Elotuzumab, Lenalidomide, and Dexamethasone Combination Demonstrates High Response Rate in High-Risk Smoldering Multiple Myeloma

The results of a phase 2 clinical trial presented at ASH 2018 suggest that early therapeutic intervention is beneficial in patients with high-risk smoldering multiple myeloma.

In this study, the combination of elotuzumab (Empliciti), lenalidomide (Revlimid), and dexamethasone in patients with high-risk smoldering multiple myeloma was well-tolerated and demonstrated a high (84%) response rate, with no progression to overt multiple myeloma to date. At 3 years, progression-free survival (PFS) with the triple regimen also compared favorably with the current standard of care with lenalidomide and dexamethasone alone (95% vs 77%).

“Genomic profiling and immune profiling is ongoing now to determine mechanisms of response and resistance in those patients, and truly understand the patients who would benefit the most from this combination of therapy,” said Irene M. Ghobrial, MD, Co-Principal Investigator, Center for Prevention of Progression of Blood Cancers, Dana-Farber Cancer Institute, Boston.

According to Dr Ghobrial, smoldering multiple myeloma—an early and asymptomatic form of the disease characterized by elevated levels of myeloma protein in the bone marrow—is often left untreated until the presence of CRAB (elevated calcium, renal failure, anemia, and bone lesions) criteria emerges. In recent years, however, researchers have begun to question whether early intervention could improve outcomes and possibly cure multiple myeloma.

“The risk of progression in high-risk smoldering multiple myeloma is approximately 50% in 2 years, and many studies have shown that as the disease progresses it starts to acquire more clo­nal heterogeneity,” Dr Ghobrial said. “By the time we treat patients with active disease, they may have too many clonal changes, and we may not be able to control the disease.”

For this study, Dr Ghobrial and colleagues looked at whether the addition of elotuzumab, an antibody that activates the immune system, to the backbone of lenalidomide and dexamethasone, would improve response and extend PFS in patients with high-risk smoldering multiple myeloma.

Patients received weekly infusions of elotuzumab 10 mg/kg on days 1, 8, 15, and 22 for the first two 28-day cycles and lenalidomide on days 1 through 21. For cycles 3 through 8, elotuzumab was administered on days 1, 8, and 15. Dexamethasone 40 mg was administered on days 1, 8, and 15 through 40. After 8 cycles or best response, patients had the option to mobilize with cyclophosphamide or with plerixafor and collect stem cells for future transplant. Patients then received maintenance therapy with elotuzumab 20 mg/kg on day 1, plus lenalidomide on days 1 through 21 of each 28-day cycle.

No Progression to Active Disease

Overall, 50 patients (median age, 62 years) were enrolled in this study between 2015 and 2016 at 8 participating sites.

The median time to response was 2.8 months, and at a median follow-up of 29 months, the study’s primary end point, median PFS, has yet to be reached.

The addition of elotuzumab to the current standard of lenalidomide plus dexamethasone showed a significant increase in PFS, Dr ­Ghobrial said.

At 36 months, the PFS was 95% with the triple-agent regimen versus 77% with lenalidomide and dexamethasone alone. Furthermore, the event-free survival was 100% at 36 months, Dr Ghobrial noted; that is, no patients have progressed to active disease to date.

For patients who completed 8 cycles of treatment with the 3-agent regimen, the overall response rate was 87%. Complete or very good partial responses, evidenced by significantly reduced myeloma protein levels, were observed in 43% of patients.

Dr Ghobrial and colleagues are currently using genomic profiling and immune profiling to understand which patients will benefit the most from this early therapeutic intervention with the 3-agent combination.

Adverse Events

The combination treatment was well-­tolerated. The most common adverse events were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade ≥3 adverse events were hypophosphatemia (34%), neutropenia (26%), and decreased lymphocyte count (22%).

Grade 4 hypophosphatemia was reported in 3 (6%) patients during treatment, and grade 4 cholecystitis, cataract, increased lymphocyte count, hyperglycemia, neutropenia, and thrombocytopenia occurred in 1 patient each. Diabetic ketoaci­dosis and sepsis led to death of 1 ­patient.

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