Maintenance therapy with lenalidomide (Revlimid, Celgene) after autologous stem cell transplant (ASCT) is clearly the standard of care for most patients with multiple myeloma, according to findings from a meta-analysis.
The pooled results from 3 randomized trials showed a 26% reduction in the risk for death with lenalidomide, representing an estimated 2.5-year increase in median survival compared with placebo.
The results of the meta-analysis were presented at the annual meeting of the American Society of Clinical Oncology.
A survival advantage for lenalidomide as maintenance therapy has not been demonstrated consistently, explained Meletios A. Dimopoulos, MD, National and Kapodistrian University of Athens, School of Medicine, Greece, speaking at a 'Highlights of the day' session.
Some previous studies found that maintenance lenalidomide after ASCT improved survival, whereas others showed no benefit, he noted.
In addition, some studies have also suggested that there may be a risk for a second primary malignancy (SPM) with lenalidomide.
"But in this analysis, there is clear evidence that lenalidomide prolongs the overall survival of the patient," said Dr. Dimopoulos.
There was also no significant difference in cumulative incidence of SPMs between the lenalidomide and the control groups.
"Second primary malignancies are related to the age of the patient and to subsequent treatments," he said.
However, one of the studies showed that patients with multiple myeloma with the worse prognosis — those who have a high International Staging System (ISS) stage (ISS-3) or adverse high-risk cytogenetics — did not benefit from lenalidomide maintenance (ISS-3: hazard ratio [HR], 1.04; high-risk cytogenetics: HR, 1.18).
Thus, some questions still remain. For high-risk patients, "we still have a major problem," Dr. Dimopoulos pointed out. "Clearly many will benefit from double transplant, and clearly bortezomib (Velcade) maintenance is promising for patients with del17p."
Another question is the optimal duration of lenalidomide maintenance. "That needs to be defined and minimal residual disease may play a role," Dr Dimopoulos noted.
"I believe that continuous therapy with combination for maintenance may provide a more appropriate answer," he concluded. "And in this particular setting, the new monoclonal antibodies combined with proteasome inhibitors and/or with lenalidomide may improve the outcomes of the patients."
Pooling Data
The meta-analysis was prospectively planned before data were pooled, and although 17 studies were identified, only 3 had control groups and were completed. These 3 trials were conducted by the Alliance for Clinical Trials in Oncology (formerly Cancer and Leukemia Group B [CALGB]) with support from the National Cancer Institute, the Intergroupe Francophone du Myélome (IFM), and the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA).
"All phase 3 studies have progression-free survival as the primary end point, and none are powered for overall survival as the primary endpoint," explained Philip McCarthy, MD, director of Blood & Marrow Transplant at Roswell Park Cancer Institute, Buffalo, New York, who presented the findings. "A meta-analysis was necessary to adequately understand the effect of lenalidomide," he explained.
For the meta-analysis, Dr McCarthy pooled data for a total of 1209 patients, but he noted that some differences among the 3 trials were pooled together.
In the CALGB 100104 study (N Engl J Med. 2012;366:1770-1781) randomly assigned patients to placebo or maintenance lenalidomide. After an interim analysis and unblinding in December 2009, those receiving placebo with disease progression could cross over to the lenalidomide group.
In the IFM 2005-02 study (N Engl J Med. 2012;366:1782-1791), all patients received induction therapy with two cycles of lenalidomide and were then randomly assigned to placebo or maintenance lenalidomide. The interim analysis and unblinding took place in January 2010. Unlike in the CALGB study, no crossover was permitted for patients who had progressed while receiving placebo.
The GIMEMA RV-MM-PI-209 trial (N Engl J Med. 2014;371:895-905) randomly assigned transplant-eligible patients to consolidation with melphalan followed by transplant or to six cycles of chemotherapy plus lenalidomide. Maintenance therapy continued until disease progression.
Dr McCarthy explained that even though the three studies were designed to continue lenalidomide until disease progression, a second primary malignancy signal was detected at the end of 2010 in the IFM and CALGB studies. Researchers conducting the IFM study decided to discontinue maintenance treatment, while CALGB and GIMEMA continued it.
All Endpoints Favor Lenalidomide
After induction and single (82%) or tandem (18%) ASCT, more than half (55%) of patients achieved a complete response or very good partial response.
The median overall survival was not reached in the lenalidomide group and was 86 months in the control group (HR, 0.74; log-rank P = .001).
Overall survival was longer for patients receiving lenalidomide than for those receiving placebo (71% vs 66% at 5 years, 65% vs 58% at 6 years, and 62% vs 50% at 7 years).
"Lenalidomide maintenance significantly prolongs survival, with an estimated 2.5-year improvement in median survival," said Dr McCarthy.
The overall survival benefit was fairly consistent across subgroups, and despite heterogeneity (P = .047) across the studies, all demonstrated a survival benefit lenalidomide.
As far as the risk for development of second cancer, there was a statistically significant increase in the lenalidomide group.
The risk for a hematologic SPM in the pooled analysis had an HR of 2.03, while for a solid tumor, the HR was 1.71. However, the absolute numbers are low, Dr McCarthy commented.
Hematologic SPMs totaled 15 for the lenalidomide group vs 8 for the control group in the CALGB study, 21 vs 9 in IFM 2005-02, and none for either group in the GIMEMA study.
Numbers of solid tumors were 17 vs 10, respectively, in the CALGB trial, 21 vs 13 in IFM 2005-02, and 5 vs 2 in the GIMEMA trial.
"The overall survival benefit of lenalidomide maintenance outweighs the risk of developing a second primary malignancy," Dr McCarthy emphasized.
"Developing early endpoints as surrogates for long-term outcome and overall survival is critically important for the future," he added. "Otherwise, trials may continue for 10 years or longer."
The study was supported Celgene. Dr McCarthy reported relationships with Bristol-Myers Squibb, sanofi, Janssen, Binding Site, Karyopharm Therapeutics, and Celgene. Dr Dimopoulos has disclosed no relevant financial relationships.
American Society of Clinical Oncology (ASCO) 2016 Annual Meeting. Abstract 8001
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Cite this: Lenalidomide Maintenance 'Clear Standard' After Transplant - Medscape - Jun 27, 2016.
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