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Abstracts Covered in this Issue:
Click on any title in the bulleted list to read the full abstract summary.
- Impact of MRD on PFS in NDMM Patients
- Biomarker for Identification of High-Risk Transplant-Eligible Myeloma Patients
- FRAIL-M: A Trial of Frail NDMM Patients
- The Impact on PFS of Adding Isa to RVd in NDMM patients
- Quadruplet vs Triplet Induction in NDMM Patients
- A Novel Biomarker with Therapeutic Implications
- Isa in Transplant-ineligible NDMM Patients
- Patient Preferences on Clinical Decision-Making in Myeloma
- New Advances in Precision Medicine in MM
Highlighted Abstract Summaries
Impact of Minimal Residual Disease on Progression-Free Survival in Patients with Newly Diagnosed Multiple Myeloma Treated with Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy in the Phase 3 GMMG-HD7 Trial
Authors: Elias K. Mai, Hans Salwender, Michael Hundemer, et al.
Background: Minimal residual disease negativity (MRDneg) in the bone marrow is linked to improved survival outcomes in newly diagnosed multiple myeloma (NDMM). The randomized, multicenter Phase 3 GMMG-HD7 trial evaluated the addition of isatuximab (Isa), an anti-CD38 monoclonal antibody, to lenalidomide, bortezomib, and dexamethasone (RVd) for transplant-eligible NDMM patients. This study explored the impact of MRDneg and continued MRDneg status on progression-free survival (PFS).
Study Overview and Results: The trial included 660 transplant-eligible NDMM patients randomized to Isa-RVd or RVd, followed by autologous stem cell transplant and maintenance therapy. The Isa-RVd arm achieved significantly higher MRDneg rates post-induction (55% vs. 41%, p<.001). MRDneg patients had better 3-year PFS compared to MRD-positive (MRDpos) patients (88% vs. 71%, p<0.001). In MRDpos patients, PFS was significantly longer with Isa-RVd (HR 0.64, p=0.03). Continued MRDneg status further improved PFS, with 3-year PFS rates of 90% for those with continued MRDneg compared to 77% for those without (p<0.001).
Relevance: This study highlights the importance of achieving and maintaining MRDneg in NDMM patients. The addition of Isa to RVd significantly increases MRDneg rates, with a favorable PFS benefit in patients who do not achieve or maintain MRDneg. These findings support the integration of Isa-RVd into induction therapy to improve long-term outcomes in transplant-eligible patients.
Link: Abstract 364
Circulating Tumor Cells as a Biomarker to Identify High-Risk Transplant-Eligible Myeloma Patients Treated with Bortezomib, Lenalidomide, and Dexamethasone With or Without Daratumumab During Induction/Consolidation, and Lenalidomide With or Without Daratumumab During Maintenance: Results From the Perseus Study
Authors: Luca Bertamini, Cathelijne Fokkema, Paula Rodríguez-Otero, et al.
Background: Circulating tumor cells (CTCs) are an emerging prognostic biomarker for newly diagnosed multiple myeloma (NDMM). Elevated CTC levels correlate with inferior minimal residual disease (MRD) negativity rates and progression-free survival (PFS). The Phase 3 PERSEUS study explored the prognostic value of CTCs in transplant-eligible NDMM patients treated with quadruplet induction regimens incorporating daratumumab (D-VRd) or standard VRd.
Study Overview and Results: In the PERSEUS trial, 451 patients had CTCs analyzed. Higher CTC levels were independently associated with worse PFS (HR 1.36, p<0.001). Patients with higher CTCs had reduced 4-year PFS, with rates declining from 93% for low CTCs (≤0.001%) to 48% for high CTCs (>1%, p<0.0001). An optimal threshold of 0.175% defined a high-risk subgroup (CTC-High), encompassing 15.3% of patients. MRD-negativity rates were significantly higher with D-VRd versus VRd in both CTC-High (69% vs. 34%, p=0.008) and CTC-Low patients. PFS also favored D-VRd in both groups, with 4-year PFS rates of 58% vs. 40% in CTC-High and 88% vs. 74% in CTC-Low patients (p<0.001). Combining CTC-High with high-risk cytogenetic abnormalities (HRCA) identified an ultra-high-risk subgroup with markedly poor outcomes (4-year PFS of 29%).
