High-Risk Smoldering Myeloma Benefits From Early Treatment

Roxanne Nelson

August 01, 2013

For patients with high-risk smoldering myeloma, early intervention could prove beneficial. Early treatment with lenalidomide (Revlimid) and dexamethasone, followed by maintenance therapy with lenalidomide, delays the time to progression to symptomatic disease and increases overall survival, according to a new study.

After a median follow-up of 40 months, the median time to disease progression was not reached in the treatment group and was 21 months in the observation group (P < .001). The 3-year survival rate was also higher in the group that received treatment (94% vs 80%; hazard ratio for death, 0.31; P = .03).

The study was published in the August 1 issue of the New England Journal of Medicine.

Patients with smoldering myeloma are generally not treated until symptoms develop, and the current standard of care is observation. The risk for progression to active disease is only about 10% annually, note lead author Jesus F. San Miguel, MD, from the Department of Hematology at the University Hospital of Salamanca in Spain, and colleagues. However, in a subgroup of high-risk patients, the probability of progression is much higher. About 40% of patients with smoldering myeloma fall into this subgroup.

"There is a great interest in the myeloma community about early intervention in multiple myeloma," Dr. San Miguel told Medscape Medical News. "Based on our results, several groups are currently investigating different strategies with new drugs in high-risk smoldering myeloma."

However, it is too early to make any changes in clinical practice. "More trials are needed and we need to better define the ultra-high-risk population before early treatment is proposed for all patients," he said.

More Studies Needed

An outside expert agrees that it is too early to change practice. Clinicians should be aware of the improvements in defining of monoclonal gammopathy of undetermined significance (MGUS), high-risk smoldering myeloma, smoldering myeloma, and active myeloma so that patients can be treated appropriately, said Joseph Mikhael, MD, associate professor at the Mayo College of Medicine in Scottsdale, Arizona, and vice-chair of the American Society of Hematology Communications Committee.

"This study is helping move the field forward, but will not result in many patients being treated now who would not have been treated previously," said Dr. Mikhael.

He noted that because the researchers used flow cytometry to define high risk, which is "not easily accessible to most treating clinicians," the results are not "easily reproducible."

"The study does teach us, however, that there are a small number of patients with smoldering myeloma who should be considered true myeloma and be treated," he told Medscape Medical News.

Because the precise definitions of MGUS, smoldering myeloma, and active myeloma are not concrete, they must constantly be redefined to ensure that the right patients are treated and that those who do not need treatment are spared therapy.

"More studies are needed to further define when treatment is necessary in myeloma" and what that treatment should be, Dr. Mikhael explained. "Although lenalidomide is an excellent option, other active agents in myeloma should be considered" if one is simply redefining active myeloma that should be treated as smoldering myeloma that does not need to be treated.

Delayed Progression, Higher Survival

In their phase 3 multicenter trial, Dr. San Miguel and colleagues randomized 119 patients with high-risk smoldering myeloma to treatment (n = 57) or observation (n = 62). Those in the treatment group received an induction regimen of lenalidomide 25 mg per day on days 1 to 21 plus dexamethasone 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals, for 9 cycles. This was followed by a maintenance regimen of lenalidomide 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years.

The primary end point was time to progression to symptomatic disease; secondary end points included response rate, overall survival, and safety.

The median time to progression was significantly longer in the treatment group than in the observation group (hazard ratio [HR], 0.18; P < .001).

During maintenance therapy, 24 patients experienced biologic progression, and low-dose dexamethasone was added to the regimen in 18 patients.

In the intention-to-treat analysis, 45 (79%) of the 57 patients in the treatment group had at least a partial response during the induction period, including 4 (7%) with a stringent complete response, 4 (7%) with a complete response, and 6 (11%) with a very good partial response.

Fifty (88%) of the 57 patients completed the 9 planned cycles of induction therapy and received maintenance therapy with lenalidomide. After a median of 15 cycles of maintenance therapy, there was improvement in the quality of the response, the researchers report.

The cutoff for the final analysis was October 2012. By that time, 4 patients in the treatment group (7%) and 13 in the observation group (21%) had died, and median overall survival was not reached in either group. Overall survival from the time of the diagnosis (median follow-up, 46 months) indicated that there was a benefit from early intervention. At 5 years, the survival rate was better in the treatment group than in the observation group (94% vs 78%; HR for death, 0.28; P = .02).

Limited Toxicity

Because these patients were asymptomatic and would otherwise not have received any therapy, the ideal treatment should have limited toxicity. Adverse events were mainly grade 2 or less in the treatment group, although 1 patient had a grade 5 respiratory infection.

During induction therapy, grade 3 events, which were uncommon, included infection (in 6% of patients), asthenia (in 6%), neutropenia (in 5%), and rash (in 3%). Grade 2 neutropenia was reported in 8 patients (13%). Rashes occurred in 32% of patients, but most cases were grade 1.

The incidence of adverse events was lower during maintenance therapy than during induction therapy.

The study was funded by Celgene.

N Engl J Med. 2013;369:438-447. Abstract

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