High Response Rates to Triplet Therapy in Smoldering Myeloma


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The high response rates among this patient population, who would otherwise remain untreated, is a promising starting point for the paradigm shift toward early therapeutic intervention in patients with high-risk smoldering myeloma.
— Irene Ghobrial, MD

High-risk patients with smoldering multiple myeloma responded to a regimen of elotuzumab (Empliciti), lenalidomide (Revlimid), and dexamethasone, in a multicenter phase II study led by Irene Ghobrial, MD, of Dana-Farber Cancer Institute, Boston.1

“The high response rates among this patient population, who would otherwise remain untreated, is a promising starting point for the paradigm shift toward early therapeutic intervention in patients with high-risk smoldering myeloma,” Dr. Ghobrial said during her presentation at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition.2

The rate of progression from smoldering disease to myeloma is about 10% per year for the first 5 years. Interest in preventing this disease progression has been growing, based on the study by Mateos et al showing a benefit with lenalidomide plus dexamethasone.2 In that study, the risk of disease progression was reduced by 82% (P < .001), and mortality at 3 years was reduced by 69% (P = .03).

The results have precipitated something of a paradigm shift in approaching this disease, revealed Dr. Ghobrial. “In many solid cancers, we don’t watch and wait before treating, yet in patients with smoldering myeloma, the practice has been to watch and wait until they have active disease,” she explained. “The questions are whether therapeutic intervention early on can prevent or delay the development of CRAB criteria [hypercalcemia, renal insufficiency, anemia, bone lesions] and organ damage and whether we can build upon the lenalidomide/dexamethasone data by using immunotherapy, like elotuzumab, to harness the immune system.”

Based on the study by Mateos and previous activity observed with elotuzumab and lenalidomide in relapsed myeloma, Dr. Ghobrial and her colleagues evaluated the impact of elotuzumab plus lenalidomide and dexamethasone in reducing disease progression at 2 years. “We chose the 2-year time point because we know that patients with high-risk smoldering myeloma have a 50% chance of disease progression at 2 years,” she shared.

Study Design

Study patients met the newly defined eligibility criteria for high-risk smoldering myeloma.3 Those with symptomatic disease, any evidence of CRAB criteria, or a myeloma-defining event were excluded.

The study was designed originally with two arms: arm A included high-dose dexamethasone (40 mg) along with weekly elotuzumab (10 mg/kg) and daily lenalidomide; arm B was the same, minus dexamethasone. “The concern was that by adding dexamethasone to elotuzumab, we could be dampening the response we get from the immune system by using elotuzumab,” she explained. “But after accruing 10 patients per arm, we halted arm B, because data from the lenalidomide/dexamethasone trial showed no effect of dexamethasone on the immune profile.”

Elotuzumab/Lenalidomide/Dexamethasone in Smoldering Myeloma

  • Induction treatment with elotuzumab, lenalidomide, and dexamethasone yielded an 82.6% response rate in patients with smoldering multiple myeloma.
  • Progression-free survival data are not yet mature.
  • The hope is that early intervention may prevent the progression of smoldering disease to myeloma.

Next, revealed Dr. Ghobrial, “we changed the study to allow us to give elotuzumab with a faster infusion, and for this we needed a higher dose. We continued with the high-dose dexamethasone arm.”

After eight cycles or best response, patients were given the option to collect stem cells for future transplant. Patients on both treatment arms were then allowed to continue on maintenance therapy, which consisted of elotuzumab (20 mg/kg) on day 1 in combination with lenalidomide on days 1 to 21 of a 28-day cycle.

The study accrued 51 patients. Dr. Ghobrial presented findings for the first 47 patients. In this group, 38% had high-risk cytogenetics, 32% had immunoglobulin A heavy-chain type, and the median percentage of bone marrow plasma cells was 20%.

100% Clinical Benefit Rate

Data were available on 23 patients who completed at least 9 induction treatments. Their overall response rate was 82.6%, including 8.7% with complete responses, 26.1% with very good partial responses or better, and 47.8% with partial responses. Another 17.4% achieved a minimal response, yielding a clinical benefit rate of 100%, she reported.

Most responses emerged by the second or third cycle, and they often improved with time. All patients experienced some change in M protein.

Progression-free survival data are still very premature, but “none of the patients on the experimental arm have developed CRAB criteria or a myeloma-defining event,” noted Dr. Ghobrial. While cautioning against cross-study comparison, she displayed a progression-free survival curve of the lenalidomide/dexamethasone regimen and the elotuzumab/lenalidomide/dexamethasone regimen. The visual comparison suggested a trend favoring the triplet may be developing. “Long-term follow-up is needed to determine whether it is better than observation or better than lenalidomide/dexamethasone,” she added.

The triplet regimen was well tolerated, with only two patients experiencing grade 4 toxicity (thrombocytopenia and neutropenia, which were both reversible). Most adverse events were grades 1 or 2, and only four patients required dose reductions.

Immune profiling and studies examining mechanisms of response and resistance are ongoing. ■

Disclosure: Dr. Ghobrial received honoraria from Amgen, Celgene, Bristol-Myers Squibb, Novartis, Takeda, and Noxxon Pharma as well as research funding from Celgene and Bristol-Myers Squibb.

References

1. Ghobrial IM, Badros AZ, Vredenburgh JJ, et al: Phase II trial of combination of elotuzumab, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma. 2016 ASH Annual Meeting. Abstract 976. Presented December 5, 2016.

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

3. Rajkumar SV, Dimopoulos MA, Palumbo A, et al: International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:e538-e548, 2014.


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