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Prognostic value of MRD dynamics during maintenance therapy for multiple myeloma in the TOURMALINE-MM3 and -MM4 trials
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Prognostic value of MRD dynamics during maintenance therapy for multiple myeloma in the TOURMALINE-MM3 and -MM4 trials
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Upload Date:
2024-01-12T00:00:00.0000000
Transcript:
Language: EN.
Segment:1 Introduction.
[MUSIC PLAYING]
BRUNO PAIVA: Welcome to this video summarizing our article entitled "MRD Dynamics During Maintenance for Improved Prognostication of 1,280 Myeloma Patients Enrolled in the TOURMALINE-MM3 and -MM4 Clinical Trials," which was recently published in the Blood journal. I'm Dr. Bruno Paiva from the University of Navarra in Pamplona, Spain. [MUSIC PLAYING]
Segment:2 What was the purpose of the study?.
BRUNO PAIVA: As many of you would know, Measurable Residual Disease or MRD status is one of the most powerful prognostic factors in multiple myeloma. There are promising, yet scarce, data on the clinical value of MRD assessment during continuous or fixed duration maintenance therapy. By contrast, due to the nature or the design of current studies, there is virtually no information on patients' MRD status during observation. However, it should be noted that, almost paradoxically, maintenance and observation are the settings where MRD status is anticipated to help tailor treatment duration. Furthermore, the interest is growing in the use of serial assessments to improve risk stratification based on MRD dynamics. In this regard, there is also promising yet preliminary data suggesting that patients attaining sustained MRD negativity for one year or more could show superior outcomes when compared to those with shorter duration of MRD remission.
BRUNO PAIVA: It is therefore reasonable to hypothesize that MRD dynamics (MRD kinetics measured in different time points) are needed to guide treatment intensification, cessation, eventually reinstatement, particularly in the maintenance or observation settings. Therefore, in this pooled analysis of the TOURMALINE-MM3 and -MM4 trials, we investigated the prognostic value of MRD dynamics over time in patients with newly diagnosed myeloma, who received, according to the design of these two clinical trials, either ixazomib or placebo as maintenance.
BRUNO PAIVA: More specifically, we evaluated Progression-Free Survival, or PFS, according to MRD dynamics, also the volatility of MRD status over time and its clinical impact, the prognostic value of late MRD conversions from positive to negative, the time from MRD reappearance to progressive disease, a question that remains unanswered, both in patients receiving ixazomib or placebo, and if there was a PFS benefit with ixazomib versus placebo according to patients' MRD status at randomization and during maintenance. [MUSIC PLAYING]
Segment:3 How was the study undertaken?.
BRUNO PAIVA: In this global, randomized, placebo-controlled, phase III MM3 and MM4 TOURMALINE studies, patients received oral ixazomib maintenance or matching placebo in 28-day cycles for up to two years, in other words, 26 cycles. TOURMALINE-MM3 enrolled transplant-eligible myeloma patients, whereas the -MM4 study enrolled patients who were ineligible for an autologous transplant. The primary endpoint of both studies was PFS. Prespecified secondary endpoints included the frequency of conversion from MRD-positive to negative status, also sustained MRD negativity, and, obviously, the correlation between patients' MRD status and survival.
BRUNO PAIVA: Bone marrow aspirates were collected for MRD evaluation at randomization, cycle 13, and at the end of treatment from all patients with a confirmed or suspected complete response as well as from patients with a Very Good Partial Response, or VGPR, in the MM3 trial. Additional samples were collected to confirm a suspected complete remission at any time point.
BRUNO PAIVA: Samples were assessed by 8-color flow cytometry. This is particularly relevant because in this trial, samples at baseline were not available for alternative methods, such as next-generation sequencing. Therefore, flow cytometry was obviously the method of choice. Back then, the assay was validated and standardized across four countries in three geographic regions using a central laboratory, implying that flow can also be used in such large multicenter clinical trials. The target goal for acquisition was 5 million cells so that an estimated sensitivity of approximately 4 per 10 to the minus 6 could be reached. A total of 2,077 bone marrow aspirates were analyzed across the two studies. And the median limit of detection that was measured in each of those samples was 7.4 per 10 to the minus 6.
