ASCO 2024: Two studies report on isatuximab combos in transplant-ineligible patients with newly diagnosed multiple myeloma

Prof Xavier Leleu - Poitiers Centre Hospitalier Universitaire, Poitiers, France

The phase III for registration study called IMROZ will be presented for the first time at ASCO 2024 by Professor Thierry Facon, actually my former boss. He will be presenting on behalf of the various investigators that have been recruiting patients in that study worldwide. A new quadruplet-based regimen presented for the first time in patients that are suffering from what we call newly diagnosed multiple myeloma cancer and that have the particularity to be what we call transplant ineligible, meaning often above 65 years old and often, let’s say, below 80 years old, a space where most of the patients with myeloma are actually diagnosed with that cancer.

In IMROZ there were two arms in this phase III study randomised 3:2 between one of the standards of care that we used to give to that population of patients, bortezomib/lenalidomide/dexamethasone, VRd, and in the study arm the addition of isatuximab which is a new CD38 monoclonal antibody immunotherapy which is added to VRd. So one arm was VRd and the other arm was isatuximab-VRd and for the sake of simplicity of the discussion I’ll call it isa-VRd.

The primary endpoint of the study was PFS, median PFS, progression free survival – patients either progressing or dying. The median PFS of the control arm was reached – approximately 54 months median PFS. The median PFS of the study arm, isa-VRd, is not reached, however, the hazard ratio is 0.596 which leads us to believe that potentially the median PFS of isa-VRd would be absolutely groundbreaking. For the first time approximately 90 months in patients suffering from that cancer, multiple myeloma newly diagnosed, but transplant ineligible which would be the first time ever that that type of population could survive up to approximately 90 months.

The study has also looked at other endpoints of interest, for example response rate, depth of response. The complete response rate, for example, in isa-VRd was also absolutely incredible – approximately 74% of the patients reached complete response or better which is very, very good. The MRD, minimal residual disease, negativity rate at 10-5 was also quite impressive in the isa-VRd arm. The best MRD negativity rate at 10-5 was reported in IMROZ at 58%, being approximately 40%-ish in the control arm which is, again, absolutely groundbreaking.

Coming to the safety profile, the safety profile of adding the isatuximab CD38 monoclonal antibody to the VRd standard of care backbone was quite safe, quite manageable. It did not add much in terms of safety profile. We have various ways to look into this, one of them is the occurrence of adverse events, patients per year adjusted – it was very comparable across arms. Another way to look at that is to look at the dose relative intensity of the drugs and, again, it was very comparable across arms.

So the conclusion of IMROZ is that we now have for that population that cannot be transplant eligible, so transplant ineligible, a new standard of care, extremely active with groundbreaking, incredible results. It’s great for the patients and their families.

What is next for this study?

Next for the study, there will be a lot of sub-analysis and other analyses of secondary endpoints, including overall survival which, in the end, is what matters to patients, other MRD assessments etc.  But the most important aspect of IMROZ is that in IMROZ the bortezomib, the V in the backbone VRd, was used as a twice-weekly regimen which is pretty dose dense. We’re going to talk in a minute about another phase III study reported here, our study from the French group which is called BENEFIT IFM2020-05. BENEFIT has been looking at a different way to give the bortezomib to try to complement IMROZ and offer the patients and their families and the physicians who are going to use the isatuximab/bortezomib/lenalidomide/dexamethasone quadruplet-based regimen various options on how to use the bortezomib to make sure that each patient could have the quadruplet regimen but, depending on the safety profile, age, comorbidities, prior history, medical history etc., the bortezomib will be tailored to each patient.

So IMROZ has been looking at one way – twice weekly – and we’re going to talk about benefit/risk, we’ve been looking at two other different ways of giving the bortezomib.

Discuss the results of the BENEFIT study?

The BENEFIT study, the so-called IFM2020-05, which is a national French study from our scientific society called Intergroupe Francophone du Myélome, was approximately in the same population, patients 65-79. Two arms randomised 1:1. A phase III study not for registration. 135 patients in either arm, baseline characteristics pretty similar across arms.