Relevance: The findings establish CTCs as a valuable biomarker for risk stratification in NDMM. The addition of daratumumab to VRd improves outcomes for high-risk patients defined by elevated CTC levels, with higher rates of deep and sustained MRD-negativity and superior PFS. These results support the integration of CTC analysis into clinical practice to guide treatment decisions and optimize outcomes for transplant-eligible NDMM patients.
Link: Abstract 487
Initial Results From the Frailty-Stratified, Randomized Controlled Bayesian Adaptive Trial of Bortezomib Versus Lenalidomide in Transplant-Ineligible Myeloma (TI-NDMM): The FRAIL-M Study
Authors: Sueh-Li Lim, John Reynolds, Lucy Pemberton, et al.
Background: Transplant-ineligible (TI) NDMM patients often face worse outcomes compared to transplant-eligible patients, with frailty significantly impacting treatment tolerability and efficacy. The FRAIL-M study addresses the lack of direct comparisons between lenalidomide (R)- and bortezomib (V)-based regimens in this population, aiming to identify effective, deliverable therapies tailored to patient frailty.
Study Overview and Results: : This frailty-stratified, adaptive Phase I/II trial uses the IMWG Frailty Score and geriatric assessment tools to categorize patients into fit, intermediate-fit, or frail strata. Patients are randomized to bortezomib-based (arm A) or lenalidomide-based (arm B) regimens, with dose modifications guided by a Bayesian Optimal Phase 2 (BOP2) design. Interim results focus on the frail stratum (n=91, median age 81 years).
- Arm 3A (Vd): Initial dosing failed to meet efficacy thresholds (20% ORR after 4 cycles), prompting dose escalation to VRd. Subsequent analyses cleared efficacy and toxicity thresholds, enabling continuation.
- Arm 3B (Rd): ORR at the end of 4 cycles was 66%, with a deliverability-limiting toxicity (DeLT) rate of 21%, demonstrating promising efficacy and manageable safety.
Relevance: The FRAIL-M trial highlights the importance of tailoring NDMM treatment to frailty, offering early evidence that lenalidomide-based regimens (Rd) may provide a favorable balance of efficacy and tolerability for frail patients. The adaptive design ensures continuous optimization of regimens to improve outcomes for this challenging population. These findings pave the way for further integration of frailty-adapted strategies in clinical practice.
Link: Abstract 4755
Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy for Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma: Final Progression-Free Survival Analysis of Part 1 of an Open-Label, Multicenter, Randomized, Phase 3 Trial (GMMG-HD7)
Authors: Hartmut Goldschmidt, Uta Bertsch, Ema Pozek, et al.
Background: The addition of anti-CD38 monoclonal antibodies like isatuximab (Isa) to standard regimens has enhanced treatment efficacy for newly diagnosed multiple myeloma (NDMM). The Phase 3 GMMG-HD7 trial previously showed that Isa combined with lenalidomide, bortezomib, and dexamethasone (Isa-RVd) significantly improved minimal residual disease (MRD) negativity rates during induction. This analysis focuses on progression-free survival (PFS) as a secondary endpoint.
Study Overview and Results: The trial enrolled 660 transplant-eligible NDMM patients randomized to Isa-RVd or RVd induction therapy, followed by autologous stem cell transplant (ASCT) and maintenance with or without Isa. At a median follow-up of 47 months, Isa-RVd demonstrated a significant PFS benefit (HR 0.70, p=0.0184) compared to RVd. Three-year PFS rates were 83% for Isa-RVd versus 75% for RVd. Multivariable analysis confirmed the PFS advantage (HR 0.64, p=0.004). Subgroup analyses showed consistent benefit across most baseline factors, except for patients with high-risk cytogenetics or poor performance status, who did not experience significant improvement. Weighted risk set analyses incorporating maintenance strategies reinforced the PFS benefit (HR 0.63, p=0.016). Overall survival (OS) was not yet mature, with 3-year OS rates of 88% for Isa-RVd versus 89% for RVd.
