The Role of Lenalidomide in Patients With Multiple Myeloma

The Role of Lenalidomide in Patients With Multiple Myeloma

Results from two separate trials presented during the 2017 ASCO Annual Meeting suggest that lenalidomide can induce deeper and longer remission in patients with multiple myeloma when used as part of induction and maintenance therapy.

In the first trial, the Myeloma XI study (Abstract 8009), a multicenter, randomized, controlled trial for newly diagnosed multiple myeloma, Graham H. Jackson, MD, of the University of Newcastle, in the United Kingdom, compared triplet induction regimens of lenalidomide to thalidomide and then examined the role of lenalidomide maintenance compared with observation. The second trial, the Cancer and Leukemia Group B (Alliance) 100104 study in collaboration with the Eastern Cooperative Oncology Group (Abstract 8037), analyzed overall survival (OS) and progression-free survival (PFS) in patients who were treated with placebo or lenalidomide and further adjusted the analysis for crossover effects.

Myeloma XI Findings

Dr. Jackson, who presented on behalf of the Myeloma XI study group, said that because lenalidomide has fewer adverse effects than thalidomide, it may offer longer-term treatment and, therefore, better disease control. Myeloma XI compared a cyclophosphamide/lenalidomide/dexamethasone (CRD) triplet (1,021 patients) with a cyclophosphamide/thalidomide/dexamethasone (CTD) triplet (1,021 patients). PFS and OS were the primary endpoints for each arm. Each group had a minimum of four cycles and continued to maximum response. The maintenance random assignment at 3 months after stem-cell transplantation compared lenalidomide until disease progression with observation. Baseline patient characteristics were similar between the CRD and CTD groups. Overall, 74% of the CTD group and 38% of the CRD group had dose modifications. Of grade 3 or higher toxicities, more patients in the CRD group developed neutropenia, anemia, and thrombocytopenia than in the CTD group (22.3% vs. 11.7%, 9.6% vs. 6.7%, and 4.6% vs. 1.7%, respectively).

There was a “much deeper response” with CRD (61%) than CTD (54%), Dr. Jackson said. In addition, CRD was associated with significantly longer PFS than CTD (36 vs. 33 months; HR 0.85, 95% CI [0.75, 0.97]; p = 0.0124). CRD also was associated with significantly longer OS than CTD (HR 0.77, 95% CI [0.63, 0.93]; p = 0.0083).

After maintenance therapy data were analyzed, there was significant improvement in PFS from 28 months with placebo to 50 months with lenalidomide therapy (HR 0.47, 95% CI [0.37, 0.60]; p < 0.0001).

Paul Richardson, MD, of the Dana-Farber Cancer Institute, discussed these findings and noted that, in this context, “the result of this study focused on the transplant-eligible population and show the use of lenalidomide-based therapy clearly conferred clinical benefit, both in terms of PFS and OS. In fact, the best outcomes were associated with lenalidomide induction plus lenalidomide maintenance.”

These results were “certainly in keeping what I would expect,” Dr. Richardson said. They “support the use of lenalidomide-based therapy, both as part of induction and maintenance in the context of transplant-eligible patients, and support findings in a variety of other clinical trials in which lenalidomide has become a key backbone of therapy,” he continued. Dr. Richardson called the degree of clinical benefit in favor of lenalidomide “very encouraging. The 3-year OS was promising, and the fact that this also occurred across all subgroups, including high-risk disease, was particularly important.”

Several issues remain in the field of myeloma research, Dr. Jackson said, including the best way to treat high-risk patients, how to personalize treatment approaches, and how to improve lenalidomide maintenance therapy.

Cancer and Leukemia Group B (Alliance) 100104 Findings

In this study, 568 patients with multiple myeloma who had received no more than 12 months of prior therapy and no prior transplantation were enrolled between December 2004 and July 2009. At a prespecified interim analysis (December 2009), results surpassed the prespecified superiority boundary (significantly improved PFS for lenalidomide maintenance vs. placebo after stem cell transplantation), and the majority of placebo-arm patients without progressive disease crossed over to lenalidomide maintenance. An updated analysis (cutoff, March 2015) showed significantly longer OS with lenalidomide maintenance (hazard ratio [HR] 0.56, 95% CI [0.42, 0.76]).

Phillip McCarthy, MD, on behalf of the Cancer and Leukemia Group B/Eastern Cooperative Oncology Group collaboration, presented the effect of random assignment on OS and PFS after adjustment for the crossover effect. To adjust for crossover effect, the group used a rank-preserving structural failure time model (RPSFTM) with crossover.

The RPSFTM “looks to see if the effect of the treatment persists after treatment stops,” Dr. McCarthy said. “Does the maintenance continue to work after treatment stops, or does the effect completely stop when treatment is discontinued?” He added that the iterative parameter estimation algorithm was used as validation. Survival was portioned with the assumption of a residual lenalidomide effect after discontinuation.

The group analyzed lenalidomide maintenance (231 patients), placebo (229 patients; intent-to-treat [ITT] population), and the crossover arm (76 patients). The median time from random assignment to crossover was 11.5 months.

“Not surprisingly, using RPSFTM makes the placebo arm look a little bit worse; we’ve taken out all of those crossover patients who are now being weighted differently,” he said.

The relative treatment effect for OS and PFS increased for lenalidomide versus placebo when the analysis was adjusted for crossover with RPSFTM and the iterative parameter estimation. The landmark analysis at the December 2009 interim (placebo crossover, 76 patients; no crossover, 34 patients) showed that the treatment effect is not dissimilar to the ITT analysis (HR 0.53, 95% CI [0.25, 1.13]).

“This updated analysis based on data from March 2015 shows significantly longer OS with lenalidomide maintenance. Adjusting for the potential diluting effects of crossover reduced median OS and PFS with placebo and improved treatment effect in the ITT analysis for OS and PFS for lenalidomide after transplant,” Dr. Richardson said. “This degree of improvement was striking because it showed that the clinical benefit after this adjustment was even greater than the original estimate. This is an important paper because it reinforces the value of lenalidomide maintenance post-transplantation.”

Dr. Richardson suggested caution in applying the results to all patients. “The Jackson paper supports the McCarthy paper very nicely. I think the issue is that this focuses on lenalidomide alone, and the field obviously goes way beyond that,” he said.  

–Michelle Dalton, ELS