Triplet regimens such as lenalidomide-bortezomib-dexamethasone (RVd) are often preferred over doublet regimens as primary therapy for fit patients with multiple myeloma, regardless of eligibility for auto-HCT. In the era of novel therapy, we have highly efficacious agents that can achieve minimal residual disease negativity without the potential acute and long-term toxicities of high-dose melphalan, which is an important emerging treatment paradigm to appreciate. I was mentored by the late Timothy J. McElwain, MD, a giant in the field and the founder of high-dose melphalan followed by auto-HCT, who once said to me, “Paul, if we can move beyond melphalan, we will be doing our patients a great service.” Melphalan, a highly genotoxic alkylator, is a great drug if you have nowhere else to go, but, if you have other options, you should use them. In my view, auto-HCT is not a one-size-fits-all proposition. Patients with multiple myeloma are living longer, and exposing them to melphalan, the most genotoxic chemotherapy we use, early in their disease may have detrimental long-term effects. Consider a patient with multiple myeloma who has survived 10 or 20 years, only to succumb to secondary leukemia. There is an increasing concern based on evidence from whole genome sequencing that any surviving cells post melphalan have more adverse genetic signatures, and the rates of myelodysplastic syndrome and acute myeloid leukemia post auto-HCT are more significant as patients live longer. In fact, using data from the Center for International Blood and Marrow Transplant Research, Radivoyevitch et al reported that the risk of myelodysplastic syndrome/acute myeloid leukemia after auto-HCT for Hodgkin lymphoma, non-Hodgkin lymphoma, and plasma cell myeloma is greater than was previously appreciated.

When considering auto-HCT-ineligible patients, some of the options for primary therapy are similar to those recommended for eligible patients and include the following: bortezomib-cyclophosphamide-dexamethasone, RVd, and lenalidomide plus low-dose dexamethasone. Other possibilities include carfilzomib-lenalidomide-dexamethasone, carfilzomib-cyclophosphamide-dexamethasone, and ixazomib-lenalidomide-dexamethasone. Doublets (eg, lenalidomide plus low-dose dexamethasone) may be preferred in very elderly or frail transplant-ineligible patients. For relapsed/refractory disease, the use of non–cross-resistant agents, if possible (eg, pomalidomide instead of lenalidomide, ixazomib or carfilzomib instead of bortezomib), and effective antibodies is key. Clinical trial participation, whether for primary multiple myeloma treatment or for relapsed/refractory disease, is a very important option for some patients. In fact, many of the novel treatments are proving to be effective in extending overall survival, and auto-HCT itself may become a “reserve” treatment. In clinical trials, auto-HCT is showing benefit in terms of progression-free survival, but no benefit in overall survival, and it is critical for us to understand why.