M.R.D. is ready for prime time!
ODCA Meeting April 12th for the use of MRD as a regulatory endpoint
Today, the FDA has approved the use of minimal (or measurable) residual disease (MRD) as a regulatory endpoint for clinical trials seeking accelerated approval for multiple myeloma. At an ODAC meeting, proponents and critics were able to voice their opinions regarding the wisdom of this decision.
As is true for many other things in medicine, some considerations can be used to support or caution against it, given the body of evidence in the literature. I received the news with great joy for two reasons. First, this development will accelerate the path for approval of medications to be used in the fight against myeloma. This means new drugs/therapies will reach patients faster and hopefully improve their outcomes. While it is true that we already have many treatment options for myeloma, the quest is not over, and still, most patients succumb to the disease. Accordingly, anything that accelerates the process by which new tools are available to clinicians is good for me.
The development costs for some of those medications have become exorbitant. The most recent estimates suggest the development of one drug could easily exceed $3 billion. The availability of early markers, allowing accelerated approval, should reduce this cost. If a pharmaceutical company finds a meaningful difference in MRD negativity versus an expected one or in a control arm, this will provide sustenance for the funding of larger phase three trials. If, on the other hand, the MRD results are not sufficiently exciting, further development of the drug should be questioned. A cynic might say that companies will increase the value of their drugs without incurring the added expenses. But they will forget that competition will have a fast pass for other compounds. They say competition keeps you honest.
Many smart clinicians remain concerned about the risks of accelerated approval of medications. However, one could argue that myeloma is a great example of how accelerated approval has worked, with some medications ultimately failing to gain full approval based on subsequent clinical trial results. While singularities can always be invoked, who could argue against the successful drug development process in myeloma?
Second, even though this process was exclusively for the use of MRD for regulatory purposes, it will likely send the message to practicing clinicians of the growing trust around the use of MRD for monitoring myeloma. Individuals will have varied levels of comfort on how they want to incorporate this information into their practice. Sometimes, individuals will be reluctant to use this information until clinical trials assigned specifically for its use are reported. Clinicians like me will continue to integrate these results with the rest of the information we use to make clinical decisions - I already do. And to the first group, I would say, “Did you ever request clinical trials be developed so that we could validate protein electrophoresis or the free light chain as a biomarker for myeloma clinical care?” I always say that MRD testing should not be considered an exceptional test in clinical decision-making. MRD results should be incorporated into all other laboratory and clinical tests as we make clinical decisions.
I recently wrote that the first instance of the use of MRD strategies for cancer treatment can probably be ascribed to the work of Drs. Min Chiu Li and Roy Hertz at the NCI. They were pioneers in the use of methotrexate to treat choriocarcinoma, back then a universally fatal disease successfully. They found that despite initial successful treatment, patients relapsed. It was later found that patients who remained positive for bHCG in the serum were more likely to relapse. Drs. Lee and Hertz proposed that these patients should continue on treatment until the test became negative. Dr. Li was considered a maverick, to be only chasing a number, and ultimately fired from his position, after which he returned to Memorial Sloan Kettering. Time proved that his approach was correct, and continuation of therapy in dose with the residual bHCG resulted in cures for those patients. History proved him right.
Of course, a common criticism of such approaches is that one must be mindful of safety – who can argue against this? But the reality is that we must balance safety with efficacy in the clinic. A unilateral approach of “first do not harm,” while admittedly safer, will shortchange patients of benefit. Fortunately, some of our treatments add only modest toxicity (e.g., daratumumab). While every toxicity has to be taken seriously, ignoring the potential benefits from the decision equation is an incomplete conversation.
I see that in social media, people have criticized the fact that myeloma has so many treatments that using the term “unmet medical need” may not be longer appropriate. And we indeed have much better treatments and a greater number of them. But unfortunately, for most patients, myeloma remains a life-shortening diagnosis. My only wish would have been that MRD, as a regulatory endpoint, could have been favored many years ago. I realize it took this many years for the data to support a hearing as we have today. However, having had MRD many years ago would have accelerated even more the fantastic process that we have seen for drug development.
In Machiavelli’s “The Prince,” he states - “at the beginning, a disease is easy to cure but difficult to diagnose; but as time passes, not having been recognized or treated at the outset, it becomes easy to diagnose but difficult to cure.” This is probably a good analogy of how comfortable people would be with the early adoption of MRD in clinical care and as a surrogate marker.
I would say that MRD is ready for prime time and has been for a long time!
— Disclosures: Consulting: AMGEN, Apple, Adaptive Biotechnologies, BMS, Celgene, Takeda, Bayer, Janssen, AbbVie, Pharmacyclics, Merck, Sanofi, Kite, and Juno. • Board of Directors - Antengene. Patent for FISH in MM - ~$2000/year