Segment:4 What were the results?.
BRUNO PAIVA: [MUSIC PLAYING] Of the 1,362 patients in this analysis, 82 were not evaluable due to either peripheral blood contamination-- I would say severe peripheral blood contamination of the bone marrow sample-- technical failure, or absence of a sample in patients with complete response. Therefore, MRD status at randomization was available to the vast majority of patients, 94% in both studies. Of these, 20% were MRD-negative. 80% were MRD-positive.
BRUNO PAIVA: Patient demographics and disease characteristics were generally well balanced between MRD-negative and positive patients, meaning that to some extent, it is difficult to predict what will be the patient MRD status according to baseline characteristics. 90% of MRD-negative patients were less than 75 years compared to 77% of MRD-positive patients. Obviously, this was likely a consequence of the greater MRD-negative rates observed in patients who received an autologous transplant in MM3 versus those who did not in the TOURMALINE-MM4 clinical trial.
BRUNO PAIVA: There were no notable differences between patients who were MRD-negative and MRD-positive at baseline in terms of pre-induction ISS, cytogenetic risk, also at diagnosis or prior treatment.
BRUNO PAIVA: Median PFS was 38.6 months in patients who were MRD-negative at randomization compared with 15.6 months in MRD-positive patients, therefore, a difference of 23 months, approximately two years. In a univariate analysis, MRD-negative status at randomization was associated with prolonged PFS in nearly all patient subgroups, regardless of demographics, disease features and diagnosis, including cytogenetics, prior therapy, conventional serological response, or geographical region of MRD testing, emphasizing the value or the achievement of complete standardization of the MRD assay being performed in different laboratories spread around the world.
BRUNO PAIVA: In a Cox regression multivariable analysis of PFS, ISS staging, cytogenetic risk of diagnosis, response at randomization, treatment with ixazomib versus placebo, and MRD status at randomization all showed independent prognostic value for PFS.
BRUNO PAIVA: The impact of ixazomib versus placebo on PFS was investigated in patients stratified according to MRD status at randomization. The respective median PFS was 38.6 versus 33.7 months in MRD-negative patients and approximately 19 versus 11.6 months in those with MRD-positive status. Therefore, treatment with ixazomib versus placebo improved PFS in patients who were MRD-positive at randomization and not those that were MRD-negative.
BRUNO PAIVA: At any time during ixazomib or placebo administration, MRD status was available in 1,226 patients. Of these, 16% were MRD-negative. 84% were MRD-positive. MRD dynamics, in other words, paired assessments at randomization and during maintenance, were available in 1,166 patients.
BRUNO PAIVA: At a 14-month landmark analysis, PFS was prolonged in patients who converted from MRD-positive to negative status compared with those with persistent positive MRD with two-year PFS rates of 76.8% versus 27.6%. PFS was also prolonged in patients with sustained MRD-negativity compared with those who converted from MRD-negative to positive status, with two-year PFS rates of 75% versus 34%.
BRUNO PAIVA: Ixazomib maintenance improved PFS in patients who were MRD-positive at the 14-month landmark compared with placebo, similarly to what was observed at randomization. The two-year PFS rates were 36.7% versus 19.1%. Again, no differences were observed among MRD-negative patients. [MUSIC PLAYING]
Segment:5 What is the significance of these findings?.
BRUNO PAIVA: To date, we believe this is one, if not the, largest myeloma data set ever reported evaluating yearly MRD status during maintenance or observation.
BRUNO PAIVA: This study demonstrated the feasibility of routine MRD evaluation using flow cytometry in large clinical trials and, in my opinion, sets the stage for serial MRD monitoring during maintenance or observation in upcoming and future clinical trials.
BRUNO PAIVA: Using a minimally invasive and nonbiopsy approach where MRD can be viewed more frequently and more broadly, such as mass spectrometry, imaging techniques, such as PET-CT, might be a valuable adjunct to either NGS or NGF as part of a systematic follow-up or monitoring of treatment efficacy.
