Long-Term Sustained Minimal Residual Disease (MRD) Negativity in Multiple Myeloma Patients Treated with Lenalidomide Maintenance Therapy: A Clinical and Correlative Phase 2 Study

Background. Prior studies consistently show that the use of maintenance therapy after completion of combination therapy translates into longer progression-free survival (PFS) in patients with multiple myeloma. Some studies show that maintenance therapy prolongs overall survival (OS). Typically, maintenance therapy is used in the setting of newly diagnosed multiple myeloma; however, emerging data suggest that (at least a subset of) patients in the early relapse setting, for example those who achieve MRD negativity, may also be candidates for maintenance therapy integrated with careful disease monitoring. Currently, lenalidomide is considered the standard of care for maintenance; however, there is only limited published data on long-term use, with respect to the ability to sustain MRD negativity, mechanisms of relapse, and late toxicities. We were motivated to develop a study focusing on long-term lenalidomide maintenance therapy and to study clinical and correlative data. Here, we report on sustained MRD negativity and clinical tolerability.

Methods. This single arm, phase 2 was designed to enroll 100 evaluable patients. Per protocol, maintenance therapy with lenalidomide 10 mg is given days 1-21 on a 28-day cycle. The initial study design had a total duration of 36 months; it was subsequently extended with additional 24 months (i.e., total of 60 months). Per standard procedures for protocol amendments, patients were offered to re-consent for the extension. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT exams at baseline, annually, at progression/end of treatment; blood work was done every 3 months. Bone marrow and blood samples were banked longitudinally per the research protocols. Based on practical considerations, the study was statistically powered for the primary end-point progression-free survival, which provided sufficient numbers of samples for the planned correlative assays focusing on MRD testing, genomic characterization of detectable disease, and profiling of the bone marrow microenvironment. All these assays were conducted in serial samples collected over time and assessed in relation to clinical outcomes.

Results. A total of 100 evaluable patients meeting eligibility criteria were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-86 years) and median ECOG score 1 (range 0-1). At the submission of this abstract, the median number of cycles delivered is currently 26 (range 1 to 48); 86 patients have completed 12 or more cycles, 57 patients have completed 24 or more cycles, and 29 patients have completed 36 or more cycles. MRD testing had been completed at least once in all patients. Thirty-four patients were MRD negative at enrollment. At median followup time of 28 months (range 3.4 to 45.6), 15/100 (15%) patients have progressed. Considering the entire follow-up time from initial MRD negativity to last follow-up on study, we found 39 (of 85 tested; 46%) and 25 (of 57 tested; 44%) to have evidence of 1 and 2 years sustained MRD negativity, respectively. Only 19 patients were tested for MRD at 3 years and 16 (84%) had sustained MRD negativity. Toxicities (grade 3) include neutrophil count decrease (N=9), hypertension (N=3), diarrhea (N=2), lung infection (N=2), and rash maculo-papular (N=2), and toxicities (grade 4) include sepsis (N=2) and platelet count decrease (N=1). The most common 1/2 toxicities were diarrhea (N=51), fatigue (N=33), and upper respiratory infection (N=23). Among evaluable patients, dose reductions of lenalidomide due to toxicities and tolerability issues were done in 6 (6%) patient.

Conclusions. Among evaluable patients who were treated with lenalidomide 10 mg maintenance therapy days 1-21 on a 28-day cycle on this study, at a median followup of 28 months, we found 46% and 44% to have evidence of 1 and 2 years sustained MRD negativity, respectively. Currently, 19 patients have been tested for MRD at 3 years; 16 (84%) show evidence of 3 years sustained MRD negativity. The toxicity profile was in accord with prior studies and tolerability was quite good reflected in only 6 patients requiring dose reductions due to toxicities. Correlative assays focusing on mechanisms of sustained MRD negativity in this study are presented in a separate abstract at this meeting.