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Should Patients with High-Risk Smoldering Myeloma Undergo Treatment?

Value-Based Care in Myeloma - Multiple Myeloma
Caroline Helwick

Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival, according to a recent study (Mateos MV, et al. N Engl J Med. 2013;369:438-447). Patients who received treatment with lenalidomide plus dexamethasone induction followed by maintenance lenalidomide had more than an 80% reduction in the risk of disease progression and almost a 70% reduction in the risk of mortality, according to María-Victoria Mateos, MD, PhD, of the Hospital Universitario de Salamanca in Spain.

Smoldering multiple myeloma is a plasma-cell proliferative disorder that is generally not treated until symptomatic disease develops. Although the risk of progression to active myeloma is low, approximately 10% annually, a subgroup of high-risk patients has been identified whose risk is closer to 50% over 2 years. This high-risk subgroup represents approximately 40% of the population with smoldering myeloma, and could be a target for an early intervention that may delay progression in a relatively nontoxic manner.

Several other trials of early intervention failed to show a benefit, and observation has long been the established standard of care for patients with smoldering myeloma, but these mainly included patients who were not selected on the basis of risk, the authors pointed out.

Study Details
The phase 3 study, conducted at 22 centers in Spain and Portugal, included 125 individuals who had received a diagnosis of smoldering multiple myeloma within the previous 5 years and who were at high risk for progression according to criteria based on plasma-cell bone marrow infiltration, monoclonal component, phenotypically aberrant plasma cells, and other established criteria of the condition.

Patients were randomized to the oral lenalidomide/dexamethasone regimen or to observation. Active treatment consisted of nine 4-week cycles of lenalidomide 25 mg on days 1 to 21, followed by a 1-week rest period, and dexamethasone 20 mg on days 1 to 4 and on days 12 to 15. Induction therapy was followed by maintenance therapy with lenalidomide 10 mg on days 1 to 21 of each 28-day cycle. Patients in the observation arm received no treatment until they progressed to active disease.

At a median follow-up of 40 months, the median time to progression to symptomatic disease was not reached in the active-treatment group, but was 21 months in the observation group (P <.001). The hazard ratio (HR) for progression with treatment was 0.18. Symptomatic disease developed in 47 patients in the observation arm (76%) compared with 13 patients in the treatment group (23%). A partial response or better was achieved by 79% of patients after induction and by 90% of patients during the maintenance phase.

These improvements translated into a survival benefit. As of the October 15, 2012, data cutoff, 7% of the treatment group had died compared with 21% of the observation group. Median overall survival was not reached in either group. The proportions of patients who were alive 3 years after study entry were 94% and 80%, respectively (HR, 0.31; P = .03). The assessment of overall survival from the time of diagnosis also significantly favored the treatment group.

Treatment Was Well Tolerated
The toxic effects of treatment were mainly limited to grade 2 or lower adverse events, primarily infections. The rate of serious adverse events during induction was 12% with active treatment versus 3% with observation. The incidence of adverse events was lower during maintenance. The rate of grade 1 and 2 infections was 18% in the treatment group, with 12% being grade 1, versus 8% with observation. No dose reductions were needed during maintenance.

Secondary malignancies are a concern with prolonged lenalidomide therapy, and these were reported in 6% of the treatment group compared with 2% of the observation group. The cumulative risk of a second primary tumor at 5 years was 20% and 25%, respectively, which was not significantly different.

The study did not address the effect of early treatment on quality of life, which should be a subject of future research, the authors suggested.

Expert Commentary
Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Center for Multiple Myeloma, Dana-Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School, Boston, commented on the findings for Value-Based Care in Myeloma. “Whilst these results are very promising and do point to the value of early intervention in selected patients with high-risk early-stage multiple myeloma, I would favor protocol participation and the cautious use of bisphosphonates in such patients whenever possible.”

“Our own program’s approach is commensurate with this, and we do not recommend pursuing treatment in higher-risk smoldering patients as a matter of routine. What is also of great importance is the need to better define patient subgroups that may benefit from earlier intervention, and until there are substantially more data supporting such strategies, further clinical trials in this population remain our priority,” Dr Richardson said.

Jeremy S. Abramson, MD, MSc, Clinical Director of the Center for Lymphoma, Massachusetts General Hospital Cancer Center, Boston, who discussed multiple myeloma at the 2013 Best of ASCO meeting in Los Angeles, CA, still maintained that early intervention for smoldering myeloma is a “matter of debate.”

“These are patients we would observe,” Dr Abramson noted, “but it remains an open question, whether with novel agents there will be benefit to treating earlier. As of now, there’s not enough data to support treating asymptomatic myeloma patients, who may not ultimately require therapy for quite some time.”

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Last modified: May 20, 2015
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