BRUNO PAIVA: Whether continuous maintenance therapy is equally beneficial for all patients, or if treatment-free intervals can be safely offered in some cases, remains a matter of debate. In this regard, our results, with the caveat of progressively shorter follow-up, suggest that the risk of progression was lower in MRD-negative patients at the 14-month landmark when compared to randomization.
BRUNO PAIVA: Another important aspect. Persistence of MRD is, perhaps with the exception of a few patients, almost always associated with progressive disease. Thus, it may be more reasonable to act from a therapeutic point of view on MRD-positive status rather than an MRD-negative result, with the persistence of MRD resulting in the treatment intensification with the aim of improving what we have shown dismal outcomes among the MRD-positive patient population.
BRUNO PAIVA: Also, according to our results, for patients who do not achieve an MRD-negative status or who convert from MRD-negative to -positive, it should be noted that although prolonged therapy significantly improves PFS, the benefit was limited to a few patients, eventually those converting from MRD-positive to negative.
BRUNO PAIVA: Therefore, the prognostic significance of MRD and its role in guiding decisions regarding treatment cessation or de-escalation remains to be established and, importantly, are being investigated in ongoing randomized studies evaluating MRD-directed therapy.
BRUNO PAIVA: Therefore, future clinical trials on a larger study cohort with multiple demographic parameters may provide us with further knowledge on the prognostic potential of MRD evaluation.
Segment:6 Conclusions.
BRUNO PAIVA: To sum up, there are five main conclusions emerging from our study. The first, MRD status is dynamic, and its prognostic value increased considerably with periodic versus single assessment. Second, the favorable prognosis of undetectable MRD was similar if achieved before or during maintenance. And, thus, it can become a relevant endpoint , also during the maintenance setting. Third, patients who lost MRD-negative status had a poor PFS, similar to patients with persistent MRD. Fourth, treatment with ixazomib versus placebo improved PFS in patients who were MRD-positive at randomization or at the 14-month landmark. And fifth, two-year ixazomib maintenance was not efficacious in patients who were MRD-negative at these time points. [MUSIC PLAYING]
Segment:7 Closing.
BRUNO PAIVA:
Segment:1 Introduction.
[MUSIC PLAYING]
BRUNO PAIVA: Welcome to this video summarizing our article entitled "MRD Dynamics During Maintenance for Improved Prognostication of 1,280 Myeloma Patients Enrolled in the TOURMALINE-MM3 and -MM4 Clinical Trials," which was recently published in the Blood journal. I'm Dr. Bruno Paiva from the University of Navarra in Pamplona, Spain. [MUSIC PLAYING]
Segment:2 What was the purpose of the study?.
BRUNO PAIVA: As many of you would know, Measurable Residual Disease or MRD status is one of the most powerful prognostic factors in multiple myeloma. There are promising, yet scarce, data on the clinical value of MRD assessment during continuous or fixed duration maintenance therapy. By contrast, due to the nature or the design of current studies, there is virtually no information on patients' MRD status during observation. However, it should be noted that, almost paradoxically, maintenance and observation are the settings where MRD status is anticipated to help tailor treatment duration. Furthermore, the interest is growing in the use of serial assessments to improve risk stratification based on MRD dynamics. In this regard, there is also promising yet preliminary data suggesting that patients attaining sustained MRD negativity for one year or more could show superior outcomes when compared to those with shorter duration of MRD remission.
BRUNO PAIVA: It is therefore reasonable to hypothesize that MRD dynamics (MRD kinetics measured in different time points) are needed to guide treatment intensification, cessation, eventually reinstatement, particularly in the maintenance or observation settings. Therefore, in this pooled analysis of the TOURMALINE-MM3 and -MM4 trials, we investigated the prognostic value of MRD dynamics over time in patients with newly diagnosed myeloma, who received, according to the design of these two clinical trials, either ixazomib or placebo as maintenance.
