Friday marked the second day of the 19th International Myeloma Society Annual Meeting in Los Angeles, California. Some of the studies presented today provided updates to data previously presented at meetings earlier this year and late last year. Updates from trials such as these give a sense of the durability of these treatments with longer follow-up. Let’s dig into a big day of updates in myeloma treatment.
Maintenance treatment following autologous stem cell transplant (ASCT) for multiple myeloma remains a topic of active investigation. A prior study showed that extended post-ASCT maintenance treatment with Kyprolis, Revlimid, and dexamethasone (KRd) after KRd as first-line therapy improved the depth and duration of response. In this study,, Dr. Andrzej Jakubowiak from the University of Chicago and colleagues evaluated the difference between KRd and standard Revlimid (R) maintenance. Results showed:
The authors note that this is the first randomized phase 3 trial demonstrating superior PFS with extended post-transplant KRd therapy compared to R maintenance and may represent a new standard of care for some patients.
In the next presentation, French researchers evaluated the impact of treatment duration with Darzalex plus Revlimid and dexamethasone (D-Rd) and response on survival time and the time before disease progression in newly diagnosed multiple myeloma patients who were not eligible for stem cell transplantation. In this analysis, patients received D-Rd or Rd treatment for 18 months or longer.
Researchers found that D-Rd significantly prolonged survival and time until disease progression compared to Rd.. No new safety concerns were identified, and side effects with D-Rd generally decreased over time. Based on these results the authors recommend D-Rd treatment should be continued for at least 18 months to improve prolonged survival and time before disease progression. In Europe, maintenance therapy is often given for a fixed duration in contrast to the U.S where maintenance therapy is typically given until the myeloma returns.
Earlier this year at ASCO 2022, Dr. Paul Richardson at the Dana-Farber Cancer Institute presented findings from one of the most important studies to investigate the optimal timing of ASCT in newly diagnosed myeloma patients.
In this analysis, Dr. Paul Richardson and colleagues evaluated data from the study to assess the best timing of ASCT based on the presence of high-risk cytogenetics. Cytogenetic abnormalities are widely accepted markers for high risk of poor prognosis in patients with multiple myeloma, such as the presence of deletion of chromosome 17p (del[17p]), translocation of chromosomes 4 and 14 (t[4;14]), and translocation of chromosomes 14 and 16 (t[14;16]). To learn more about chromosomal abnormality terminology please see our recent FAQ blog here.
The results showed:
These findings suggest that early transplant may be critical for patients with high-risk cytogenetics.
Sarclisa
In this presentation, Dr. Paul Richardson and colleagues report the final overall survival analysis of the Phase 3 ICARIA-MM study which compared Sarclisa-Pomalyst-dexamethasone with Pomalyst-dexamethasone in patients with relapsed/refractory myeloma. The initial results from this trial were the basis for the approval of Sarclisa in combination with Pomalyst-dexamethasone. Sarclisa is in the same class of treatments as Darzalex.
The results of the final analysis showed an improvement in survival by 6.9 months and significantly improved the duration of clinical benefit (that is, time before another treatment is required). These findings support the use of Sarclisa-Pd as a standard-of-care therapy for patients with relapsed/refractory myeloma.
The next presentation European researchers reported updated, longer-term results from the phase 3 IKEMA, which investigated Sarclisa-Kd compared to Kd in relapsed myeloma patients who received 1-3 prior lines of therapy. The results showed:
Achieving MRD negativity led to better outcomes in both treatment arms, with Isa-Kd patients having a more than 2-fold higher likelihood of achieving MRD negativity. These results demonstrate the benefit of adding Sarclisa to Kd for the treatment of relapsed myeloma patients who received 1-3 prior lines of therapy.
Mezigdomide
CELMoDs are new class of drugs being developed in multiple myeloma that are related to, but functionally different from the immunomodulators like Revlimid and Pomalyst. For example, they stimulate the immune system and kill myeloma cells directly, even for myeloma that has become resistant to certain therapies.
In this presentation, Dr Paul Richardson presented results from a phase 1/2 study that assessed the safety, tolerability, and preliminary efficacy of mezigdomide plus standard treatments in patients with relapsed or refractory myeloma. Patients were randomized to receive either mezigdomide, Velacade, and dexamethasone (MeziVd) or mezigdomide, Kyprolis, and dexamethasone (MeziKd). Enrolled patients had previously received between 2 and 4 treatment regimens.
The results showed:
The researchers concluded that that MeziVd and MeziKd demonstrated a manageable safety profile and promising efficacy in patients with RRMM. These results support further evaluation of these mezigdomide combinations in phase 3 studies.
Blenrep (belantamab mafodotin)
Blenrep is a BCMA-targeting antibody–drug conjugate approved for patients with relapsed/refractory myeloma as monotherapy at 2.5 mg/kg once every three weeks. Preclinical data has shown there is an added benefit when Blenrep is combined with standard of care treatments. Researchers reported early results from a phase 1/2 study evaluating the safety, tolerability, and preliminary efficacy of Blenrep in combination with Kd in patients with relapsed/refractory myeloma after 1-3 prior lines of treatment.
The results from 19 patients showed that low platelet counts (30%) and blurred vision (20%) were the most frequent side effects. Of the 10 patients evaluated for efficacy, 9 achieved a response to therapy. The researchers conclude thatBlenrep combined with Kd has a safety profile that is in keeping with that expected for each individual drug, adding that recruitment is ongoing in an expansion phase based on the preliminary safety and efficacy results.
