18th International Myeloma Workshop

Safety and efficacy of isatuximab plus bortezomib, lenalidomide, and dexamethasone combined therapy for NDMM

Dr Enrique Ocio - Marqués de Valdecilla University Hospital, Santander, Spain

This study is the updated results of the phase Ib study of isatuximab in combination with bortezomib, lenalidomide and dexamethasone in patients that are non-transplant eligible or with no immediate intent for transplant. In fact, the work that we are doing here is to evaluate a new form of infusion of isatuximab as a fixed volume infusion.

What was the methodology used in this study?

This is, as I said, for transplant ineligible patients and they are treated with a quadruplet – isatuximab, bortezomib, lenalidomide and dexamethasone. They received four cycles of VRd of six weeks each of them and in combination with isatuximab. There was a part 1 in which isatuximab was administered as the standard weight based infusion but subsequently, in the part B of the study, 46 patients were treated with a fixed volume infusion of isatuximab. That means that they all received the same volume, 250ml, that makes it easier to administer and probably decreases the duration of infusion.

What were your findings?

The key finding of this study is that we are evaluating this quadruplet combination and with this novel way of administration of isatuximab. The first important point is that we decreased, greatly decreased, the time of infusion for isatuximab, particularly in the second and subsequent infusions. It was for part A with the usual way of administration and part B was similar with three, almost four, hours of infusion but it went down from this four hours to two hours in the second infusion and one hour and twenty minutes for the third infusion. That really indicates that we are able to shorten the infusion duration in one hour from the initial way of infusion.

The second important point is that this way of infusion and this quadruplet really is safe and is well tolerated for these patients. We have a few patients that are out of study due to adverse events and related to the medication. There are some of them but some of them are not related with COVID disease, with diverticulitis, with some secondary malignancies, probably all of them non-related to the treatment. So it is quite well tolerated with very few treatment emergent adverse events non-haematological and grade 3/4. So it was quite well. There were some haematological toxicities but they are well managed with dose reductions and discontinuations in some cases.

I think it’s also very important to focus on the infusion related reactions and also with this type of infusion that as we are decreasing the time and also we are improving the management of these infusion related reactions. In part A, the previous one, 52% of the patients had infusion related reactions in the first infusion and we went down from this 52% to 22% with a fixed volume infusion that we are now evaluating. So, again, it speaks about the good tolerability of this method.

Finally, of course, we have to speak about the responses and the efficacy of this quadruplet of isatuximab and VRd quadruplet in elderly multiple myeloma patients. The overall response rate was 98% with 53% complete response that is in part the primary endpoint of the study. Also, interestingly, almost 50%, 42% of the patients, had achieved a complete response that was MRD negative, so immunophenotypic complete response.  So good tolerability, convenient for the patients and also with a very good efficacy.

How can these results impact the future treatment of NDMM?

We are now in young patients with multiple myeloma focussed and we are now using a lot quadruplets - these anti-CD38 monoclonal antibodies in combination with VRd, or VTd now moving into VRd. For non-transplant eligible patients, with elderly patients, we are also incorporating the anti-CD38 monoclonal antibodies in this scenario but mainly in triplets. This is one of the first data we have with a quadruplet using an anti-CD38 monoclonal antibody, isatuximab, in combination with bortezomib, lenalidomide and dexamethasone. So it’s like a full schema for these elderly patients. Even we have here patients up to 87 years of age, so quite elderly patients, and here we demonstrate that it’s feasible to use this quadruplet. Probably this is not for everybody, for all these elderly patients, but at the end we will have to demonstrate or define which of these elderly patients would really benefit from a quadruplet that, as I said, is convenient, easy, safe and also effective.