9 years and counting....

The last U.S.-led randomized study comparing different treatments for newly-diagnosed AL amyloidosis was published in 2004. The one before that was published in 1999. Two randomized studies, 14 years. To put this in some perspective, despite the fact that neither of my two teenage children have expressed any particular interest in conducting large-scale studies in AL amyloidosis, they are only two behind the national medical community during their lifetimes. 

The premature closure of the ECOG-led intergroup E4A08 study, a randomized Phase III trial comparing melphalan and dexamethasone (MD) to MD + bortezomib (MD-Bz) as initial treatment for AL-amyloidosis patients who have not had prior therapy thus represents a missed golden opportunity to advance the field. This was a trial endorsed by SWOG. I served as the SWOG PI for E4A08, and have some insight as to the problems which led to the trial's closure. 

While checking out another amyloidosis-focused site (The Amyloidosis Weekly, edited by a friend and colleague, Bob Orlowski) I found a posted research abstract from the Accrual Working Group (AWG) of the National Cancer Institute's Myeloma Steering Committee which examined barriers to accrual to NCI-sponsored myeloma trials.  Dr. Matthias Weiss, the lead author of the study, provided me with a copy of the poster he presented at the 2012 American Society of Hematology meeting in Atlanta. 

The authors analyzed the results of Survey Monkey surveys returned by 246 researchers and/or support staff affiliated with cooperative oncology research groups like SWOG or ECOG-ACRIN. The surveys asked respondents to rank 10 potential barriers to accrual identified by the AWG in terms of their importance in slowing accrual in large multi-center trials. Predictably, attitudes of community-based respondents differed from those of academic/university-based ones. Dr. Weiss told me he believes barriers 3, 5 and 8 were key to the demise of E4A08, which is plausible, despite the fact that there are NO (ZERO, NADA, ZIPPO) FDA-approved therapeutic agents for initial treatment of AL amyloidosis. I believe a variation of barrier 10 was also a factor: some sites wouldn't allocate the resources needed to open a trial to which they were not likely to accrue more than 1 or 2 patients. Also, shockingly, several reputable investigators at some of the larger SWOG and ECOG centers expressed that they were uncomfortable with the control arm (melphalan plus dexamethasone), and thus wouldn't even open the study. I bet Dr. Jaccard, a leading amyloidosis specialist in France, laughs about that (see why).

Time to look in the mirror and ask ourselves whether we want to remain relevant in the arena of clinical AL amyloidosis research. The next possible standard of care for AL amyloidosis will be determined by our European colleagues who CAN get this study done (and are in the midst of proving it). Shame on us. Lets not allow another 9 years to pass before we get a big up-front AL study done in the United States.