Relevance: This analysis highlights the sustained PFS advantage of adding Isa to RVd for transplant-eligible NDMM patients. The combination improves outcomes during induction therapy and supports its integration into frontline regimens, regardless of subsequent maintenance strategy. The findings validate prior MRD-related results and suggest potential for broader application as trial data matures.
Link: Abstract 769
Daratumumab-Based Quadruplet Versus Triplet Induction Regimens in Frontline Transplant-Eligible Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis
Authors: Joao Tadeu Damian Souto Filho, Lucas Oliveira Cantadori, Edvan De Queiroz Crusoe, et al.
Background: The emergence of daratumumab-based quadruplet regimens has reshaped frontline induction therapy for transplant-eligible newly diagnosed multiple myeloma (TE-NDMM) patients. While these regimens improve response rates and progression-free survival (PFS), their long-term impact on overall survival (OS) requires further evaluation.
Study Overview and Results: This systematic review and meta-analysis included data from four studies involving 3,327 TE-NDMM patients, comparing daratumumab-based quadruplet regimens (D-VRd or D-VTd) to triplet regimens (VRd or VTd). Key findings include:
- Survival Outcomes: Quadruplet regimens significantly improved OS (pooled HR 0.60; 95% CI 0.48–0.75; p<0.00001; I²=0%), and also extended PFS (pooled HR 0.49; 95% CI 0.37–0.65; p<0.00001; I²=52%).
- Subgroup Analysis: Comparisons between D-VRd and VRd demonstrated significant benefits with the daratumumab-based regimen for both OS (pooled HR 0.68; p=0.03; I²=0%) and PFS (pooled HR 0.41; p<0.00001; I²=0%).
Relevance: This meta-analysis consolidates evidence that daratumumab-based quadruplet regimens substantially improve both OS and PFS in TE-NDMM patients compared to triplet regimens. These findings provide strong support for integrating daratumumab into frontline therapy to optimize survival outcomes in this population.
Link: Abstract 258
Increased Expression of the Sialyltransferase Gene ST3GAL1 Predicts Lack of Sustained MRD Negativity and Increased Risk of Progression in Newly Diagnosed, Transplant-Eligible Multiple Myeloma Patients: Insights From the CASSIOPEIA Study
Authors: Michael O'Dwyer, Aideen Edele Ryan, Aoise O'Neill, et al.
Background: Hypersialylation, mediated by the enzyme ST3GAL1, plays a role in immune evasion and resistance to therapy in multiple myeloma (MM). Prior findings in the CASSIOPEIA trial linked elevated ST3GAL1 expression to inferior progression-free survival (PFS) during induction therapy. This analysis focuses on the impact of ST3GAL1 during maintenance therapy with daratumumab (Dara) versus observation and its effect on sustained minimal residual disease (MRD) negativity.
Study Overview and Results: In part 2 of the CASSIOPEIA trial, patients with a partial response or better post-induction were randomized to Dara maintenance or observation. Key findings include:
- ST3GAL1 Expression and PFS: Higher ST3GAL1 expression was significantly associated with shorter PFS in the overall cohort (p=0.0017). Among MRD-negative patients at day 100 post-consolidation, those with elevated ST3GAL1 had significantly worse PFS (HR 1.65; p=0.03).
- MRD Sustainability: Among MRD-negative patients, 81% of those with low ST3GAL1 achieved sustained MRD negativity (10⁻⁵) at week 105, compared to only 40% of patients with high ST3GAL1 (p=0.009).
- Preclinical Insights: Desialylation of MM cell lines abrogated pro-tumorigenic macrophage polarization, enhanced complement-dependent cytotoxicity (CDC), and improved antibody-dependent cellular phagocytosis (ADCP) when combined with Dara.
