Three-agent regimen effective, safe in high-risk smoldering multiple myeloma
ORLANDO — The combination of ixazomib, lenalidomide and dexamethasone appeared highly effective for patients with high-risk smoldering myeloma, according to phase 2 study results presented at ASH Annual Meeting and Exposition.
More than 90% of patients responded to therapy, and 50% achieved complete response or very good partial response.
“That is huge for this group of patients,” Mark W. Bustoros, MD, instructor of medicine at Dana-Farber Cancer institute and Harvard Medical School, told Healio. “We were surprised by the efficacy. The combination also is very tolerable.”
Smoldering myeloma is heterogeneous. Some patients progress in a short time while others may be asymptomatic for long periods.
The annual risk for progression from smoldering myeloma to active disease is about 10% in the first 5 years. Within 20 years, approximately 78% of patients progress to overt multiple myeloma.
Prior research demonstrated the efficacy of lenalidomide (Revlimid, Celgene) — an immunomodulatory agent — in combination with dexamethasone for high-risk smoldering multiple myeloma.
The combination of ixazomib (Ninlaro, Takeda) — an oral proteasome inhibitor — lenalidomide and dexamethasone already is approved in the United States for patients with previously treated multiple myeloma.
Bustoros and colleagues conducted their study to determine whether early intervention with these three agents would improve 2-year PFS among adults with high-risk smoldering multiple myeloma. They also assessed response rate, response duration, safety, depth of response and minimal residual disease.
All study participants were aged 18 years or older and had at least 10% clonal plasma cells in bone marrow. They also had any one of several high-risk features, such as serum M protein of 3.0 g/dL or greater, immunoparesis with reduction of two uninvolved immunoglobulin isotypes, or serum involved/uninvolved free light chain ratio of at least 8 but less than 100.
Exclusion criteria included bone marrow plasma cells greater than 60% or MRI with more than one focal lesion.
Investigators enrolled 61 patients (median age, 61 years; range, 41-76; 51% men).
Median plasma cell infiltration was 25% (range, 10-55), median M-protein was 1.6 (range, 0.4-4.1).
Baseline fluorescence in situ hybridization showed 56% of patients had translocation t(11;14), deletion 17p or 1qgain. All patients had at least three high-risk criteria, 38% had four high-risk criteria and 28% had five high-risk criteria.
Treatment was administered on an outpatient basis in 28-day cycles.
In the nine-cycle induction phase, patients received 4 mg ixazomib on days 1, 8 and 15; 25 mg lenalidomide on days 1 to 21; and 40 mg dexamethasone on days 1, 8, 15 and 22.
After induction, investigators performed stem cell collection for eligible patients.
During induction, patients received 15 cycles of maintenance therapy with 4 mg ixazomib on days 1, 8 and 15, plus 15 mg lenalidomide on days 1 to 21.
Event monitoring continued for up to 3 years.
Median follow-up was 15 months (range, 3-31) and, at data cutoff, patients had undergone a median 10 treatment cycles (range, 2-24).
Researchers reported a 93.8% ORR. This included 15 patients (31%) with a stringent complete response, nine (19%) with very good partial response, 21 (44%) with partial response and three (6%) with minor response.
Bustoros and colleagues also used next-generation sequencing to perform minimal residual disease analysis on patients who achieved complete response at cycle 9. Sixty-nine percent of those patients were minimal residual disease negative using a sensitivity of 10-6.
Sixteen patients have completed the trial and are in follow-up. No patients had progressed to overt myeloma by data cutoff.
The combination appeared highly tolerable, Bustoros said.
The most common grade 3 adverse events included hypophosphatemia (8.3%), hypertension (6.2%), hyperglycemia (4.2%) and rash (2.1%). Hematologic adverse events included thrombocytopenia (grade 3, 2.1%) and neutropenia (grade 3, 4.2%; grade 4, 2.1%). No patients developed anemia.
“Of course, we need longer follow-up,” Bustoros told Healio. “However, so far, the data look promising. We hope that, in time, this will be an effective and convenient approach that allows high-risk patients to control their disease.” – by Mark Leiser
Reference: Bustoros M, et al. Abstract 580. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosure: Bustoros reports honoraria from Takeda. Please see the abstract for all other authors’ relevant financial disclosures.