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Upfront autologous HSCT superior to novel therapies for multiple myeloma
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First-line treatment with autologous hematopoietic stem cell transplantation prolonged PFS compared with chemotherapy including bortezomib in younger patients with newly diagnosed multiple myeloma, according to results of a randomized phase 3 study scheduled for presentation at the ASCO Annual Meeting.
Thus, autologous HSCT should remain the preferred first-line treatment option over novel therapies for younger patients with newly diagnosed multiple myeloma, according to the researchers.
Michele Cavo
“For more than 2 decades, chemotherapy at the doses requiring the support of autologous stem cells has been considered the gold standard for younger and fit patients with newly diagnosed multiple myeloma,” Michele Cavo, MD, head of the Seràgnoli Institute of Hematology at University of Bologna, said during a press briefing. “Over the past 10 to 15 years, therapies with novel, non-genotoxic drugs have dramatically increased the response rate and significantly expanded survival in previously untreated myeloma patients. Remarkable activity of novel therapies has recently put into question the role of upfront autologous stem cell transplantation in multiple myeloma.”
Cavo and colleagues sought to compare the efficacy of bortezomib (Velcade; Takeda, Millennium), melphalan and prednisone (VMP) regimen with that of autologous HSCT in 1,266 patients aged 65 years or younger with newly diagnosed multiple myeloma.
All patients received induction therapy with bortezomib, cyclophosphamide and dexamethasone, and then were randomly assigned to receive four cycles of VMP (n = 512) or one to two courses of high-dose melphalan with single autologous HSCT (n = 754). Patients treated in centers with a tandem HSCT policy were randomly assigned to receive VMP or single or double autologous HSCT.
Patients then underwent a second randomization to consolidation therapy with bortezomib, lenalidomide (Revlimid, Celgene) and dexamethasone or no consolidation therapy, followed by lenalidomide maintenance until progression or toxicity.
PFS from the time of the first randomization served as the study’s primary endpoint.
Cavo reported data from an interim analysis performed in January after 33% of the required events had occurred.
Median follow-up from the time of the first randomization was 23.9 months.
Although median PFS had not yet been reached, patients assigned high-dose melphalan and autologous HSCT were less likely to experience disease progression than patients assigned VMP (HR = 0.76; 95% CI, 0.61-0.94).
This benefit persisted across patient subgroups, including among patients with revised International Staging System stage III disease (HR = 0.52; 95% CI, 0.32-0.84) and high-risk cytogenetics (HR = 0.72; 95% CI, 0.54-0.97).
A greater proportion of patients assigned transplant also achieved at least a very good partial response (84% vs. 74%; OR = 1.9; 95% CI, 1.42-2.54).
Results of a Cox regression analysis showed randomization to the transplantation arm independently predicted improved PFS (HR = 0.61; 95% CI, 0.45-0.82).
“These preliminary results do support the conclusion that upfront high-dose chemotherapy and autologous transplant continues to be the best treatment option for fit patients with newly diagnosed myeloma even in the novel agent era,” Cavo said. – by Alexandra Todak
Reference:
Cavo M, et al. Abstract 8000. Presented at: ASCO Annual Meeting; June 3-6, 2016; Chicago.
Disclosure: The study was funded by the Haemato Oncology Foundation for Adults in the Netherlands. Cavo reports honoraria and travel expenses from and consulting/advisory roles with Amgen, Bristol-Myers Squibb, Celgene, Janssen and Takeda. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
Perspective
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Saad Z. Usmani, MD, FACP
With the arrival of noncytotoxic agents in the early 2000s, the role and timing of high-dose melphalan was evaluated in several randomized phase 3 studies. Palumbo and colleagues with the European Myeloma Network conducted two randomized phase 3 trials evaluating lenalidomide and low-dose dexamethasone induction followed by conventional chemotherapy — melphalan, prednisone and lenalidomide (Revlimid, Celgene) in one trial, and cyclophosphamide, prednisone and lenalidomide in the other — or high-dose melphalan with autologous stem cell transplant (HDM–ASCT, single or tandem). Both trials showed PFS and OS benefits with HDM–ASCT but were criticized for not having proteasome inhibitors in induction treatment.
Attal and colleagues then presented the Intergroupe Francophone du Myelome (IFM) 2009 data — which compared early vs. late HDM-ASCT — at the ASH Annual Meeting and Exposition in 2015. Results showed a PFS benefit in favor of early HDM–ASCT. All patients on the IFM 2009 trial received lenalidomide, bortezomib (Velcade, Takeda/Millennium) and dexamethasone induction and lenalidomide maintenance, thus quelling concerns about suboptimal induction.
Now, Cavo and colleagues have presented another clinical trial in which bortezomib, cyclophosphamide and dexamethasone induction was followed by either bortezomib, melphalan and prednisone consolidation or HDM–ASCT (single or tandem). Data from the study follow the same theme: HDM–ASCT conferred superior PFS. The PFS benefit was seen in patients with standard- and high-risk cytogenetics and was more pronounced in the tandem HDM–ASCT arm.
If we are compelled to using best available evidence and data to treat our patients, then upfront/early HDM–ASCT should remain the standard of care for transplant-eligible patients with multiple myeloma.
References:
Attal M, et al. Abstract 391. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Florida.
Gay F, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)00389-7.
Palumbo A, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1402888.
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