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No Need for Triple Therapy or Second Transplant for Multiple Myeloma

Fuerst, Mark L.

doi: 10.1097/01.COT.0000513048.92804.7c
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SAN DIEGO—In the upfront treatment of multiple myeloma, the addition of triple therapy with bortezomib, lenalidomide, and dexamethasone (RVD) for consolidation or a second autologous hematopoietic cell transplant is not superior to a single transplant followed by lenalidomide maintenance, according to the largest randomized controlled trial of post-transplant therapy for multiple myeloma ever conducted in the U.S.

Standard care for multiple myeloma consists of an initial course of combinations of proteasome inhibitors, thalidomide analogues, corticosteroids, and alkylating agents, and then high doses of melphalan, autoHCT, and maintenance therapy with lenalidomide.

“In the era of thalidomide analogues and proteasome inhibitors used in initial therapy for myeloma, and the use of prolonged maintenance therapy with lenalidomide, post-transplant consolidation, or a second transplant do not produce incremental progression-free survival (PFS) benefit,” said lead author Edward A. Stadtmauer, MD, of the Abramson Cancer Center, University of Pennsylvania in Philadelphia.

Stadtmauer presented the findings at the American Society of Hematology 2016 annual meeting (Abstract LBA-1).

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Multiple Myeloma Study

The researchers, participating in a national collaborative effort of 54 centers, enrolled 758 patients and randomly assigned them to receive either standard care, standard care plus additional chemotherapy, or standard care plus a second round of autoHCT.

With almost all patients nearing the end of follow-up, the study's Data and Safety Monitoring Board released the current results. Those results showed there was no difference in overall survival at 38 months, with a rate of about 82 percent to 85 percent of patients in the three arms, and PFS ranged from about 52 percent to 56 percent in the three arms, with the differences not being statistically significant. Median overall survival has not been reached.

“These results are very important because they answer a question that has been ongoing and has not been compared head-to-head: ‘Does the addition of these interventions result in a true advantage for these patients?’” said Stadtmauer. “The conclusion of this study, so far, is that the other interventions are not superior to initial melphalan therapy followed by a single autoHCT followed by lenalidomide maintenance.”

Lenalidomide maintenance after autoHCT has improved PFS and overall survival, however, the role of additional interventions after autoHCT such as tandem autoHCT or triple therapy consolidation remains to be determined.

Stadtmauer reported on a phase III clinical trial that included transplant-eligible patients with symptomatic multiple myeloma under 71 years of age (median age 57 years) within 12 months of initiating therapy and without prior progression. Men accounted for about 60 percent of the study population, and about 70 percent of the patients had Karnofsky performance scores of 90 percent or higher.

A review of pre-transplant therapies showed that more than half of the patients had received combination therapy with bortezomib, lenalidomide, and dexamethasone, about 15 percent of them had received cyclophosphamide-bortezomib-dexamethasone, and about 12 percent had received bortezomib-dexamethasone.

The patients were randomly assigned to receive melphalan 200 mg/m2 autoHCT and 4 cycles of consolidation with lenalidomide 15 mg daily days 1-14; dexamethasone 40 mg on days 1, 8, and 15; and bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 every 21 days versus tandem melphalan 200 mg/m2 autoHCT or versus a single autoHCT.

Randomization was stratified by disease risk, cytogenetic abnormalities del13q by karyotype, del17q, t(4;14), t(14;16), t(14;20), and hypodyploid; or high beta-2 microglobulin. One quarter of the patients had high-risk disease by microglobulin and cytogenetics criteria.

All arms included lenalidomide maintenance at the maximum tolerated dose of 5-15 mg orally daily until progression, with dose modifications for toxicities.

In addition to similar survival rates, the cumulative incidences of disease progression at 38 months were also similar, ranging from 42 percent to 47 percent in the three arms.

There were 39 cases of second primary malignancy reported in 36 patients. Cumulative incidences were 6.0 percent for patients who received consolidation therapy, 5.9 percent for patients who received tandem transplants, and 4.0 percent for the patients who received only lenalidomide maintenance therapy. These percentages are consistent with what has previously been reported, noted Stadtmauer.

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New Treatments

“Despite remarkable advances in the therapy and outlook for patients with multiple myeloma over the past decade, ultimately many patients will have their disease progress. So, there is always room for improvement,” said Stadtmauer. “New therapies and interventions need to be actively investigated to see how much they further benefit the early treatment of patients with myeloma. I believe that the results of this study suggest it would be reasonable to compare any new treatments to the standard therapy of melphalan followed by a single autoHCT followed by lenalidomide maintenance.”

A long-term follow-up trial to track outcomes in these patients is ongoing. The researchers plan to examine associations between outcome and the rate of conversion to complete response; reasons for not receiving assigned therapy; assessment of minimal residual disease; and correlations between initial therapy and myeloma biology with outcome.

Mark L. Fuerst is a contributing writer.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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