SAN DIEGO – The standard approach of waiting to treat smoldering multiple myeloma until it progresses to active disease is being called into question by robust results from a phase III trial of early treatment with lenalidomide and dexamethasone.

Among 119 patients with smoldering myeloma who were at high risk of disease progression, 59% of those randomized to no treatment converted to symptomatic myeloma, compared with 15% of those given lenalidomide (Revlimid) and dexamethasone as induction therapy, followed by lenalidomide maintenance.

The estimated hazard ratio was 6.0, corresponding to a median time to progression of 23 months in the abstention arm vs. median not reached in the active treatment arm (P less than .0001). Median follow-up was 32 months (range, 12-49 months).

Early treatment also produced a benefit in overall survival, with an acceptable toxicity profile and no safety warnings at the present time, Dr. María-Victoria Mateos said at the annual meeting of the American Society of Hematology (ASH).

She pointed out that conventional agents have shown no benefit in overall response rate, time to progression, or overall survival, whereas novel agents such as thalidomide increased partial responses by 30% or more, but at a cost of higher toxicity and shorter time to treatment in those patients achieving a partial response.

At last year’s ASH meeting, the Spanish Myeloma Group presented results from the trial showing lower conversion rates in the abstention arm, but the longer follow-up has strengthened the findings and the case for early treatment, said session comoderator Dr. Meral Beksac, professor of hematology at Ankara (Turkey) University.

"This is the first [study] with such big success," she said in an interview. "What is a matter of debate is how to select those patients with high-risk smoldering myeloma, and I think their definition is a good one. It’s not based on gene expression; it’s a widely applicable definition."

Several risk factors predicting high-risk symptomatic disease have been used, including more than 10% of plasma cells (PCs) in bone marrow; serum monoclonal component (MC) greater than 30 g/L; more than 95% aberrant PCs by immunophenotyping; or abnormal MRI studies, explained Dr. Mateos of the University Hospital of Salamanca (Spain).

In this trial, the high-risk population was defined by the presence of more than 10% of PCs in bone marrow and MC greater than 30 g/L, or – if only one criterion was present – patients had to have 95% of aberrant PCs within the total PCs bone marrow compartment by immunophenotyping plus immunoparesis.

Patients in the active treatment arm received nine 4-week cycles of lenalidomide (25 mg daily) on days 1-21 plus dexamethasone (20 mg daily) on days 1-4 and 12-15, followed by maintenance until disease progression with lenalidomide (10 mg) on days 1-21 every 2 months. The trial was amended in May 2010, however, to monthly lenalidomide maintenance, and was further amended in August 2011 to stop treatment at 2 years.

Of the nine patients who progressed on active treatment, five progressed after early discontinuation from the trial, Dr. Mateos said. In all, 14 patients developed biological progression during maintenance, and low-dose dexamethasone was added according to the protocol. Of these patients, 2 had a partial response and 10 experienced stable disease, of which 8 remain stable after a median follow-up of 19 months.

At 5 years, 94% of patients who were treated with lenalidomide plus dexamethasone were alive, compared with 79% who were given no treatment (HR, 5.01; P = .03,), she said.

Dr. Beksac said that cost might be an issue in translating the results to daily practice, particularly with the monthly lenalidomide maintenance schedule. She also suggested that in light of new data presented at the meeting (on affirmation of a second-cancer signal after lenalidomide in new multiple myeloma patients, and on evidence that lenalidomide maintenance holds back myeloma in the elderly), some physicians may want to wait until more is known about the risk of second primary malignancies (SPMs) with lenalidomide therapy.

"Maybe we can wait at least 2 more years to see the SPMs and to be on the safer side, and then it could be a clinical practice," she said.

SPMs were detected in three patients, representing 5% of the 57 patients treated with lenalidomide and dexamethasone. Of the two prostate cancer cases, both men had prostate hyperplasia prior to treatment, according to their medical records, whereas the patient diagnosed with polycythemia vera had a JAK2 gene mutation, the major cause of PV, at study entry, Dr. Mateos pointed out.

Dr. Mateos reported receiving honoraria from Celgene, Millennium Pharmaceuticals, and Janssen. A coauthor reported receiving honoraria from Celgene and Janssen, and four coauthors reported employment with Celgene, the maker of lenalidomide. Dr. Beksac reported receiving honoraria from and serving as a speaker for Celgene and Janssen-Cilag.

Evidence Mounts for Early Treatment of Smoldering Myeloma