MORE DATA are in to support early intervention for high-risk smoldering multiple myeloma—an early, asymptomatic entity lacking the presence of CRAB criteria (elevated calcium, renal failure, anemia, bone lesions). The latest come from two phase II studies presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition, which built upon the backbone of lenalidomide plus dexamethasone by adding elotuzumab or ixazomib. Response rates exceeded 90%, and evolution to active disease was not observed.

Irene Ghobrial, MD

Irene Ghobrial, MD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston, reported a response rate of 84% for the triplet of elotuzumab, lenalidomide, and dexamethasone.¹ Progression-free survival at 3 years with the regimen was 95%, which she said compares favorably with the doublet of lenalidomide plus dexamethasone (77%), as reported by Mateos et al.² The reduction in risk for lenalidomide/dexamethasone in that study was 82% (P < .001).

Mark Bustoros, MD, of Dana-Farber Cancer Institute and Harvard Medical School, reported the interim analysis of 29 patients of 57 accrued for the ongoing trial of ixazomib/lenalidomide/ dexamethasone oral triplet. This combination yielded a response rate of 93%, with 56% of the patients achieving a complete or very good partial response to date.³ Dr. Ghobrial was the senior author of that study as well.

Mark Bustoros, MD

Kenneth Shain, MD, PhD

Myeloma experts interviewed by The ASCO Post maintained that, while interesting, the results have not been validated and are not yet clinically applicable outside the clinical trial setting. Kenneth Shain, MD, PhD, Director of the Myeloma Working Group at Moffitt Cancer Center, Tampa, Florida, said it is still unclear which patients warrant early intervention. “I choose carefully not to treat ‘high-risk’ smoldering myeloma outside of a clinical trial. We still don’t have a crystal ball as to which patients may benefit.”

Rationale for Early Intervention

ALTHOUGH PATIENTS with smoldering multiple myeloma are typically monitored and not treated, some researchers have questioned whether early intervention could improve outcomes and even cure the disease before its full impact is felt.

“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 continued. “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.”

“In patients with early breast cancer, such as ductal carcinoma in situ, we don’t say we’ll wait until you have metastatic lesions and then we’ll treat you. Yet in multiple myeloma, we still tell patients with smoldering disease, who have a high M spike, we will wait until you have CRAB criteria, and then we’ll treat,” she said. “In recent years, we have started to determine whether it’s time for us to treat high-risk smoldering myeloma.”

Study Details

THE PHASE II study of the elotuzumab regimen evaluated 50 patients with high-risk smoldering disease. Patients had to have bone marrow clonal plasma cells ≥ 10% and 1 or more of a long list of other high-risk features, such as serum M protein ≥ 3.0 g/dL or serum involved/uninvolved free light chain ratio ≥ 8 (but less than 100). The study excluded patients with symptomatic disease or any evidence of CRAB criteria, including the newer criteria for myeloma (SLiM CRAB).

“In recent years, we have started to determine whether it’s time for us to treat high-risk smoldering myeloma.”

— Irene Ghobrial, MD

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For the 50 patients enrolled, the heavy chain type was immunoglobulin (Ig)G for 66% and IgA for 30%; mean bone marrow plasma percentage was 20%, and mean ß2-microglobulin level was 2.1 mg/dL. High-risk cytogenetics were observed in 44.4% of patients, including 1q21 amplification in 24.4%.

For this study, the regimen included the monoclonal antibody elotuzumab, which activates the immune system, added to the standard backbone of lenalidomide/dexamethasone. Patients received weekly 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, patients received elotuzumab infusions on days 1, 8, and 15. Dexamethasone (40 mg) was administered on days 1, 8, and 15. After eight cycles or best response, investigators gave patients the option of stem cell mobilization and collection. Patients then continued on maintenance therapy for 24 cycles, with elotuzumab (20 mg/kg) on day 1 in combination with lenalidomide on days 1 through 21 of a 28-day cycle.

No Progression to Active Disease

THE MEDIAN time to response was 2.8 months, and at a median follow-up of 29 months, median progression-free survival had not been reached with elotuzumab, lenalidomide, and dexamethasone. When compared to the historical control of lenalidomide plus dexamethasone, which yielded a progression-free survival rate of 77% in the Mateos et al study,² the addition of elotuzumab to this backbone increased progression-free survival to 95%. In the Ghobrial et al trial, event-free survival (ie, no progression to SLiM-CRAB criteria) was 100% at 36 months.

