KarMMa-3 was the first randomised BCMA bi-specific CAR T study for multiple myeloma. It was about 386 patients, a 2:1 randomisation that patients got either ide-cel or a standard of care regimen such as DPd, DVd, IRd, Kd or EPd. So this was a paper that was published in The New England Journal earlier this year and had a hazard ratio of 0.49 in terms of progression free survival, so 13.3 versus 4.4 months for CAR T versus standard of care.
What we wanted to look at was how many of the patients that were enrolled actually had high-risk characteristics of their disease. So really the treatment of multiple myeloma is evolving over time and as that happens we wanted to see how many patients had been exposed to most of the treatments we’ve already had, even though this was an earlier line study. So this was for patients who were in third, fourth and fifth line compared to those whose average was sixth line for the original KarMMa study. The categories we used for high-risk characteristics were basically high-risk cytogenetics, which is a classical reason we call patients high risk; R-ISS stage 3 disease, which again we usually only look at at diagnosis but for these patients that are going onto a relapsed/refractory study we might not have that information from diagnosis, so for all the studies we look at the R-ISS staging at enrolment; high tumour burden and we don’t have a great scoring system yet, like lymphoma, that we use formally for PET-positive disease or image-positive disease, but here high tumour burden meant greater than 50% myeloma in the bone marrow. Extramedullary plasmacytomas, which are both paramedullary and completely extramedullary, were included and then triple class refractory disease which, we’re learning more and more that really even if it’s late line versus early line, once patients become refractory to a PI, IMiD and a CD38 their PFS and overall survival tends to be pretty dismal and why these new therapies are so important.
In those five subgroups for high-risk characteristics, we were able to show that patients actually did really well relative to the standard of care. Again, the hazard ratio for all patients was 0.49 and when you look at the Kaplan-Meier curves for all these high-risk cytogenetics, all the way to triple-class refractory disease, the hazard ratios ranged from 0.4 to 0.86. There were those with extramedullary disease, PFS was 7.2 versus 2 months, versus those with R-ISS stage 3 disease. We didn’t have as many patients though again these were post-hoc analyses so there are some reasons why this is not the best data that we can get but the first time we are able to do this with this many patients. But in the R-ISS stage 3 disease the PFS was 5.2 versus 3.0 months so, again, maybe that can be used as a biomarker to say maybe we can decrease the tumour burden for these patients before they go to CAR T to actually improve outcomes.
Then the safety was very similar so patients in general did just as well as those patients who didn’t have high risk disease. CRS, ICANS, infections, cytopenias were all relatively similar for these patients. In terms of response rates, again the patients who had the CAR T did better for all of the different five subgroups but some had a little bit lower response rate compared to others, but the CR rates were significantly better for the patients who got the CAR T in the different groups.
How can these results impact the future treatment of r/r multiple myeloma?
It’s so important that we learn where we need to put all these treatments. We have so many myeloma treatments which is phenomenal, that we can get different options for different patients and really personalise it to what that patient is going to do the best with. But CAR T has been one of those things that in the US it has been approved in fifth line and there are so many of my patients I can’t get to fifth line to get that CAR T. So now that hopefully this, as well as some of the other CAR Ts that have been presented, are going to get approved earlier, we’ll actually be able to provide access for a vulnerable group which are our high risk patients who are not able to get these therapies down the road.
The other big thing for the future is the study also looked at soluble BCMA levels. What they were able to see was that at the beginning, at time of screening, patients in both the standard of care versus the CAR T arms all had similar soluble BCMA levels. But when they got treated and at the nadir we saw much more decrease in the clearance of that soluble BCMA level for the patients who got CAR T. Then at progression the standard of care patients had a much higher level of soluble BCMA. So still more studies to be done but could this become a biomarker that helps us say, okay, these are the patients who are responding and when it’s coming back can we use it with MRD to say we need to treat again, especially for our high risk patients. And does this mean that the disease really is different when it comes back from CAR T? Anecdotally many of us say that myeloma is easier to treat post-CAR T than it was going into CAR T, so does soluble BCMA have something to be able to monitor that with. Again, that will hopefully change in the future where we might finally have a biomarker to help us guide with these therapies.