Issue: May 10, 2018
January 23, 2018
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Stem cell transplant maintains benefit for multiple myeloma in era of novel agents

Issue: May 10, 2018
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Saad Z. Usmani

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.

Perspective from

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.