Early Intervention With New Drug Combo Beneficial in Myeloma?

November 30, 2018

This study looked at the benefit of early therapeutic intervention with the combination of elotuzumab, lenalidomide, and dexamethasone in patients with high-risk smoldering multiple myeloma.

The combination of elotuzumab, lenalidomide, and dexamethasone was well tolerated and demonstrated a high response rate without progression to overt multiple myeloma (to date of publication), according to results of a study (abstract 154) presented at the American Society of Hematology (ASH) 2018 Annual Meeting & Exposition, held December 1–4 in San Diego.

“This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, lenalidomide, and dexamethasone in patients with high-risk smoldering multiple myeloma,” wrote Chia-jen Liu, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, and colleagues.

In this multicenter study, researchers enlisted 50 participants (median age, 62 years; 32 women) who fulfilled smoldering multiple myeloma criteria, per Rajkumar et al (Blood, 2015). Bone marrow samples representing 32 patients were taken for whole exome sequencing of plasma cells. The researchers found recurrent mutations in the MAPK pathway (KRAS, NRAS) and the tumor suppressor gene TP53 in 40% of cases. They also found mutations in the NF-KB and plasma cell differentiation pathways in 13% of patients.

Patients received elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles, plus lenalidomide on days 1–21. During cycles 3 through 8, they received elotuzumab infusions on days 1, 8, and 15, with dexamethasone (40 mg) administered on days 1, 8, and 15 to 40 of 50 patients.

Following either 8 cycles or best response, patients were allowed the option to mobilize with either cyclophosphamide or plerixafor and harvest stem cells for future transplant. The team then permitted patients to continue on maintenance therapy, which consisted of elotuzumab (20 mg/kg) on day 1, as well as lenalidomide on days 1–21 of a 28-day cycle.

Using interphase fluorescence in situ hybridization (FISH), Liu and colleagues observed high-risk cytogenetics in 20 patients. The median time to response was 2.8 months (range, 1.8–4.6 months), with the most frequent toxicities being fatigue (92%), diarrhea (72%), and hyperglycemia (62%). The most frequent grade 3 or higher adverse events included hypophosphatemia (34%), neutropenia (26%), and decreased lymphocyte count (22%).

The researchers successfully collected stem cells from all mobilized patients. As of this abstract date, the overall response rate was 84%, with 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. After finishing the study, 47 of 50 patients are currently being followed up, and none of the patients have yet progressed to overt multiple myeloma, with progression-free survival being tracked.

“The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt multiple myeloma to date,” concluded the researchers. “Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention.”

Joseph Mikhael, MD, professor in the applied cancer research and drug discovery division at the Translational Genomics Research Institute, reflected on the results of the study in an interview with Cancer Network. “We currently do not treat smoldering myeloma,” he said. “The appetite to treat smoldering myeloma is low-most of us would prefer to define the highest-risk smoldering myeloma and just treat them as true myeloma. This combination is unlikely to be a genuine treatment for myeloma and is likely undertreating true myeloma. This study has a very small number of patients (N = 50), so it cannot inform its efficacy in preventing progression. In addition there is no control arm. The genomic information collected may be helpful to identify certain themes but are not definitive.”