Patients were to receive either a different standard of care called isatuximab/lenalidomide/dexamethasone. To explain to the audience here, bortezomib/lenalidomide/dexamethasone is one of the standards of care for that specific newly diagnosed multiple myeloma, fit, non-transplant eligible population. But in other countries there is another standard of care, slightly more expensive so it’s not available necessarily in all countries worldwide. But in countries who wish to pay for it there is another standard of care called daratumumab/lenalidomide/dexamethasone, daratumumab being the first CD38 immunotherapy and the isatuximab we’re talking about here being the new one. So there are countries like my country where daratumumab/lenalidomide/dexamethasone is another standard of care – VRd and DRd.

So in BENEFIT we were interested into using DRd as a standard of care. So IMROZ would have been looking at the addition of isatuximab to the first standard of care, VRd, but BENEFIT would be looking at another standard of care, the other standard of care, daratumumab/lenalidomide/dexamethasone. However, we replaced daratumumab by isatuximab, the novel CD38 immunotherapy. So the control arm is isatuximab/lenalidomide/dexamethasone and the study arm looked at now isatuximab/lenalidomide/dexamethasone plus bortezomib. So the question we're asking in BENEFIT is if you have the backbone 100% immunotherapy based, what is the addition of the bortezomib which is less immunotherapy driving but more direct anti-cancer killing?

So the primary endpoint was the minimal residual disease which is not considered by the FDA, Food and Drug Administration, as an acceptable endpoint. So we looked at the MRD negativity rate at 10-5 at 18 months. So when we looked at the 18-month MRD negativity rate after 21 months median follow-up it was, again, similar to IMROZ, very impressive. So the study is positive but the results were higher than we expected initially when we started the study. The rate of MRD negativity in the isatuximab/bortezomib/lenalidomide/

dexamethasone arm is at 53%, it is at 26% in the isatuximab/lenalidomide/dexamethasone arm and this 26% is what we expect for that arm, it was 31% in the standard of care daratumumab/lenalidomide/dexamethasone arm.

The particularity of benefit is that we did look at MRD at 18 months but also at 12 months and the MRD negativity was incredible – an increased rate, three times better in the quadruplet isatuximab/bortezomib/lenalidomide/dexamethasone versus the triplet isatuximab/lenalidomide/dexamethasone was already there at 12 months.

We also looked at an even more, at a deeper, more stringent threshold of MRD negativity rate not at 10-5 but now at 10-6 and we found out that at 18 months, similarly to 12 months, 30% of the patients were negative at 10-6. So, again, in newly diagnosed myeloma transplant ineligible it’s probably presented for the first time ever, and absolutely incredible for that population. So it’s a great hope for that population that cannot be transplanted and needs very specific treatment to succeed in surviving.

The particularity of benefit is also that we have been using a different Velcade, bortezomib, regimen. We’ve been using bortezomib weekly instead of, in IMROZ, twice weekly. So it’s much less dense to the patients, they only come to the hospital at 1, 8 and 15 for the first 12 months then 1 and 15 for the subsequent six months. At month 18, the primary endpoint, all of the patients stop bortezomib, had stopped dexamethasone at 12 months, and only remain on isatuximab and lenalidomide for the rest until progression.

So from BENEFIT and from IMROZ we have different ways of giving bortezomib and so we know can adapt for a given patient the best way of giving the quadruplet and the bortezomib. The bortezomib drug is the drug that is most likely to create some safety issues if a patient had to suffer a little bit from this regimen. In BENEFIT the survival is not mature yet, we only report the primary endpoint which is MRD. The safety profile was similar to IMROZ, manageable, acceptable, slightly excess of safety profile neurotoxicity with bortezomib but this is something we know the investigators know how to manage.

So, again, IMROZ for registration and BENEFIT as supportive, I think validate for the 65-79 years old patients, at least for these patients, a new standard of care with isatuximab, bortezomib, lenalidomide and dexamethasone.