events during induction therapy with Len-dex; Grade 3 adverse events during this time included anemia (1), asthenia (4), diarrhea (1), and skin rash (2), while three patients experienced a Grade 2 deep vein thrombosis. During maintenance therapy, there were no Grade 4 adverse events reported; one patient developed a Grade 3 infection.

De. Mateos reported that this analysis shows that in high-risk SMM patients, delayed treatment resulted in early progression to symptomatic disease (median 25 months), while Len-dex as induction followed by lenalidomide as maintenance therapy significantly prolonged the TTP, with a trend to improve the overall survival. Additionally, tolerability is acceptable and there were no safety warnings at this time concerning SPM, Dr. Mateos added.