San Diego, California—Therapy consisting of elotuzumab plus lenalidomide and dexamethasone yielded a high response rate and demonstrated tolerability in patients with high-risk smoldering multiple myeloma, according to results from a clinical trial by Irene M. Ghobrial, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, and colleagues.

Dr Ghobrial presented the results of the study, which was conducted to determine the survival benefit of early elotuzumab plus lenalidomide and dexamethasone therapy in patients with smoldering multiple myeloma, as well as whether genomic studies can be used to identify patients best suited for this early intervention, at the 2018 ASH Annual Meeting.

The phase 2 clinical trial included 50 patients with high-risk smoldering multiple myeloma; the median age of these patients was 60 years. A total of 18 (36%) patients were men, and 32 (64%) were women. Patients were recruited between January 2015 and December 2016.

Those who had symptomatic multiple myeloma or received previous therapy for symptomatic multiple myeloma were excluded. Of note, patients previously treated for smoldering multiple myeloma were deemed eligible for study participation.

Before the intervention was started, Dr Ghobrial and colleagues took bone marrow samples from 32 of the patients for baseline assessment and whole exome sequencing of plasma cells. The primary end point of the study was progression-free survival (PFS) at 2-years.

For the first 2 cycles spanning 28 days each, patients were given elotuzumab 10 mg/kg weekly on days 1, 8, 15, and 22; they also received lenalidomide on days 1 through 21. Elotuzumab was then administered on days 1, 8, and 15 during cycles 3 through 8, along with dexamethasone 40 mg on days 1, 8, and 15.

When patients achieved a best response or reached 8 cycles, they were given the choice to mobilize with cyclophosphamide or plerixafor, as well as have stem cells collected for future transplants. After this point, a 28-day maintenance therapy cycle was initiated. This regimen included elotuzumab 20 mg/kg being administered on day 1, in combination with lenalidomide on days 1 through 21.

At the point when these data were presented, 40 patients had completed 24 treatment cycles; 38 of these patients are being actively followed-up with, as 2 died during therapy. According to Dr Ghobrial and colleagues, there is no evidence of disease progression among these patients.

At a median follow-up of 29 months, the 2-year PFS was not reached. At 36-months, however, the 3-year PFS and event-free survival rates were 95% and 100%, respectively. The overall response rate was 84% and included 3 (6%) patients with complete remission, 18 (37%) with very good partial responses, 20 (41%) with partial responses, 5 (10%) with minimal response, and 3 (6%) with stable disease.

In addition, the median time to response was 2.8 months.

Using fluorescence in situ hybridization (FISH), Dr Ghobrial and colleagues identified 20 (40%) patients with high-risk cytogenetics, defined by the presence of del17p, t(4;14), and gain 1q.

Ultimately, the study findings pointed to recurrent mutations in the MAPK pathway and the TP53 gene of 16% and 24%, respectively; 13% of patients had mutations in the NF-KB and plasma cell differentiation pathways. Whole exome sequencing led to the somatic copy number alterations (SCNAs) 1q duplication, 13q, 17p, and 1p deletions being identified in 25%, 31%, 12%, and 7% of cases, respectively.

“Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by whole exome sequencing. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment,” Dr Ghobrial and colleagues explained.

Adverse events most frequently reported in the study included fatigue (92%), diarrhea (72%), and hyperglycemia (62%). The most common adverse events grade ≥3 were hypophosphatemia (34%), neutropenia (26%), and lymphocytopenia (22%).

Although no patients were reported as having disease progression to overt multiple myeloma, the small patient cohort and lack of a comparator arm prompt the need for further research of this combination in larger settings.

 “The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM [multiple myeloma] to date,” Dr Ghobrial and colleagues said.

“Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention,” they concluded.—Hina Khaliq

Liu C, Ghobrial IM, Bustoros M, et al. Phase II trial of combination of elotuzumab, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma. Presented at: the 60th ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 154.