BRUNO PAIVA: More specifically, we evaluated Progression-Free Survival, or PFS, according to MRD dynamics, also the volatility of MRD status over time and its clinical impact, the prognostic value of late MRD conversions from positive to negative, the time from MRD reappearance to progressive disease, a question that remains unanswered, both in patients receiving ixazomib or placebo, and if there was a PFS benefit with ixazomib versus placebo according to patients' MRD status at randomization and during maintenance. [MUSIC PLAYING]
Segment:3 How was the study undertaken?.
BRUNO PAIVA: In this global, randomized, placebo-controlled, phase III MM3 and MM4 TOURMALINE studies, patients received oral ixazomib maintenance or matching placebo in 28-day cycles for up to two years, in other words, 26 cycles. TOURMALINE-MM3 enrolled transplant-eligible myeloma patients, whereas the -MM4 study enrolled patients who were ineligible for an autologous transplant. The primary endpoint of both studies was PFS. Prespecified secondary endpoints included the frequency of conversion from MRD-positive to negative status, also sustained MRD negativity, and, obviously, the correlation between patients' MRD status and survival.
BRUNO PAIVA: Bone marrow aspirates were collected for MRD evaluation at randomization, cycle 13, and at the end of treatment from all patients with a confirmed or suspected complete response as well as from patients with a Very Good Partial Response, or VGPR, in the MM3 trial. Additional samples were collected to confirm a suspected complete remission at any time point.
BRUNO PAIVA: Samples were assessed by 8-color flow cytometry. This is particularly relevant because in this trial, samples at baseline were not available for alternative methods, such as next-generation sequencing. Therefore, flow cytometry was obviously the method of choice. Back then, the assay was validated and standardized across four countries in three geographic regions using a central laboratory, implying that flow can also be used in such large multicenter clinical trials. The target goal for acquisition was 5 million cells so that an estimated sensitivity of approximately 4 per 10 to the minus 6 could be reached. A total of 2,077 bone marrow aspirates were analyzed across the two studies. And the median limit of detection that was measured in each of those samples was 7.4 per 10 to the minus 6.
Segment:4 What were the results?.
BRUNO PAIVA: [MUSIC PLAYING] Of the 1,362 patients in this analysis, 82 were not evaluable due to either peripheral blood contamination-- I would say severe peripheral blood contamination of the bone marrow sample-- technical failure, or absence of a sample in patients with complete response. Therefore, MRD status at randomization was available to the vast majority of patients, 94% in both studies. Of these, 20% were MRD-negative. 80% were MRD-positive.
BRUNO PAIVA: Patient demographics and disease characteristics were generally well balanced between MRD-negative and positive patients, meaning that to some extent, it is difficult to predict what will be the patient MRD status according to baseline characteristics. 90% of MRD-negative patients were less than 75 years compared to 77% of MRD-positive patients. Obviously, this was likely a consequence of the greater MRD-negative rates observed in patients who received an autologous transplant in MM3 versus those who did not in the TOURMALINE-MM4 clinical trial.
BRUNO PAIVA: There were no notable differences between patients who were MRD-negative and MRD-positive at baseline in terms of pre-induction ISS, cytogenetic risk, also at diagnosis or prior treatment.
BRUNO PAIVA: Median PFS was 38.6 months in patients who were MRD-negative at randomization compared with 15.6 months in MRD-positive patients, therefore, a difference of 23 months, approximately two years. In a univariate analysis, MRD-negative status at randomization was associated with prolonged PFS in nearly all patient subgroups, regardless of demographics, disease features and diagnosis, including cytogenetics, prior therapy, conventional serological response, or geographical region of MRD testing, emphasizing the value or the achievement of complete standardization of the MRD assay being performed in different laboratories spread around the world.
BRUNO PAIVA: In a Cox regression multivariable analysis of PFS, ISS staging, cytogenetic risk of diagnosis, response at randomization, treatment with ixazomib versus placebo, and MRD status at randomization all showed independent prognostic value for PFS.
