High-dose melphalan plus salvage ASCT improved outcomes in relapsed myeloma

High-dose melphalan chemotherapy plus salvage autologous stem cell transplantation in patients with relapsed multiple myeloma significantly prolonged time to progression compared with conventional low-dose cyclophosphamide, according to results of a randomized, open-label, phase 3 trial.

No standard treatment exists for relapsed myeloma, and the role of autologous stem cell transplantation in this patient population is not clear, according to background information provided by researchers.

Gordon Cook, MB, ChB, PhD, consultant hematologist and myeloma lead at St. James Institute of Oncology in the United Kingdom, and colleagues compared high-dose melphalan (Alkeran, GlaxoSmithKline) plus salvage ASCT with cyclophosphamide in patients with first progressive or relapsed multiple myeloma. All patients had undergone previous ASCT, and at least 18 months elapsed since their previous transplant.

Prior to study randomization, 293 patients underwent induction therapy with bortezomib (Velcade, Millennium), doxorubicin and dexamethasone, followed by peripheral blood stem-cell mobilization and harvesting, if appropriate.

The 174 patients with sufficient peripheral blood stem cells were randomly assigned to 200 mg/m2 high-dose melphalan plus salvage ASCT (n=89) or 400 mg/m2 oral cyclophosphamide weekly for up to 12 weeks (n=85).

Disease progression served as the primary endpoint. Median follow-up was 10.1 months.

Cook and colleagues reported significantly longer median time to progression (19 months vs. 11 months; HR=0.36; 95% CI, 0.25-0.53) among patients assigned melphalan plus salvage ASCT.

Philip L. McCarthy, MD

Philip L. McCarthy

At the time of data cut-off, median OS had not been reached in either arm but researchers did not observe significant differences. Rates of 3-year OS were 80.3% (95% CI, 69.3–91.2) for the salvage ASCT group and 62.9% (95% CI, 46.6–79.2) for the cyclophosphamide group.

The most commonly reported grade 3 to grade 4 adverse events following induction therapy were thrombocytopenia (51%), neutropenia (43%) and peripheral neuropathy (12%). After randomization, researchers reported higher rates of neutropenia (76% vs. 13%) and thrombocytopenia (72% vs. 5%) in the salvage ASCT group.

“Salvage ASCT can now be considered a standard treatment after re-induction therapy for eligible patients with multiple myeloma relapsing after first ASCT, especially beyond 12 months to 18 months after first relapse,” Philip L. McCarthy, MD, of the adult blood and marrow transplant program at Roswell Park Cancer Institute, wrote in an accompanying editorial. “New therapies directed against other multiple myeloma intracellular pathways and antibodies that target cell surface antigens might serve as experimental comparisons to salvage transplant after disease progression.”

For more information:

  • Cook J. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70245-1.
  • McCarthy PL. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70279-7.

Disclosure: The study was funded by Cancer Research UK. The researchers report honoraria, research funding and speakers bureau fees from Janssen. McCarthy reports advisory board roles with Celgene, Janssen, Millennium, Sanofi and Takeda.

Perspective
Saad Usmani, MD

Saad Z. Usmani

  • Multiple myeloma (MM) has become a chronic, manageable disease for a significant majority of patients. High-dose melphalan–autologous stem cell transplantation (HDM-ASCT) was the first therapeutic modality that was shown to extend survival benefit in MM more than 2 decades ago, albeit with significant acute toxicities. Over the years, HDM-ASCT has become of a much safer, better tolerated modality, and many transplant centers can manage these patients in the outpatient setting. But the upfront utility of HDM-ASCT has come under scrutiny in the era of novel agents.

    Data from the Center for International Blood & Marrow Transplant Research (CIBMTR) show that HDM-ASCT is only utilized for 13.4% of newly diagnosed MMs in the United States (Costa LJ. Abstract #596. Presented at: ASH Annual Meeting and Exposition; Dec. 8-11, 2012; Atlanta). But emerging, prospectively randomized phase 3 data suggests its early utility significantly improves PFS, with a trend toward improvement in survival outcomes (Palumbo A. Abstract #763. Presented at: ASH Annual Meeting; Dec. 7-10, 2013; New Orleans; Bocadorro M. Abstract #8509; Presented at: ASH Annual Meeting; Dec. 7-10, 2013; New Orleans).

    HDM-ASCT also appears to have utility in the relapsed MM setting. With each relapse, MM patients appear to exhaust the bone marrow reserve and develop cytopenia. This makes subsequent treatment decisions and management quite challenging, not to mention that many patients are deemed ineligible for clinical trials based on cytopenia. HDM-ASCT may be an attractive option for fit and eligible patients in such an instance. Several small series and a large CIBMTR retrospective look (Michaelis LC. Biol Blood Marrow Transplant. 2013;19:760-766) showed patients — who initially got a 24- to 36-month PFS benefit from their first HDM-ASCT — appear to get more “mileage” from a salvage HDM-ASCT. The NCRI Myeloma X Relapse phase 3 trial supports these observations and makes the case to consider salvage HDM-ASCT in fit patients.

    • Saad Z. Usmani, MD, FACP
    • HemOnc Today Editorial Board member
  • Disclosures: Usmani reports no relevant financial disclosures.