Lenalidomide Maintenance Post-ASCT Improves Survival in Myeloma

Philip L. McCarthy, MD

Maintenance therapy with lenalidomide (Revlimid) following autologous stem-cell transplantation (ASCT) conferred a survival benefit for patients with newly diagnosed multiple myeloma, according to results from a meta-analysis published in the Journal of Clinical Oncology.¹

Compared with patients assigned to placebo or observation (n = 603), those assigned to lenalidomide (n = 605) had superior progression-free survival (PFS; 52.8 vs 23.5 months), with a hazard ratio (HR) of 0.48 (95% CI, 0.41-0.55). Median follow-up was 79.5 months for all surviving patients at the March 1, 2015 data cutoff. At that time, median overall survival (OS) was 86.0 months for the placebo or observation group and had not been reached for the lenalidomide maintenance group (HR, 0.75; 95% CI, 0.63-0.90; P = .001).

“This study demonstrates a statistically significant and clinically meaningful improvement in OS with lenalidomide maintenance. With new, highly active, triplet induction regimens enhancing depth and duration of response as well as ongoing studies evaluating the optimal timing of ASCT, the use of lenalidomide maintenance for transplantation-eligible patients can be considered a standard of care,” first author Philip L. McCarthy, MD, Blood and Marrow Transplant Program, Roswell Park Cancer Institute, and coinvestigators wrote.

“The costs of maintenance therapy should be weighed against the costs of shorter survival, earlier progression, and earlier use of subsequent lines of therapies for patients without maintenance. Understanding the role of minimal residual disease detection and immune reconstitution after ASCT, as well as developing early endpoints as surrogates for long-term outcomes, should allow us to develop clinical strategies to further improve OS,” continued McCarthy et al.

Investigators reviewed data from 3 randomized, controlled trials—Cancer and Leukemia Group B 100104 (CALGB), Gruppo Italiano Malattie Ematologiche dell’Adulto RV-MM-PI-209 (GIMEMA), and Intergroupe Francophone du Mye ́lome 2005-02 (IFM)—involving 1208 patients. The intent-to-treat population included all patients who were randomly assigned to lenalidomide versus placebo or observation and who received high-dose melphalan or ASCT, regardless of whether they received maintenance therapy.

About 43% of patients in the GIMEMA study, 24.1% in CALGB, and 3.6% in IFM received lenalidomide for at least 4 years (the IFM percentage includes 2 cycles of lenalidomide consolidation). The mean treatment duration was 28 months with lenalidomide maintenance and 22 months with placebo or observation.

The risk for progression or death was 52% lower in patients assigned with lenalidomide maintenance (HR, 0.48; 95% CI, 0.41-0.55). Each study confirmed the PFS improvement associated with lenalidomide maintenance. Where data were available, patients in all subgroups in the 3 studies experienced the PFS benefit.

The 7-year survival rate was 62% with lenalidomide maintenance compared with 50% with placebo or observation. At the nearly 80-month median follow-up, 64% of patients in the lenalidomide maintenance group were still alive compared with 54% of patients in the placebo or observation group. Investigators added that the HRs for the subgroup analyses favored lenalidomide maintenance except for patients with International Staging System stage III disease.

Patients in the CALGB and IFM trials were analyzed for treatment-emergent adverse events (TEAEs). Rates of treatment discontinuation as a result of TEAEs were 29.1% in the lenalidomide maintenance group and 12.2% in the placebo or observation group.

Patients assigned to lenalidomide maintenance were more likely to discontinue treatment due to blood and lymphatic system disorders (4.3% vs 2.1%) and general disorders and administration site conditions (4.7% vs 1.5%).

Similarly, patients assigned lenalidomide maintenance experienced a greater rate of secondary primary malignancies both before progression (5.3% vs 0.8%) and before and after progression (6.1% vs 2.8%).

“We learn several lessons from this study and others that have evaluated the role of maintenance therapy after ASCT,” Joseph R. Mikhael, MD Mayo Clinic Arizona, wrote in an accompanying editorial.2 The first and perhaps most important [thing] is that maintenance lenalidomide is indeed a new standard of care for most patients. The results of this study are impressive, with a remarkable near 30-month improvement in PFS and an OS improvement. Few single treatments have had this degree of impact on PFS and OS in myeloma. Although some subgroups may not benefit to the same degree, as described later (namely high-risk patients), it is such a prolific improvement that maintenance lenalidomide should be considered as standard practice after transplantation.”

Mikhael noted that multiple myeloma is “an incredibly heterogeneous disease” with a wide range of prognoses, and despite overall improvements in survival, high-risk patients are still likely to die within 3 years of diagnosis.

“Whether we can really change the disease biology of high-risk patients with maintenance therapy remains unclear and should remain the subject of additional study. By contrast, there is another cohort of patients who have long-term response to induction therapy and ASCT who never receive maintenance therapy, the majority of whom seem to have hyperdiploidy,” he wrote.

“Paradoxically, many of these low-risk patients survive for >10 years with myeloma and may never achieve a deep response of complete remission, almost as if they were restored to a monoclonal gammopathy of undetermined significance—like state. If we could predict these patients well in advance, they might not require continuous therapy.”

Mikhael concluded by saying that “nearly all” patients with multiple myeloma should receive maintenance therapy with lenalidomide after ASCT.

“Maintenance therapy in myeloma further adds to a recent evidence-based trend to increase the intensity of therapies before ASCT, continue the prolific use of ASCT in eligible patients, and provide longer term therapy to delay first relapse,” he wrote. “With the development of even more potent and yet more tolerable agents in the future, we are drawing closer to the ultimate goal of transforming multiple myeloma to a chronic, if not curable, disease.”

References

1. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: A meta-analysis [published online]. J Clin Oncol. 2017;35(29):3279-3289. doi: 10.1200/JCO.2017.72.6679.
2. Mikhael JR. Maintenance lenalidomide after transplantation in multiple myeloma prolongs survival—in most. J Clin Oncol. 2017;35(29):3269-3271. doi: 10.1200/JCO.2017.74.7014.