Name:
IKEMA study: improving outcomes for multiple myeloma patients
Description:
IKEMA study: improving outcomes for multiple myeloma patients
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Upload Date:
2023-01-18T00:00:00.0000000
Transcript:
Language: EN.
Segment:0 .
[MUSIC PLAYING]
MARIA-VICTORIA MATEOS: Hello, my name is Maria-Victoria Mateos. I work as a hematologist and a director of the Myeloma Unit at the University Hospital of Salamanca in Spain. IKEMA is a Phase 3 randomized study conducted in relapsed and refractory myeloma patients.
MARIA-VICTORIA MATEOS: After one to three prior lines of therapy, patients were randomized
3: 2 x to receive
3: carfilzomib and dexamethasone plus the monoclonal antibody anti-CD38, isatuximab versus carfilzomib and dexamethasone. The treatment was planned as continuous therapy until progressive disease and the primary endpoint of this study was a progression-free survival. The first results so far reported a year ago confirmed the superiority of the three-drug based combination isatuximab in combination with carfilzomib and dexamethasone over carfilzomib and dexamethasone.
3: In terms of progression-free survival, and indeed the median progression-free survival for isatuximab in combination with Kd in these relapsed and refractory myeloma population was of almost three years significantly superior in comparison with carfilzomib and dexamethasone for which the median progression-free survival was approximately 18 months.
3: During this ASH 2022 meeting, we had the opportunity to see how this superiority for isatuximab in combination with carfilzomib and dexamethasone was confirmed in some key subgroup of patients. For example, patients with relapsed, as well as patients with just one or more than one prior line of therapy. And these are basically the key subgroups in which the subanalysis were conducted in the IKEMA and reported during this ASH meeting.
3: And this means that definitely Isa-Kd is one of the best options for therapy for relapsed and refractory myeloma patients just after one prior line of therapy, even including those patients with relapsed. And, of course, when we have a look to the forest plot we can see how other populations like elderly patients, patients with some degree of renal impairment, patients with high-risk cytogenetic abnormalities also get a significant benefit from this combination.
3: [MUSIC PLAYING] One of the key presentations at ASH 2022 based on the IKEMA study has been the analysis conducted in patients who early versus late relapsed [INAUDIBLE] This information is extremely important because we know that early relapses usually are associated with a poor prognosis in patients with multiple myeloma.
3: In this IKEMA study the definition for early relapsed was those patients who relapsed less than one year from initiation of the most recent line of therapy for patients with two or more prior lines of therapy, as well as those patients who relapsed less than one and a half year for patients who had received just one prior line of therapy. And in addition, for those patients who had received autologous stem-cell transplantation the early relapse that are included, relapses occurring less than 12 months from autologous stem-cell transplantation.
3: When we evaluated in principle the baseline characteristics of the patients between early versus late relapses, it is important to remark that some imbalance in baseline characteristics were observed and basically these imbalances were based on [? Isa ?] state at the study entry as well as high risk cytogenetic abnormalities basically because these high-risk features were more present in those patients who relapsed again.
3: In addition, patients with early relapses had more prior lines of therapy, less prior autologous stem-cell transplantation, and were more frequently refractory than those classified as late relapses. In terms of durability of the treatment, the median durability of treatment was longer in patients with late relapse, but the relative dose intensity for the drug studies was slightly lower.
3: From my point of view, the most interesting information is coming from the outcomes. And in terms of progression-free survival, the median progression-free survival was longer for isatuximab, carfilzomib, and dexamethasone in both early and late relapsing patients. But I would like to remark the fact that in early relapses those patients definitely with high risk features, the median progression-free survival for Isa-Kd was 24.7 months versus 17.2 months for carfilzomib and dexamethasone.
3: In late relapses this benefit is even more evident with a hazard ratio of 0.54 and the median PFS for Isa-Kd was 42.7 months versus 21.9 months for carfilzomib and dexamethasone. This data are extremely important because this means that isatuximab in combination with carfilzomib and dexamethasone would represent maybe the best choice for relapsed and refractory myeloma patients after at least one prior line therapy.
3: But especially if we phase with early relapsed patients, I think that Isa-Kd is showing in this subanalysis the best outcomes that we can offer to our patients. In addition in this subanalysis, the investigators subanalyzed the patients in early and late relapses, but refractory to the last regime. What is extremely important because today majority of the patients are usually refractory to the last line of therapy.
3: And in this situation, again, the hazard ratio for progression-free survival is a comparable 0.55 in both the early as well as a late relapses and refractory to the last regime, indicating or confirming the superiority of Isa-Kd. When the response rate as well as the minimal residual disease negativity rate was evaluated, it was confirmed how also in early as well as in late relapses, isatuximab added to carfilzomib and dexamethasone reported a higher overall response rate, higher complete response rate, as well as undetectable measurable residual disease [? rate. ?] In terms of a safety profile, no major differences between early versus late relapses, confirming what I previously said.
3: Improved median progression-free survival and depth of response with isatuximab in combination with the carfilzomib and dexamethasone in patients with relapsed multiple myeloma, regardless of early or late relapse and support to the use of Isa-Kd as a standard of care in this subgroup of patients.
3: In the IKEMA study, which Isa-Kd was compared with the carfilzomib and dexamethasone. The primary endpoint of progression-free survival. But the key secondary endpoints were to evaluate the different response rate including the different response categories, including the undetectable measurable residual disease. First of all, in terms of overall response rate, the overall response rate for Isa-Kd was slightly superior in comparison with Kd, 86.6% versus 83.7%. This means that both combinations are actually effective in relapsed or refractory myeloma.
