Thank you very much for the opportunity to review the IMROZ study design and the data. The background here is that bortezomib, lenalidomide and dexamethasone, or VRd, were previously the standards of care for initial therapy of patients who were either transplant eligible or transplant ineligible with newly diagnosed multiple myeloma. The outcomes were still not optimal, especially in the transplant ineligible population that has traditionally not done as well as folks who could get a transplant. So we’ve always wanted to build upon the VRd backbone and the importance of the study and the study design is that it added isatuximab, which is an anti-CD38 antibody, to both an initial, if you will, induction phase as well as to a subsequent maintenance or continuation of therapy phase in the experimental arm which was therefore four drugs versus VRd and then lenalidomide and dexamethasone, or Rd, as the continuation phase in the control arm.
What was the study design?
This was a randomised study for patients that were transplant ineligible. It was an international study so there were sites in America, in Europe and in many other countries. Patients were randomised either to VRd for six months followed by Rd continuation therapy or the other arm was with the isatuximab-VRd for six months followed by isatuximab with Rd, or lenalidomide dexamethasone, as a continuation of therapy.
At the beginning the bortezomib, or V, was given twice a week, later on it was switched to once a week and eventually it was stopped in both arms. The isatuximab at the beginning was on a weekly basis but eventually went to a once a month schedule to try to maximise convenience for patients.
What were the results?
The main endpoint was to look at progression free survival on the study and there was a significant advantage for patients who got the quadruplet initial therapy followed by isatuximab with lenalidomide dexamethasone compared to VRd followed by Rd in the control arm. Essentially there was about a 40% reduction in the risk of progression or death at five years of follow-up. If you look at the absolute numbers of people who had not progressed, on the quadruplet arm almost two-thirds of patients at five years had not yet progressed whereas on the control arm which got the triplet followed by the doublet, under 50% of people at five years were still progression free.
Just to give you a little bit of perspective, in myeloma in the past, years and years ago before some of the current very active therapies were available, it used to be that the average survival of patients was less than five years and now we have progression free survival being better than five years. Progression free survival just means benefit from the first line of therapy and once patients do progress they can get a second line later on.
Other really nice things about the study is that minimal residual disease negativity was evaluated as was complete response. The complete response rate was higher with the quadruplet, with the isatuximab, compared with the VRd followed by Rd. Minimal residual disease negativity was higher and the duration of the MRD, something called sustained MRD negativity, which means that patients were MRD negative on more than one timepoint, was also higher for patients who got the quadruplet. Also in terms of quality of life and toxicity there were relatively few increased side effects with the quad versus the triplet and quality of life was preserved on both arms.
What is the clinical significance of these results, especially from a US perspective?
From a US perspective, the real significance is that now we have proof that a quadruplet is the best choice for initial therapy in transplant ineligible patients compared with a triplet. In the past there were concerns that perhaps giving four drugs to this generally older and perhaps slightly more frail population might not be safe but, in fact, the study showed that indeed patients did well from a side effect perspective. About a third, almost, of patients actually on the study were frail, they qualified for frailty according to the standard criteria and they also had an improvement with the quadruplet.
The other concern that folks have sometimes had is, gosh, if you use the CD38 antibody as part of your initial therapy, when people relapse they may have fewer options left and they may have a worse overall survival in the long run. Because if you don’t have as many things to give them in second line then you could be in trouble. But the study, in fact, showed that that was not the case, there was a trend favouring overall survival to be better on the quadruplet. So giving your best treatment up front gives you a long-term benefit, not just a short-term benefit, I think that’s really significant.
We also collected data on PFS2. PFS2 is the progression free survival on whatever treatment the physician has decided to put the patient on after the first progression. If the disease at relapse was more aggressive you might expect maybe that those patients would do worse on their second therapy than the people who had just gotten VRd. But, in fact, that wasn’t the case – patients who had the isatuximab quadruplet did better in PFS2 than patients who just got VRd. Again, the whole package really supports using your best therapy up front for this transplant ineligible patient population.
Where does the study sit in the US treatment landscape?
Right now, the IMROZ study is the only trial that has looked at the quadruplet of an anti-CD38 with a proteasome inhibitor and immunomodulatory drug and a corticosteroid in transplant ineligible patients, including a frail population. It’s the only quadruplet with those combinations of drugs that is FDA approved. So if you are in your practice and you see a patient with transplant ineligible myeloma, this is one of the category 1, now, recommendations from the NCCN, the National Comprehensive Cancer Network. Again, it’s the only one that’s officially FDA approved in this ineligible population so it really should be something that everybody thinks about as an option in this setting for all patients in this category.
Could you discuss the HRQoL of patients being treated with Isa-VRd compared to VRd alone?
Definitely one of the important datasets that was collected and is still being collected on the trial is health-related quality of life because there were concerns, as I mentioned earlier, that maybe giving four drugs to an older, generally more frail, population could be a negative and that patients could have more side effects, a worse quality of life. In fact, on both of the arms quality of life was maintained compared to baseline and there was no drop-off with the quadruplet compared with the triplet, again, indicating that it’s safe and effective to give four drugs to this older patient population.
Is there anything else that you would like to add?
I really think these data are very exciting because they bring patients a new treatment option that is more effective than what they had before, with a relatively low increased risk of side effects. With any anti-CD38 antibody there is a small increase in risk of infectious complications, that’s true in other myeloma settings for both daratumumab as well as for isatuximab. There can also be problems with neuropathy which are mostly related to the bortezomib, and sometimes there are some increased risk of cytopenias or low blood counts when you add an anti-CD38. But isatuximab is a very effective agent compared with some of the other anti-CD38s that are out there.
My impression generally is that there are fewer infusion-related reactions and so I have no hesitancy to give it to patients who maybe have, let’s say, chronic obstructive pulmonary disease or another baseline, ongoing, pulmonary process. There are also subcutaneous versions of this agent that are in development that hopefully will soon be available and could improve the convenience for patients.
