A Review of the Treatment for Multiple Myeloma - Episode 18
Ola Landgren, MD, PhD: In terms of the payer’s perspective here, should transplant still be part of the standard of care, or should it be determined based on MRD [minimal residual disease] or what’s your thinking?
John Fox, MD, MHA: I suppose that’s a great question. It certainly isn’t addressed in the NCCN [National Comprehensive Cancer Network] guidelines today. But based on this FORTE trial, I look at that and say these patients who got a transplant did no better, unless they were at high risk, than patients who continued triple therapy. Why would we expose a patient to the toxicities of an autologous transplant compared to continuing therapy? Not only is that the patient-friendly thing to do if there’s no difference in the outcomes, but if it’s also a lower cost to the patient and to the system, I think those are the questions that we need to ask. Also, if our staging systems or our risk prediction systems aren’t adequate today, then we need to focus on how we would better predict who’s going to be a long-term responder without the need for transplant. So, I look at this study and say not every patient needs to have a transplant, even though they may be transplant eligible.
Ola Landgren, MD, PhD: John, you’re bringing up the issue of toxicity. If we go back and look at these early studies that were done in the ’80s and look in the ’90s, I think there are close to 10 trials that have evaluated high-dose melphalan in the context of multiple myeloma. At that time, the induction therapy was quite inferior compared to today. So, we don’t really have any benefit data that are solid from a large number of studies in the current era. That’s really lacking. The perspective that transplant really is useful comes from older studies for the most part in the literature.
When it comes to the toxicity profile, the immediate impact on the cytopenias is obvious. Patients have diarrhea, fatigue, and all those things. There’s much less information with long-term toxicities because patients used to, unfortunately, have a shorter lifespan in the past. If you look today, the average patient, according to the SEER [Surveillance, Epidemiology, and End Results program], is around 50 years old with no other comorbidities, and probably has a 10-year to possibly 20-year projected overall survival. So, if you give melphalan and you follow someone over time, what’s going to happen? What’s the risk for AML [acute myeloid leukemia] or MDS [myelodysplastic syndrome]?
There was actually a study looking into available data published in the fall of 2018 from the CIBMTR [Center for International Blood and Marrow Transplant Research] registry, and they compared it to the general population. They looked at the rate of AML and MDS in these transplanted patients from the registry, and then they used SEER as the comparison. What they show is that the added risk from transplant is about 50 times. This means there is a 50 times higher risk of having AML or MDS at 10 years of follow-up.
John Fox, MD, MHA: Wow.
Ola Landgren, MD, PhD: You could criticize and say that 50 times, times what? The risk is low. It’s only about 1% or 2% or something like that. The counter argument would be if you don’t have good therapies, the disease is more dangerous than this low absolute risk. But still, the risk magnitude is quite high, and if we add 10 more years of follow-up, where are we going to land? These are important perspectives.
John Fox, MD, MHA: Your initial point was that the paradigm for treating transplant-eligible patients hasn’t changed, even though the backbone therapies, the induction therapies, have. We really need to understand what the role of transplant, let alone tandem transplant, is in these patients who we get to MRD-negativity at initial treatment for the newly diagnosed patient. This is because if we’re exposing patients to a single transplant or multiple transplants without evidence of long-term benefit or at least in terms of overall survival, then we’re actually likely causing harm.
There’s a study published this year in Journal of Clinical Oncology that looked at transplant followed by another transplant versus triple therapy versus monotherapy with lenalidomide and showed no difference in the survival and progression-free survival. You look at that study and look at the cost of those different regimens and say, “If we’re not improving survival and improving patient quality of life, then we’re actually devaluing care because we’re paying more for the same outcome.”