REGN5458
Dr. Naresh Bumma from The Ohio State University reported updated findings from a first-in-human, open-label phase 1/2 trial assessing the safety, tolerability, and preliminary efficacy of REGN5458, a BCMA- and CD3-directed bispecific antibody, in patients with relapsed/refractory multiple myeloma who were refractory, or intolerant to, two or more prior lines of systemic therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody. The results showed:
The researchers conclude that REGN5458 monotherapy shows a manageable safety and tolerability profile. The phase 2 portion of the study is currently recruiting.
Myeloma experts Dr. Ajay Nooka and Dr. Ravi Vij review they day’s highlights here.
Thousands of myeloma researchers and clinicians from all over the world gathered in Los Angeles, California at the 19th International Myeloma Society (IMS) annual meeting to present and discuss the latest advances in multiple myeloma clinical research. Today, we learned how researchers use data to better predict which patients with multiple myeloma may have a long-lasting response to therapy and which are more likely to experience an early relapse. We also learned that newly diagnosed patients with high-risk disease experienced deep responses to the four-drug induction regimen of Darzalex-Kyprolis-Revlimid- dexamethasone without unacceptable toxicities prior to autologous stem cell transplant (ASCT).
Minimal residual disease (MRD) is an important topic in the field of multiple myeloma, in large part because we have very active treatment regimens that can bring deep and sustained responses to patients, something that was not possible just several years ago. Measuring MRD refers to counting the number of multiple myeloma cells that remain in a patient after a course of therapy is completed. Achieving MRD negativity (that is, no disease detected after treatment) is associated with a significantly longer time before disease progression (progression-free survival [PFS]) and overall survival; however, to date, there has been limited information about its clinical meaning in patients treated with CAR T-cell therapy.
MRD Negativity After Treatment With Abecma (idecabtagene vicleucel)
In the first presentation, investigators from Spain analyzed MRD at months 1, 3, 6 and 12 after Abecma infusion regardless of clinical response in the KarMMa phase 2 clinical trial, which investigated Abecma at different cell doses in 128 patients with triple-class refractory myeloma. Abecma, manufactured by Bristol-Myers Squibb, was the first CAR-T product to receive FDA approval to treat multiple myeloma. The results showed MRD negative patients had significantly greater median PFS (time before disease progression) than MRD positive patients at 1 month following Abecma treatment (11.5 vs 2 months).
Further studies will be needed to better understand the prognostic implication of different response rates and MRD status in patients treated with CAR T-cell therapy.
High-Risk Patients and MRD Negativity
Cytogenetic abnormalities are widely accepted markers for high risk of poor prognosis in patients with multiple myeloma, such as the presence of gain or amplification of chromosome arm 1q21 (gain/amp[1q21]), deletion of chromosome 1p (del[1p]), deletion of chromosome 17p (del[17p]), translocation of chromosomes 4 and 14 (t[4;14]), translocation of chromosomes 14 and 16 (t[14;16]), and translocation of chromosomes 14 and 20 (t[14;20]). To learn more about chromosomal abnormality terminology please see our recent FAQ blog here. MRD negativity has recently emerged as a surrogate for longer survival, regardless of a patient’s cytogenetic risk. Information from newer clinical trials suggests that extended intensified treatment can help achieve MRD negativity in patients with who may have one or more of these high-risk features, which may lead to improved outcomes.
In the next presentation today, researchers from Italy reviewed data from the FORTE trial to assess the impact of high-risk cytogenetic abnormalities in newly diagnosed patients. The FORTE trial evaluated the use of Kyprolis as a part of an induction and consolidation regimen (following ASCT) and maintenance (combined with Revlimid) for newly diagnosed myeloma patients. They evaluated treatment on its ability to lengthen time until disease progression and 1-year sustained MRD negativity according to patient risk.
The authors showed that MRD-negative patients with amp(1q), high circulating tumor cells levels, or multiple high-risk chromosomal abnormalities were at high risk of becoming MRD positive regardless of their treatment. During the exposure to Kyprolis-Revlimid maintenance, patients were at lower risk of becoming MRD positive compared to Revlimid alone. The findings suggest that patients should know if they have any high-risk features/markers and speak to their provider about treatment implications.
To learn more about MRD, we have several educational resources available:
The next abstract used data from the CoMMpass study to evaluate methods that may help better predict how patients respond to therapy. The MMRF CoMMpass Study was designed to provide researchers with as much information as possible about myeloma, by collecting and studying genomic data from more than a thousand patients over the course of their myeloma journey. Researchers from the United Kingdome used data from the CoMMpass study to validate a mutational signature in which absence of mutations across five genes (MGAM, CCDC168, PDXDC1, ABCC1, S1PR2) was associated with better outcome following Kyprolis, Cytoxan, dexamethasone treatment. When applied to data collected from 154 patients in the CoMMpass study who had received upfront Kyprolis-based therapies, the signature was validated. The authors conclude that this genetic signature can be used by clinicians to predict a patient’s response to Kyprolis.
More details about the MMRF CoMMpass Study can be viewed here.
Newly diagnosed, transplant-eligible multiple myeloma patients with high-risk features—defined by the presence of del17p, t(4;14) and/or t(14;16)—is associated with poor outcome. Data presented today from a phase 2 trial from the Intergroupe Francophone du Myelome (IFM) revealed how adding Darzalex to Kyprolis-Revlimid-dexamethasone as induction and consolidation plus double transplant may benefit newly diagnosed, transplant-eligible high-risk myeloma patients. The results showed:
The findings suggested that Dara-KRD as induction prior ASCT is safe and allows deep responses in transplant-eligible newly diagnosed multiple myeloma patients with high-risk cytogenetic profile.
Be sure to hear what myeloma experts Dr. Suzanne Lentzsch and Dr. Saad Usmani have to say about the day’s presentations here.
Stay tuned for more updates from IMS 2022!