The overall response rate was 84%, increasing to 87% for the 46 patients who completed at least 8 cycles of treatment. For these optimally treated patients, 7% achieved a complete response and 37% achieved a very good partial response, as evidenced by significantly reduced M protein levels. At 36 months, 95% of patients were alive.

In response to a question about the dichotomy between the low rate of complete response (7%) and the long progression-free survival, Dr. Ghobrial suggested this is possibly due to the “interference with the antibody, ie, the elotuzumab effect,” in which immune activation interferes with measurement of response. “That’s why a very good partial response is probably more reflective of the true response and why progression-free survival is more important than depth of response,” she maintained.

“There were no differences in response based on high-risk cytogenetics alone,” she added. A very good partial response or better was achieved by 45% of the high-risk cohort and by 46% of patients without high-risk cytogenetics. In ongoing correlative studies, the genomic profile with whole-exome sequencing and ultra–low-pass whole-genome sequencing has indicated some potential correlations with response.

Tolerability

The treatment was also well tolerated, according to the researchers. The most common toxicities were fatigue (92%), diarrhea (72%), and hyperglycemia (62%). Grade 3 or higher adverse events were mainly hypophosphatemia (34%), neutropenia (26%), and reduced lymphocyte count (22%). Grade 4 hypophosphatemia was observed in 3 patients (6%) during treatment, and grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in 1 patient each (2%).

Two patients died: 1 was due to uncontrolled diabetes, bowel perforation, and septic shock at cycle 20, and the other was due to myocardial infarction and uncontrolled hypertension at the end of cycle 24.

Dr. Ghobrial and colleagues are currently utilizing genomic profiling and immune profiling to understand which patients will benefit most from this early therapeutic intervention.

Ixazomib/Lenalidomide/Dexamethasone

THE INCLUSION and exclusion criteria were similar for the phase II study presented by Dr. Bustoros. Most of the 29 patients had several high-risk characteristics: 44.8% had 3, 34.5% had 4, and 20.7% had 5 high-risk features at baseline.

Treatment was up to 9 cycles of ixazomib at 4 mg on days 1, 8, and 15; lenalidomide at 25 mg on days 1 through 21; and dexamethasone at 40 mg on days 1, 8, 15, and 22, every 28 days. This was followed by up to 24 cycles of maintenance therapy with ixazomib at 4 mg and lenalidomide at 15 mg.

“The high response rate and convenient schedule [for ixazomib, lenalidomide, and dexamethasone] … are promising in this patient population at high risk of progression to symptomatic disease.”

— Mark Bustoros, MD

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After a median follow-up of 15 months, the overall response rate was 93.1%, rising to 100% when 2 patients with a minimal response were counted. Complete responses were seen in 27.6%, and very good partial responses or better were achieved in 24.1%.

“The high response rate and convenient schedule, with a low-toxicity profile observed to date, are promising in this patient population at high risk of progression to symptomatic disease,” Dr. Bustoros said.

The investigators are testing for minimal residual disease in patients with complete and very good partial responses and conducting RNA sequencing of the tumor microenvironment to understand the immune state in smoldering myeloma and its role in treatment response and outcomes. Whole-exome sequencing of tumor cells is also underway, to characterize genomic predictors of response and disease course. ■

DISCLOSURE: Dr. Ghobrial has consulted for Takeda, Janssen, Bristol-Myers Squibb, and Celgene. Dr. Bustoros has consulted for Takeda and received honoraria from Dava Oncology and Takeda. Dr. Shain has served as an advisor or consultant for Celgene, Janssen, Takeda, and Bristol-Myers Squibb and has received grant funding from AbbVie.

REFERENCES

1. Liu C-J, Ghobrial IM, Bustoros M, et al: Phase II trial of combination of elotuzumab, lenalidomide and dexamethasone for high-risk smoldering multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 154. Presented December 1, 2018.

2. Mateos M-V, Hernandez M-T, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013.

3. Bustoros, Liu C-J, Reyes K, et al: Phase II trial of the combination of ixazomib, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma. 2018 ASH Annual Meeting & Exposition. Abstract 804. Presented December 3, 2018.