Elotuzumab Combination Prevents Progression from Smoldering to Symptomatic Myeloma

In a phase II trial of patients with high-risk smoldering multiple myeloma (SMM), 84 percent of participants responded to treatment with elotuzumab, lenalidomide, and dexamethasone, with no patients progressing to overt multiple myeloma during three-year follow up. Irene Ghobrial, MD, from the Dana-Farber Cancer Institute in Boston, presented the results at the 2018 ASH Annual Meeting.

Fifty patients (median age = 60 years; range = 29-79 years) were enrolled in the trial between January 2015 and December 2016. Eligible participants had high-risk SMM (defined according to criteria proposed by S. Vincent Rajkumar, MD, in a 2015 Blood article, which include a serum M protein ≥30g/L, immunoparesis with reduction of 2 uninvolved immunoglobulin isotypes, serum involved/uninvolved FLC ratio 8-100, and progressive increase in M protein level, presence of t(4;14) or del17p or 1q gain).

People with any evidence of symptomatic MM or who had received any prior therapy for symptomatic MM were excluded, though prior therapy for SMM was not an exclusion criterion.

In the first two 28-day treatment cycles, patients received elotuzumab 10 mg/kg on days 1, 8, 15, and 22, plus lenalidomide 25 mg on days 1 through 21. For cycles 3 through 8, patients received elotuzumab on days 1, 8, and 15, and dexamethasone 40 mg on days 1, 8, and 15.

After completion of eight treatment cycles or best response, patients were given the option to undergo stem cell mobilization with cyclophosphamide or plerixafor to harvest cells for future transplant. Participants were then allowed to continue on maintenance therapy (elotuzumab 20 mg/kg on day 1, plus lenalidomide on days 1-21 of a 28-day cycle).

As of data presentation, 40 patients completed all 24 treatment cycles. Two patients died during treatment (due to diabetic ketoacidosis and uncontrolled hypertension/myocardial infarction), so 38 patients are on active follow-up. Dr. Ghobrial noted that these patients have no evidence of disease progression.

At a median of 29 months of follow-up (range not provided), two-year progression-free survival (PFS; primary endpoint) was not reached. At 36-month follow-up, PFS was 95 percent and event-free survival was 100 percent.

The overall response rate (ORR) of 84 percent, including:

  • 3 complete remission (6%)
  • 18 very good partial responses (37%)
  • 20 partial responses (41%)

Five patients experienced minimal response (10%) and three had stable disease (6%).

The median time to response was 2.8 months (range = 1.8-4.6 months).

Twenty patients (40%) had high-risk cytogenetics, defined by the presence of del17p, t(4;14), and gain 1q detected on fluorescence in situ hybridization (FISH). The investigators obtained bone marrow (BM) samples from 32 patients before treatment initiation for baseline assessment, and whole-exome sequencing was performed on samples at the time of starting therapy.

They found that recurrent mutations in the MAPK pathway (KRAS, NRAS) and the TP53 gene were detected in 40 percent of patients (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13 percent of patients.

The following somatic copy number alterations (SCNAs) were identified in 25 percent, 31 percent, 12 percent, and 7 percent of participants, respectively: 1q duplication, del13q, del17p, and del1p.

“Interestingly, in six patients, high-risk somatic copy number alterations (1q gain and del17p) were not reported in FISH but were detected by whole-exome sequencing,” Dr. Ghobrial added. “Certain mutations were more enriched in patients with poorer response (minimal response or stable disease), potentially indicating some areas of drug resistance and findings that would help with precision medicine where we pick patients with highest likelihood of response.”

The most commonly observed adverse events (AEs) included: fatigue (92%), diarrhea (72%), and hyperglycemia (62%). The most common grade ≥3 AEs were hypophosphatemia (34%, including 3 patients with grade 4 hypophosphatemia), neutropenia (26%, including 1 patient with grade 4 neutropenia), and lymphocytopenia (22%; including 1 patient with grade 4 neutropenia).

While Dr. Ghobrial reported that no patients have shown progression to overt MM, the results of this phase II trial are limited by the small patient enrollment and the lack of a comparator arm. Overall survival data also were not available at the time of presentation.

“We are now looking at the exact mechanism of response in these patients to find which patients will benefit most from this early therapeutic intervention,” Dr. Ghobrial concluded.

The authors report financial relationships with Celgene and Bristol-Myers Squibb, the sponsors of this trial.

Reference

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

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