BRUNO PAIVA: The impact of ixazomib versus placebo on PFS was investigated in patients stratified according to MRD status at randomization. The respective median PFS was 38.6 versus 33.7 months in MRD-negative patients and approximately 19 versus 11.6 months in those with MRD-positive status. Therefore, treatment with ixazomib versus placebo improved PFS in patients who were MRD-positive at randomization and not those that were MRD-negative.
BRUNO PAIVA: At any time during ixazomib or placebo administration, MRD status was available in 1,226 patients. Of these, 16% were MRD-negative. 84% were MRD-positive. MRD dynamics, in other words, paired assessments at randomization and during maintenance, were available in 1,166 patients.
BRUNO PAIVA: At a 14-month landmark analysis, PFS was prolonged in patients who converted from MRD-positive to negative status compared with those with persistent positive MRD with two-year PFS rates of 76.8% versus 27.6%. PFS was also prolonged in patients with sustained MRD-negativity compared with those who converted from MRD-negative to positive status, with two-year PFS rates of 75% versus 34%.
BRUNO PAIVA: Ixazomib maintenance improved PFS in patients who were MRD-positive at the 14-month landmark compared with placebo, similarly to what was observed at randomization. The two-year PFS rates were 36.7% versus 19.1%. Again, no differences were observed among MRD-negative patients. [MUSIC PLAYING]
Segment:5 What is the significance of these findings?.
BRUNO PAIVA: To date, we believe this is one, if not the, largest myeloma data set ever reported evaluating yearly MRD status during maintenance or observation.
BRUNO PAIVA: This study demonstrated the feasibility of routine MRD evaluation using flow cytometry in large clinical trials and, in my opinion, sets the stage for serial MRD monitoring during maintenance or observation in upcoming and future clinical trials.
BRUNO PAIVA: Using a minimally invasive and nonbiopsy approach where MRD can be viewed more frequently and more broadly, such as mass spectrometry, imaging techniques, such as PET-CT, might be a valuable adjunct to either NGS or NGF as part of a systematic follow-up or monitoring of treatment efficacy.
BRUNO PAIVA: Whether continuous maintenance therapy is equally beneficial for all patients, or if treatment-free intervals can be safely offered in some cases, remains a matter of debate. In this regard, our results, with the caveat of progressively shorter follow-up, suggest that the risk of progression was lower in MRD-negative patients at the 14-month landmark when compared to randomization.
BRUNO PAIVA: Another important aspect. Persistence of MRD is, perhaps with the exception of a few patients, almost always associated with progressive disease. Thus, it may be more reasonable to act from a therapeutic point of view on MRD-positive status rather than an MRD-negative result, with the persistence of MRD resulting in the treatment intensification with the aim of improving what we have shown dismal outcomes among the MRD-positive patient population.
BRUNO PAIVA: Also, according to our results, for patients who do not achieve an MRD-negative status or who convert from MRD-negative to -positive, it should be noted that although prolonged therapy significantly improves PFS, the benefit was limited to a few patients, eventually those converting from MRD-positive to negative.
BRUNO PAIVA: Therefore, the prognostic significance of MRD and its role in guiding decisions regarding treatment cessation or de-escalation remains to be established and, importantly, are being investigated in ongoing randomized studies evaluating MRD-directed therapy.
BRUNO PAIVA: Therefore, future clinical trials on a larger study cohort with multiple demographic parameters may provide us with further knowledge on the prognostic potential of MRD evaluation.
Segment:6 Conclusions.
BRUNO PAIVA: To sum up, there are five main conclusions emerging from our study. The first, MRD status is dynamic, and its prognostic value increased considerably with periodic versus single assessment. Second, the favorable prognosis of undetectable MRD was similar if achieved before or during maintenance. And, thus, it can become a relevant endpoint , also during the maintenance setting. Third, patients who lost MRD-negative status had a poor PFS, similar to patients with persistent MRD. Fourth, treatment with ixazomib versus placebo improved PFS in patients who were MRD-positive at randomization or at the 14-month landmark. And fifth, two-year ixazomib maintenance was not efficacious in patients who were MRD-negative at these time points. [MUSIC PLAYING]
Segment:7 Closing.
BRUNO PAIVA:
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