With more potent therapies and new triplet regimens continuing to improve the management of patients with multiple myeloma, a lack of clarity looms around the role and timing of autologous stem cell transplantation.
Ajai Chari, MD, director of clinical research in the Multiple Myeloma Program, Icahn School of Medicine at Mount Sinai in New York, and Navneet Majhail, MD, MS, director of the Blood & Marrow Transplant Program at the Cleveland Clinic, share their views on related research presented at ASH.
Prior to having the currently available drug classes, the vast majority of transplant-eligible patients — up to ages 65 or 70 years, depending on the cancer center — would receive a transplant, Chari explained.
Autologous transplantation is now being questioned as a part of up-front treatment for patients who get induction regimens such as bortezomib (Velcade; Millennium, Takeda Oncology), lenalidomide (Revlimid, Celgene) and dexamethasone, according to Majhail.
In a randomized trial comparing conventional dosing treatment with the three agents only vs. the conventional triplet regimen plus early autologous stem cell transplantation, researchers from France and the Dana-Farber Cancer Institute demonstrated findings suggesting that transplantation should remain a standard of care in young patients and that combining drug therapy and transplantation could serve as a future reference strategy.
“This study showed us that PFS was superior for the early transplant across all age groups, risk status, and interestingly, even depth of response,” Chari said. “Even patients who had a complete response prior to going to transplant seemed to have a longer PFS with transplant relative to conventional therapy.”
The investigators looked at eight cycles of the triplet regimen vs. three cycles of the triplet regimen, followed by consolidation with autologous transplantation, then followed by two more cycles of the same regimen, with both receiving 1 year of maintenance therapy, Majhail detailed.
“PFS was significantly better in the transplant arm — 61% vs. 48%,” Majhail said. “They did not see a difference of OS.”
Acknowledging the importance of the research in favor of maintaining transplant as part of clinical practice, Chari noted two major caveats.
“The results were released from the Intergroupe Francophone Du Myelome, and the investigators stopped lenalidomide after 1 year,” he said. “That’s important because in the U.S., clinicians usually treat with lenalidomide until progression.”
Although the reasons for the differences could range from cost to toxicity, Chari said variance in practice patterns requires consideration before saying “this applies to everybody.” Further, he said the results beg the question of indefinite maintenance therapy and support the need for continued enrollment in the American cohort of this clinical trial.
“There’s also a lot of interest in frontline therapies being quadruplet regimens, not just triplet,” Chari said. He noted researchers have historically added cyclophosphamide to determine if four drugs bested three, to no avail — partly due to increased neutropenia, without improved efficacy.
Considering the balance of risks and benefits is critical when moving from a triplet to quadruplet regimen, he said, emphasizing “it’s hard to get better than a monoclonal antibody in terms of minimizing side effects” and the eagerness in the community to see quadruplet frontline therapies as comparator arms in future research.
In another randomized study with a 2-by-2 factorial design, investigators in Europe and Australia looked at consolidation with melphalan (Alkeran, GlaxoSmithKline) followed by autologous stem cell transplantation or a combination of cyclophosphamide, lenalidomide and dexamethasone — then to maintenance with lenalidomide and prednisone or lenalidomide alone.
“Here again, this showed that the PFS and the OS were significantly better in the transplant arm,” Majhail said. From the start of consolidation, median PFS was 43.3 months with melphalan and transplant vs. 28.6 months with the drug combination; further, OS at 4 years was 86% vs. 73%.
“Even in the era of novel agents for multiple myeloma, offering autologous stem cell transplantation should continue to be part of the treatment strategy for these patients outside the context of a clinical trial,” he said.
Although most patients are referred for autologous transplantation outside the context of clinical trials, Majhail noted there are some schools of thought about delaying transplant at the time of relapse for patients induced with these new agents.
“There are ongoing clinical trials addressing the question of early vs. a delayed transplant,” he said. “What these abstracts highlight is outside of enrolling patients on both kinds of clinical trials, you should refer these patients for an autologous transplant as a part of their up-front treatment.”
Attal M, et al. Abstract 391. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Gay F, et al. Abstract 392. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: Chari reports financial relationships with Amgen, Array Bio Pharma, BMS, Celgene, Novartis, Janssen, Pharmacyclics, Millenium/Takeda. Majhail reports no relevant financial disclosures.