Parameswaran Hari, MD, Chief of Hematology/Oncology at the Medical College of Wisconsin, spoke with DocWire News about how new therapeutic agents are changing the role of upfront allogeneic hemopoietic cell transplantation (AHCT) for newly-diagnosed multiple myeloma, and considerations for deciding on this approach in the clinic.

This is the second in a three-part conversation with Dr. Hari. Watch part one, where Dr. Hari reviews some highlights in multiple myeloma from the ASH annual conference.

DocWire News: How are new agents for multiple myeloma (MM) affecting the value of upfront allogeneic hematopoietic cell transplantation for this disease?

Dr. Hari: Allogeneic hematopoietic stem cell transplantation is very rarely used in myeloma these days. And we have some data from a Phase II multicenter study in the US that will be reported out fairly soon at ASCO, hopefully in 2021. However, it used to be an option that was pretty much restricted to young patients with ultra-high-risk disease.

Immunotherapy, in a more sophisticated fashion, whether it’s going to be with chimeric antigen receptor (CAR) T cells or bispecific engagers, I think will seriously challenge and perhaps completely displace allogenic transplant. Having said that, we don’t know if anything in therapeutic trials right now will cure myeloma. And allogeneic transplant, especially for the younger patients, does hold out the promise of a cure, although in a minority of patients. So I think allogeneic transplant is probably on its way out, and newer forms of immunotherapy that are much more sophisticated and much more tolerable to the patient are coming in. That makes it applicable broadly. Even outside of the young patient who could have gotten an allogeneic transplant, this becomes much more applicable even to older patients which is the majority of patients in myeloma.

DocWire: What are the important considerations when deciding on upfront autologous hematopoietic cell transplantation (AHCT)?

Dr. Hari: The autologous transplantation is still the majority of transplant for myeloma, the vast majority in fact. Some 7,000 to 8,000 transplants are being done annually in the US for myeloma with autologous transplant. And with regards to autologous transplant, I think this ASH, they had a session that was entitled, “Autologous Transplant is the Backbone of Upfront Therapy in Myeloma,” right? Perhaps was probably the most aptly named session of all of ASH that I saw, and it showed a plethora of findings.

So, the most important among these findings was the update of the IFM 2009 study that compared upfront autologous transplant versus lenalidomide, bortezomib, and dexamethasone (VRd) consolidation and maintenance. And in that study, consistent with the previous results, it just established that progression-free survival was superior if autologous transplant is used as an upfront therapy. In fact, patients live a longer disease-free first remission if they do an upfront transplant in their first remission. In the patients who deferred the upfront transplant, the vast majority of them did end up getting the transplantation when they relapsed. But this relapse was sooner than they would have had if they had received the upfront transplant.

So, that was a finding of that study. Then we also saw the results of the FORTE study which is a large study that compared carfilzomib, lenalidomide, and dexamethasone (KRd) induction with or without transplantation, and also a different induction with carfilzomib, cyclophosphamide, and dexamethasone (KCd). And when the study was initially read out with short follow-up, it appeared that the deep remission rate or the minimal residual disease (MRD)-negative remission rates were irrespective of transplant, were good for KRd for 12 cycles, and was just as good as transplant. However, now with longer follow-up, it turns out that if you undergo a transplant in their first remission, you enjoy a longer progression-free survival. And that was also a significant finding from this ASH. In addition, we had a couple of other longer European studies that reported out the benefit in terms of progression-free survival for patient who undergo an upfront autologous transplant.

I think the role of autologous transplant in myeloma is pretty much solid, at this time. I think CAR T cells will start challenging that role or bispecific engagers or some of the newer drugs, any of them. But it’s up for grabs, that space. However, transplant still remains the fastest, and the cheapest in fact, way of getting to a deep MRD-negative remission. And as we know from all of these studies, a long first remission is the backbone of a long life with myeloma and the best way to get along first remission is to use an upfront transplant.