Should ASCT be Standard of Care for Frontline Treatment of Patients With Multiple Myeloma?

At the 2023 Great Debates & Updates in Hematologic Malignancies Meeting, C. Ola Landgren, MD, PhD, Sylvester Comprehensive Cancer Center at University of Miami, Florida, participated in a debate on whether high-dose chemotherapy with melphalan followed by autologous stem cell transplant (ASCT) after completion of induction therapy should continue to be the standard of care in frontline treatment of patients with multiple myeloma (MM). 
 
He argued that this treatment should not continue as the standard of care, including clinical benefit, quality of life, and second malignancies in his argument.

Transcript:

I'm Ola Landgren, I'm a professor of medicine. I'm chief of the myeloma division and director of the Myeloma Research Institute at the Sylvester Comprehensive Cancer Center at University of Miami in Miami, Florida. I’m at the Great Debates & Updates meeting here in New York City. 
 
In the morning session today at the meeting, I was invited at one of the debates and it was a debate focusing on a controversial topic that has been discussed quite a lot. I think it continues to draw a lot of attention, and that is really the role of the use of high-dose chemotherapy with melphalan followed by autologous transplant. Should patients with myeloma continue to be recommended to do this therapy? 
 
I was asked to argue no, and I had a debate with my long-term friend and colleague, Dr Amrita Krishnan from the City of Hope in California. And she was arguing [the side of] yes. I think that we discussed very similar topics, we just drew different conclusions. And of course we were asked to argue for no, in my case versus yes in Amrita's case. 
 
I think the discussion was on, first of all, the clinical benefit. And my argument for no was that there is no survival benefit. There are 2 large, randomized trials published in the New England Journal of Medicine, the IFM 2009 study that now has been updated with 8 years of follow up, still not showing any overall survival benefit or transplant. And the DETERMINATION study that came out in 2022 from Dana-Farber here in the US, showing also no survival benefits, so transplants do not make patient live longer. Dr Krishnan said that's what I was going to say, and I said that is what I'm going to say. But she also pointed out that the studies looked at progression-free survival as the primary endpoint and both studies were in favor of transplant if you use progression-free survival. 
 
What I highlighted on that particular note was that if you stratify patients that have a good response with the combination therapy without transplant, patients that can achieve a deep response, MRD negativity, [then] there is no difference even for progression-free survival when you compare transplant versus no transplant.
 
My overall argument in favor of no for transplant was there is no survival benefit. There is also no progression-free survival benefit if you can achieve MRD negativity with combination therapy. 
 
I also highlighted how the French updated 2009 study showed that there is also no progression-free-2 or PFS-2 benefit, which is the time to the second relapse. People who argue that transplants should be done early because that's when it works the best, they've actually been proven wrong by the French study, that there is no such benefit. That was kind of the clinical focus. 
 
We also talked about 2 other aspects. One was the quality of life, and the third was the role of second malignancies. As for quality of life, we both talked about similar things that the American Study, the DETERMINATION study, had reported last year in New England Journal of Medicine: that transplant decreases quality of life, but also we showed that patients, they do recover over time, according to the study.
 
I highlighted also in addition to that, that there have been pooled studies looking at other health effects, long-term chronic disease conditions beyond secondary malignancies and quality of life and things like that—these are how people's overall health status was impacted. And there is an American study showing that patients that undergo transplant, up to 60% of long-term follow-up patients, have grade 3 or 4 adverse events looking at other health conditions. So the long-term effects of transplant is actually quite poorly studied, but I tried to highlight that. And, of course, I picked the biggest study which happened to include data from City of Hope, which was Dr Krishnan's institution but that's the part of the debate style.
 
The last part focusing on secondary malignancies, I think we also looked at similar data. We focused a lot on the DETERMINATION study. Dr. Krishnan's interpretation was that there was not a whole lot of difference if you bundle all the malignancies, and I agreed with that, but I highlighted the ones that are the really bad ones—the development of acute myeloid leukemia and myelodysplastic syndrome, and they are known to be associated with melphalan.
 
I highlighted the fact that there were 10 cases after transplant and 0 in the non-transplant arm. I did recognize, and I emphasized that probably, unfortunately, there could be patient developing AML and MDS in the non-transplant group in the future as we have longer follow-up, because myeloma, unfortunately, seems to have a biological propensity for developing these conditions. 
 
But the addition of melphalan is significant and there have been studies all the way back to the 70s and the 80s showing that. I think the fact that you had the secondary malignancies is a major concern. And I also highlighted our group's discovery, where we have shown that you develop very unique mutations, you increase the mutational burden by over 20% by exposing patients to melphalan. That's in a nutshell what we discussed.

Source:

Landgren CO. Debate - Will ASCT Continue to Be the Standard of Care in Frontline Therapy? - No. Presented at the Great Debates & Updates in Hematologic Malignancies Meeting; April 13-15, 2023; New York, NY.