Triple Combo Therapy May Slow Smoldering Multiple Myeloma Progression into Overt Myeloma, Phase 2 Trial Shows

Early treatment with a triple combination therapy containing Empliciti (elotuzumab), Revlimid (lenalidomide), and dexamethasone in patients with smoldering multiple myeloma — a precursor of multiple myeloma — may halt the disease’s progression into the full-blown condition, a Phase 2 trial shows.

The results were presented at the American Society of Hematology (ASH) 2018 Annual Meeting, Dec. 1-4 in San Diego, California, in a presentation titled “Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma.”

Smoldering multiple myeloma is a prior stage of multiple myeloma. While the condition presents no symptoms, patients have a 50% higher risk of developing the full, symptomatic form of multiple myeloma within two years.

Recent studies have shown that early treatment of smoldering myeloma may delay or prevent the progression into full-blown disease, and researchers have been looking for effective treatments to use in these patients.

Researchers at Dana-Farber Cancer Institute, in collaboration with Bristol-Myers Squibb and Celgene, designed a Phase 2 trial (NCT02279394) to determine the efficacy of Empliciti in combination with the immunomodulatory agent Revlimid and dexamethasone in preventing disease progression in patients with high-risk smoldering multiple myeloma.

The single-arm, non-randomized, open-label study included 50 participants — 18 men and 32 women, median age 62 years — enrolled across eight clinical sites in the U.S.

Patients received the triple combination for eight four-week cycles, after which they were allowed to continue on maintenance therapy with Empliciti and Revlimid for 28 days.

The study’s primary goal was to determine the proportion of patients who had not progressed two years after starting treatment. Secondary endpoints included response rate, time to progression, overall survival, and safety of the combination therapy.

In agreement with the benefits seen in an early analysis, the triple combination reduced disease burden in 84% of patients — including 6% complete responses, 37% very good partial responses, and 41% partial responses. An additional 10% of patients had minimal responses and 3% saw their disease stabilize.

All but three participants have completed the treatment and are under follow-up. Importantly, until the date of the analysis — nearly two years of follow-up — none of the participants progressed into full multiple myeloma.

The treatment was overall well-tolerated, with the most common adverse events being fatigue, diarrhea, and high blood sugar. Severe or worse adverse events included low phosphate levels and reduced numbers of lymphocytes and neutrophils (two kinds of immune cells).

Bone marrow samples collected from 32 patients at the study’s start showed that 16% of them had mutations in two key genes regulating cell division — KRAS and NRAS — and 23% had mutations in the tumor-suppressor gene TP53. Mutations in the pro-inflammatory NF-KB gene and plasma cell differentiation pathways were detected in 13% of patients.

Interestingly, patients harboring mutations in DNA repair pathway genes responded modestly to the triple therapy, suggesting these could function as biomarkers to select patients more likely to respond.

Overall, the results show that “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,” researchers said. “Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention.”