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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.
Perspective
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Patients with smoldering multiple myeloma (SMM) represent a heterogeneous population, with a subgroup of about one-third of patients considered to be at high risk for progression within 2 years As first-line treatments for multiple myeloma have advanced to the degree that they are better tolerated with improved responses, the question has become whether the standard of care for patients with SMM should change from observation to initiation of antimyeloma therapy in order to prevent progression.
Several studies have attempted to answer this question. The largest — the QuiRedex study by the Spanish Myeloma Group — showed that, at median follow-up of 75 months, median time to progression was not reached with lenalidomide and dexamethasone compared with 23 months in the observation arm (P < .0001).
At ASH, Bustoros and colleagues presented results of a phase 2 study that used the combination of ixazomib, lenalidomide and dexamethasone for induction and maintenance in high-risk SMM.
Interpretation of these findings requires appreciation for the accumulation of data that therapeutic interventions for SMM can delay disease progression to symptomatic myeloma, as well as understanding of the myeloma pathogenesis. Two randomized studies have demonstrated that lenalidomide without dexamethasone can delay progression of SMM. In addition, the GEM-CESAR study — also presented at ASH — evaluated carfilzomib (Kyprolis, Amgen), lenalidomide and dexamethasone along with autologous stem cell transplant. Results showed a 93% PFS rate at 30 months.
Therefore, it appears that early interventions using single, doublet or triplet therapies can offer a benefit in delaying progression and improving OS. Because, by definition, patients with SMM do not have symptomatic disease, one could argue that these patients — although at high risk for progression — have not developed clonal evolution to the point that their plasma cells and microenvironment are as resistant to treatment as symptomatic patients. The question remains whether there is an optimal regimen that balances the degree of intensity of therapy to treat patients with SMM and the clinical benefit.
In the study by Bustoros and colleagues, grade 3 or higher adverse events were generally less than 5%, as in prior studies using lenalidomide. Additional follow up is required to determine whether long-term adverse effects were similar to prior studies showing a slight increase in secondary primary malignancies associated with lenalidomide use.
Minimal residual disease data in this study remains pending. However, this may be a key endpoint to compare between regimens, as minimal residual disease negativity correlates with prolonged survival in symptomatic disease.
Another critique of this and other studies is how high-risk SMM is defined. In study by Bustoros and colleagues, patients had varying degrees of high-risk features. The criteria for high-risk SMM continues to be revised and, in this regard, meta-analyses of high-risk SMM with common features in high-risk criteria — as well as real-world data — will be useful as more people with SMM are treated within and outside the context of clinical trials. Nevertheless, we now have an accumulating wealth of data to suggest that therapeutic interventions for SMM can provide a clinical benefit that favors treatment over observation, particularly for patients at high risk for progression. The question still remains how these data can best be applied in the community off-trial to treatment of patients with SMM.
References:
Lakshman A, et al. Blood Cancer J. 2018;doi:10.1038/s41408-018-0077-4.
Lonial S, et al. J Clin Oncol. 2019;doi:10.1200/JCO.19.01740.
Mateos MV, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(16)30124-3.
Mateos M-V, et al. Abstract 781. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Munshi NC, et al. JAMA Oncol. 2017;doi:10.1001/jamaoncol.2016.3160.