3: But when we evaluated the depth of the response, we can see how the complete response rate was 28.5% for carfilzomib and dexamethasone. And the complete response rate for patients treated with isatuximab in combination with Kd was 44.1. Indicating that although the overall response rate seems to be comparable, definitely the complete response rate is significantly higher for isatuximab in combination with carfilzomib and dexamethasone.
3: And indeed, they see our odds ratio versus Kd was 2.09. When we have a combination like isatuximab, carfilzomib, and dexamethasone with 44% of the patients achieving complete response, it is today mandatory to evaluate the undetectable measurable residual disease. And this is what it was done in the [? IKEMA ?] study. And when the minimal residual disease was evaluated in the intent-to-treat patient population, we see how 33.5% of the patients treated with Isa-Kd achieved a minimal residual disease negative versus 15.4% with the carfilzomib and dexamethasone alone.
3: This superiority resulted in odds ratio of 2.78. And it is maintained when we evaluated the minimal residual disease negativity rate only in the population achieving complete response. And Isa-Kd resulted in 26.3% of MRD negativity in the CR subgroup of patients versus 12.2% in the carfilzomib and dexamethasone arm.
3: This information is relevant because when we evaluated how these MRD negativity rate translated in terms of outcome, in terms of progression-free survival, it is important to see how the achievement of undetectable measurable residual disease is one of the most important prognostic factors predicting progression-free survival. And the median progression-free survival has not been treated with either Isa-Kd or Kd when the minimal residual disease is negative.
3: This is important. But again, important to remark that more patients receiving isatuximab in combination with carfilzomib and dexamethasone have a probability of achieving minimal residual disease negative. And as I previously told you, 33.5%. When we evaluated the impact of the minimal residual disease positive, so those patients in which the MRD is not negative, in the [INAUDIBLE] patients treated with Isa-Kd resulted into a longer median progression free survival than Kd with minimal residual disease positive.
3: This can be maybe related with the immunomodulatory effect of the monoclonal antibody anti-CD38 isatuximab. And this means that this immunomodulatory effect is able to maintain under control for a longer period of time, even the presence of measurable residual disease in this population. So I think that the minimal residual disease evaluation in the IKEMA study doesn't confirm the prognostic value of the achievement of minimal residual disease negative.
3: And point number two, when we added the monoclonal antibody isatuximab to Kd, we are going to increase the probability of achieving minimal residual disease negative. And this translates today into a longer progression-free survival. And with longer follow-up, we will see maybe also a longer overall survival.
3: The implication of the data reported at ASH 2022 in IKEMA is, well, basically isatuximab in combination with carfilzomib and dexamethasone does represent a standard of care for relapsed or refractory myeloma patients after one to three prior lines of therapy. The benefit is sustained across the different subgroup of patients. I would like to remark how patients after just one prior line of therapy did benefited from isatuximab in combination with carfilzomib and dexamethasone.
3: And this benefit is also maintained in patients who have received two or three prior lines of therapy. In addition, the subanalysis reported at ASH 2022 in early versus late relapse is maybe one of the most relevant ones. Why? Because when we [? face ?] with relapsed and/or refractory myeloma patients, early relapsing after the first line of therapy or early relapsing after whatever prior line of therapy, this means that we [? face ?] in front of us higher risk of myeloma patients.
3: And to have the possibility of using isatuximab in combination with Kd resulting in median progression-free survival longer than three years, I think that these are maybe, in my opinion, one of the most exciting data. The most exciting combination we have in order to rescue these early relapse myeloma patients. Indeed, during ASH meeting, and although maybe cross trial comparisons are not appropriated, we have the opportunity to see other combinations like BCMA-targeted therapy in this specific population with early relapses after just one prior line of therapy.
3: And the data I would say that are not so good as they reported in the IKEMA study and specifically in the combination of isatuximab in combination with carfilzomib and dexamethasone. So this is a combination included in the European Guidelines for the management of patients with multiple myeloma. And as I previously told you, I think that it does represent of a combination of first choice for relapsed and/or refractory myeloma.
3: Next step is, point to number one, to utilize isatuximab, carfilzomib, and dexamethasone in relapsed and/or refractory myeloma. The next step is to move with this type of combinations to the first-line of therapy during ASH meeting.
3: We had the opportunity to see some clinical studies conducted in the first-line of therapy in multiple myeloma patients of newly diagnosed utilizing isatuximab, carfilzomib, and dexamethasone plus the immunomodulatory drug lenalidomide. Some studies in all comers. Some other studies in patients with high-risk features. And definitely what we expected is to have a longer follow-up in order to confirm the superiority of these combinations, Isa-based combinations, for patients with multiple myeloma since the first-line of therapy.
3: If I can add a comment about the future development for isatuximab, I have also to mention that during ASH meeting, a clinical study, the first data of a safety run in part study during ASH meeting, the preliminary data of a cohort of asymptomatic myeloma patients was presented.
3: These patients were treated with isatuximab in combination with lenalidomide and dexamethasone. The first 20 patients included in this phase III ITHACA study showed also positive preliminary data in terms of safety and efficacy. The phase III clinical trial is ongoing. And we will have maybe with longer follow-up. And when the study is completed, a new standard of care not for myeloma patients, but for asymptomatic myeloma patients based on lenalidomide and dexamethasone plus isatuximab.
3: [MUSIC PLAYING]