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Stem cell transplant maintains benefit for multiple myeloma in era of novel agents
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Treatment with high-dose melphalan followed by autologous hematopoietic stem cell transplant conferred longer PFS with minimal toxic effects compared with novel agents among patients with multiple myeloma, according to results from a meta-analysis published in JAMA Oncology.
OS appeared similar across all assessed treatment approaches.
“Given the unprecedented efficacy of novel agents, investigators have sought to reevaluate the role of [high-dose melphalan followed by autologous stem cell transplant],” Saad Z. Usmani, MD, FACP, chief of plasma cell disorders and director of clinical research in hematologic malignancies at Levine Cancer Institute at Carolinas HealthCare System and a HemOnc Today Editorial Board Member, and colleagues wrote. “All prospective studies performed in the recent era have consistently shown a PFS benefit, but their effect on [response rates] and OS compared with the standard-dose therapy has been variable.”
Usmani and colleagues conducted a conventional meta-analysis using data from four randomized controlled trials (n = 2,421) that compared high-dose melphalan therapy plus autologous HSCT with standard-dose therapy using novel agents, including bortezomib (Velcade, Millennium/Takeda), lenalidomide (Revlimid, Celgene), and dexamethasone consolidation and tandem transplantation.
Overall, patients treated with high-dose melphalan/HSCT had a 27% higher chance for complete response (OR = 1.27; 95% CI, 0.97-1.65) than patients who received novel agents.
High-dose melphalan/HSCT also improved PFS (HR = 0.55; 95% CI, 0.41-0.74), and trended toward improved OS (HR = 0.76; 95% CI, 0.42-1.36) in the three studies that reported that endpoint.
Longer follow-up appeared associated with improved PFS (HR per month = 0.98; 95% CI, 0.96-0.99) and OS (HR per month = 0.9; 95% CI, 0.37-0.65).
Researchers also conducted a network meta-analysis (n = 3,171) that included one additional randomized study. Patients in the trial underwent single high-dose melphalan/HSCT and then were randomly assigned to undergo tandem high-dose melphalan/HSCT; consolidation with bortezomib, lenalidomide and dexamethasone; or no further therapy.
Tandem high-dose melphalan/HSCT showed the largest benefit for PFS compared with standard-dose novel agents (HR = 0.49; 95% CI, 0.37-0.65), followed by single high-dose melphalan/HSCT with bortezomib, lenalidomide and dexamethasone (HR = 0.53; 95% CI, 0.37-0.76); and single high-dose melphalan/HSCT alone (HR = 0.68; 95% CI, 0.53-0.87). None of these approaches had a significant effect on OS.
“The median survival of [patients with multiple myeloma] is about 10 years now,” Usmani told HemOnc Today. “Naturally, if we want to see an OS difference between modalities — say from 10 years to 12 years — we cannot determine a winner just after 3 to 4 years of follow-up. In fact, all the ‘transplant vs. standard-of-care therapy’ trials from the 1990s onward started to see the OS curves separating after about 6 to 7 years of follow-up. With this context in mind and similar access to post-relapse therapies, one wouldn’t be surprised if OS difference emerges with longer follow-up.”
High-dose treatment-related mortality was minimal (< 1%).
Study limitations included a limited number of studies, heterogeneous treatments delivered and unreported outcomes.
“Upfront high-dose therapy/autologous HSCT remains an effective treatment strategy for patients with newly diagnosed multiple myeloma and has an acceptable profile of toxic effects and costs,” the researchers wrote.
“This meta-analysis supports a transplant evaluation for patients with newly diagnosed [multiple myeloma] within the first 6 months of diagnosis,” Usmani said. “Many patients may appear ineligible at diagnosis due to disease sequelae but improve their performance status with therapy.
“A small subset of patients (around 5%) may be at risk for developing second primary malignancies; therefore, we need to develop better predictive models to identify those patients at [multiple myeloma] diagnosis and consider alternative treatment approach for them,” he added. – by Cassie Homer
For more information:
Saad Z. Usmani, MD, FACP, can be reached at saad.usmani@carolinashealthcare.org.
Disclosures: Usmani reports consultant/advisory or speakers bureau roles with Amgen, Celgene, Janssen, Millennium, Onyx, Sanofi, Skyline and Takeda; and research funding from Array BioPharma, Bristol-Myers Squibb, Celgene, Janssen, Onyx, Pharmacyclics, Sanofi and Takeda. Please see the full study for all other authors’ relevant financial disclosures.
Perspective
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Henry Chi Hang Fung
Autologous HSCT has been the standard of care for younger patients with multiple myeloma for decades. With the introduction of novel agents, the role of autologous HSCT has been repeatedly challenged, partly due to the perceived high costs and the potential morbidity and mortality associated with the transplant.
In comparison with novel therapies for treatment of multiple myeloma, autologous HSCT is no longer considered costly; the transplant-related morality is minimal; and it is as safe as novel therapy, with less than 1% transplant-related mortality. Many transplants occurred in outpatient units.
In this meta-analysis, the authors have demonstrated that, despite the use of novel agents for induction, transplant continues to improve PFS, but not OS, compared with a nontransplant approach. However, the studies included in this analysis did not compare transplant with “no transplant,” as they either adopt a delayed transplant approach per protocol or significant numbers of patients received a salvage transplant at disease progression. Thus, this meta-analysis strongly supports the continued role of autologous HSCT as part of the initial treatment for patients with multiple myeloma.
Of interest, a tandem transplant approach showed the most favorable outcomes, which may even become a “comeback kid.” Against the above background, induction with multiple novel agents, consolidation with single or tandem autologous HSCT follow by maintenance should remain the standard of care for patients with multiple myeloma.
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