Relevance: Elevated ST3GAL1 expression predicts inferior MRD sustainability and poorer PFS, highlighting its role as a prognostic biomarker in MM. These findings support the exploration of desialylation strategies to overcome resistance mechanisms and improve outcomes in MM patients receiving Dara-based therapies.
Link: Abstract 250
Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone (Isa-VRd) in Patients With Newly Diagnosed Multiple Myeloma (NDMM): Analyses of Minimal Residual Disease (MRD) Negativity Dynamics in the Phase 3 IMROZ Study
Authors: Robert Z. Orlowski, Meletios-Athanasios Dimopoulos, Xavier Leleu, et al.
Background: The IMROZ Phase 3 trial demonstrated that transplant-ineligible patients (pts) with NDMM achieved significantly higher progression-free survival (PFS) and MRD negativity (MRD-neg) rates with isatuximab combined with VRd (Isa-VRd) followed by Isa-Rd maintenance, compared to VRd followed by Rd. This analysis explores the dynamics of MRD-negativity and its correlation with treatment outcomes.
Study Overview and Results: The IMROZ trial enrolled 446 pts randomized to Isa-VRd or VRd induction therapy, followed by Isa-Rd or Rd maintenance. Isa-VRd demonstrated higher MRD-neg rates at the end of initiation (50% vs. 41%) and at 36 months (68.6% vs. 50.8%). Sustained MRD-negativity (sustMRD-neg) rates over ≥12, ≥24, and ≥36 months were consistently higher with Isa-VRd (e.g., 36% vs. 13% at ≥24 months). Patients treated with Isa-VRd also exhibited faster and more frequent positive-to-negative MRD conversions during maintenance, with conversion rates increasing over time (e.g., 47% vs. 32% at month 36). MRD-neg status correlated with PFS benefit, with shorter time to MRD-neg in the Isa-VRd arm. Concordance between MRD-neg assessments using next-generation sequencing (NGS) and next-generation flow (NGF) was strong (70–76%).
Relevance: Isa-VRd induction therapy, followed by Isa-Rd maintenance, offers a deeper and more sustained MRD-negativity response compared to VRd alone. These results further validate the role of Isa in achieving superior outcomes in transplant-ineligible NDMM patients and support its use in both induction and maintenance therapy settings.
Link: Abstract 770
Authors: Ghulam Rehman Mohyuddin, Rajshekhar Chakraborty, Katherine Berger, et al.
Background: Advances in myeloma therapies have increased the complexity of treatment decisions, often requiring patients to weigh progression-free survival (PFS) benefits against potential risks and side effects. This survey explored patient preferences in clinical decision-making for treatment scenarios with comparable overall survival (OS) but differing PFS outcomes.
Study Overview and Results: A survey conducted via the HealthTree® Cure Hub included 747 respondents (median age 66, 59% female). Participants were presented with four scenarios involving trade-offs between PFS improvements and treatment-associated risks:
- Triplet vs. Quadruplet Induction: In a scenario comparing 3-drug and 4-drug induction regimens with similar OS but improved PFS in the 4-drug arm (84% vs. 67% at 4 years), 51% chose the 4-drug regimen.
- Consolidation vs. Extended Induction: Participants were offered a choice between a one-time treatment (akin to transplant) with 3 months of side effects and improved 5-year PFS (81% vs. 65%) versus 4 additional months of weekly induction therapy. Preferences were evenly split (47% vs. 53%).
- Single vs. Double Maintenance Therapy: When evaluating maintenance therapy, 84% preferred single-drug maintenance with shorter PFS but fewer risks compared to the 16% who opted for two-drug maintenance.
- Treatment for Relapsed Disease: In a scenario where a treatment improved PFS by 2 months without OS benefit, 93% chose not to receive the therapy.
