Early oral lenalidomide-based treatment significantly delayed disease progression in an industry-sponsored phase III study of patients who had high-risk smoldering multiple myeloma.
The delay in disease progression with early lenalidomide "translated into a significant overall survival benefit; the proportion of patients who were alive at 3 years was 94% in the treatment group versus 80% in the observation group," reported Dr. María-Victoria Mateos of the Hospital Universitario de Salamanca (Spain) and her associates in the New England Journal of Medicine.
The study findings suggest that patients with smoldering multiple myeloma who are at high risk of progression to active disease should be targeted for early intervention (N. Engl. J. Med. 2013;369:438-47 [doi: 10.1056/NEJMoa1300439]).
Three years after entry into the study, 77% of the patients who received lenalidomide had progression-free survival, compared with only 30% of those who received usual care. Usual care involved simple observation, since there are no other therapeutic options in the early stage of the disease.
The treatment response rate was 79% during the induction phase to reduce the tumor burden, which increased to 90% during the maintenance phase. The regimen’s toxicity was judged to be moderate, and the incidence of second primary tumors was low.
The overall risk of progression with smoldering multiple myeloma is low, at 10% per year. However, a large subgroup of patients has been identified as high risk, with a 50% or more probability of progression to active disease within 2 years of diagnosis. Early intervention rather than observation has been attempted for this subgroup, but, so far, alkylating agents, bisphosphonates, interleukin-1B receptor antagonists, and thalidomide have failed to show clinical benefit.
Dr. Mateos and her colleagues performed the phase III, open-label, randomized trial at 19 medical centers in Spain and at 3 in Portugal, enrolling 119 patients with high-risk smoldering multiple myeloma. This was defined as a plasma-cell bone marrow infiltration of at least 10% and a monoclonal component, or only one of the two criteria plus at least 95% phenotypically aberrant plasma cells in the bone marrow plasma-cell compartment, with reductions in one to two uninvolved immunoglobulins of more than 25% of normal values.
Patients were randomly assigned to receive either usual care (62 patients) or treatment (57 patients). Treatment comprised an induction phase of nine 4-week cycles of oral lenalidomide plus dexamethasone, followed by a maintenance phase of low-dose lenalidomide, for a total duration of no more than 2 years.
For patients in the treatment group who showed asymptomatic biologic progression during the maintenance phase, dexamethasone was permitted. Patients in the observation group received no treatment until they progressed to symptomatic disease. The median follow-up was 40 months (range, 27-57 months).
Myeloma progressed in 13 patients (23%) in the treatment group, compared with 47 patients (76%) in the observation group.
Four patients in the treatment group died during follow-up, for an overall mortality of 7%. There was one death from a treatment-related toxic effect (a fatal respiratory infection), one from surgical complications unrelated to myeloma or its treatment, and two from disease progression. In contrast, 13 patients in the observation group died, for an overall mortality of 21%; all of the deaths were from disease progression, the researchers noted.
Infections were the most common nonhematologic adverse events; the incidence was not significantly different between the treatment and observation groups. Most infections were of low severity, but one patient in the treatment group developed a grade 5 respiratory infection and died. Serious adverse events were more common in the treatment group (12%) than in the observation group (3%).
The cumulative risk of developing a second primary tumor at 5 years was 20% in the treatment group and 25% in the observation group. These included breast cancer in one patient in the treatment group, prostate cancer in two patients in the treatment group, polycythemia vera in one patient in the treatment group, and myelodysplastic syndrome in one patient in the observation group. The most common grade 3 adverse events were infection (6% of patients), asthenia (6%), neutropenia (5%), and rash (3%).
Overall, 88% of the patients in the treatment group completed induction therapy and 70% completed maintenance therapy.
"Future studies should address the effect of early treatment on the quality of life, which we did not assess in this trial," Dr. Mateos and her associates noted.
This trial was funded by Celgene, which also was involved in the data collection and analysis. Dr. Mateos reported ties to Celgene, GenMab, and other companies; her associates reported ties to numerous industry sources.