Improvements of myeloma overall survival – where does this extra time come from?
Better treatments improve survival!
We have witnessed a dramatic improvement in the survival of myeloma patients. In the late 90’s a collaborative effort concluded that more extensive combinations with other chemotherapy agents were no better than melphalan and prednisone alone. Back then, as I was finishing training, the median survival barely exceeded 2 years.[1] Leapfrog to 2024, and you will see much better outcomes. With a risk of bias, three large institutional series show that myeloma survival should routinely exceed ten years when modern therapies are used.[1] The treatments used in these 3 series are not the best by today's standards (most patients started treatment 5 years ago or longer). And yet, most clinical trials have not shown improvements in overall survival.
So, there is a big discrepancy between what is reported in these retrospective studies and what the clinical trials results show.
So how is this better survival possible? If we add the magnitude of gains of trials showing improvements in overall survival, we cannot possibly add another 8+ years. How can these survival gains be realized when stem cell transplant trials (e.g., Determination or IFM 2009) have not improved overall survival? Is it because hematologists are smarter? Or is it because our supportive care adds another 8 years of life?
The answer is clear and self-evident. This improvement is due to the availability of newer, better treatments.
When commenting on clinical trials, we often hear that “treatment A” is incapable of improving overall survival when the question was never really asked. Clinical trials not empowered or designed to test a hypothesis of improvement of overall survival, cannot be said to fail to show improvements in overall survival. It is a classic Type 2 statistical error. “Absence of evidence is not evidence of absence.” For some cancers, it is hard, if not outright impossible, to design trials empowered to test for overall survival. This is particularly challenging in myeloma, where the pace of progress is so rapid that the answer may no longer be relevant by the time a clinical trial reads out.
However, improvements in survival won’t happen unless patients get the best possible treatments. A large, randomized Phase 3 trial (Perseus) shows progression free survival that is close to 85% at 4 years for patients treated with four drug combinations and stem cell transplant. And yes, you guessed it right, it has not been shown to improve overall survival (yet). The best-in-class treatment for patients who are ineligible for stem cell transplant, the MAIA clinical trial has shown a progression free survival that exceeds 5 years. This one has shown an improvement in overall survival.
However, patients will not benefit from these advances unless they get the best treatments. SEER still reports a 5-year survival for myeloma of 61%. Were these patients being routinely treated with the best drugs the numbers would be much better. This survival probability at a myeloma center of excellence would be unacceptable.
There is a world of difference between saying, “The drug does not improve overall survival,” versus “The drug has not (yet) shown to improve survival.” The latter should be the one more commonly used, not the former. You can only say it does not improve survival if the trial was designed for this hypothesis and only under such specific circumstances. The former statement is often presented erroneously as a statement of fact. The latter statement merely reflects our current state of knowledge.
Lay news outlets will convert this language as these drugs “providing no benefit.” Sigh!
The gains in overall survival are difficult to demonstrate in clinical trials but ultimately accrue for the benefit of patients. Slowly, and sometimes only incrementally, it all accrues, and we should celebrate. Among the difficult-to-treat cancers, myeloma is a shining example of the accretion of survival benefit derived from innovative treatments. Ocam’s razor indicates that!
[1] MTCG. J Clin Oncol 1998; 16:3832, Joseph, N et al, JCO 2020, Pasvolsky at el Am J Hematol April 2023, Cote el al Blood C J Sep 2023