Relevance: The survey highlights significant variability in patient preferences, influenced by perceived trade-offs between toxicity and PFS benefits. While patients balanced risks and benefits for induction and consolidation therapies, most preferred less toxic maintenance and relapsed disease options when OS was unaffected. These findings underscore the importance of incorporating patient priorities into treatment discussions, clinical trial designs, and drug development strategies to support patient-centered care in multiple myeloma.
Link: Abstract 2281
Proteogenomic Screens Identify Plasma Cell-Specific Vulnerabilities to Halt Oncogenic Transcription in Multiple Myeloma
Authors: Arnold Bolomsky, Smriti Kanangat, Michele Ceribelli, et al.
Background: Oncogenic transcription programs in multiple myeloma (MM) build upon transcriptional networks of normal plasma cells, driven primarily by master transcription factors (TFs) IRF4 and MYC. While these TFs are critical for malignant plasma cell survival, they remain elusive therapeutic targets. This study employed large-scale proteogenomic screens to uncover novel dependencies for MM oncogenic transcription and identify druggable targets.
Study Overview and Results: Using CRISPR-based genome-wide screens in MM cell lines, 645 and 576 essential genes for IRF4 and MYC expression were identified, with 79 genes overlapping between the two. Key findings include:
- Novel Dependencies: Mediator complex gene MED12 emerged as a top dependency, alongside other components of the CDK8 subcomplex (MED13, CCNC) and established targets like SWI/SNF chromatin remodeling genes.
- Drug Synergy: High-throughput drug screens identified significant synergy between CDK8 inhibitors and other compounds targeting IRF4/MYC activity, including IMiDs, SWI/SNF inhibitors, MEK inhibitors, and mTOR inhibitors.
- Precision Targeting: CDK8 inhibitors showed consistent activity across diverse genetic backgrounds, including RAS-mutated cell lines, highlighting their broad therapeutic potential.
Relevance: This meta-analysis consolidates evidence that daratumumab-based quadruplet regimens substantially improve both OS and PFS in TE-NDMM patients compared to triplet regimens. These findings provide strong support for integrating daratumumab into frontline therapy to optimize survival outcomes in this population.
Link: Abstract 763
Importance of Staying Current with New Data
In the ever-evolving field of oncology, it is critical for clinicians to stay abreast of the latest research and clinical developments. The treatment landscape for MM is rapidly changing, with new therapies and combinations being explored and validated through ongoing clinical trials. Integrating new data into clinical practice is essential to providing the best possible care for patients. By staying informed of the latest findings, you have the potential to effectively implement the most up-to-date treatment strategies for your patients with MM.
To further explore the emerging importance of anti-CD38 agents in MM, we encourage you to review an important accredited series, The Cutting Edge of MM: The Evolving Role of CD38-directed Strategies, available now on the Managing Myeloma website. In this fast-paced podcast series featuring rapid-fire discussion of clinical trials and their translation to practice, you’ll learn about the most up-to-date data in CD38-targeting agents in multiple myeloma and new insights into how the CD38 monoclonal antibodies are changing the treatment of myeloma.
The Cutting Edge of MM:
The Evolving Role of CD38-directed Strategies
References
Abstract 364: Mai EK, et al. Impact of Minimal Residual Disease on Progression-Free Survival in Patients with Newly Diagnosed Multiple Myeloma Treated with Isatuximab, Lenalidomide, Bortezomib and Dexamethasone Induction Therapy in the Phase 3 GMMG-HD7 Trial. Blood. 2024;144 (Supplement 1):364. doi: https://doi.org/10.1182/blood-2024-194768
Abstract 487: Bertamini L, et al. Circulating Tumor Cells As a Biomarker to Identify High-Risk Transplant Eligible Myeloma Patients Treated with Bortezomib, Lenalidomide and Dexamethasone with or without Daratumumab during Induction/Consolidation, and Lenalidomide with or without Daratumumab during Maintenance: Results from the Perseus Study. Blood. 2024;144 (Supplement 1):487. doi: https://doi.org/10.1182/blood-2024-199550
Abstract 4755: Lim S-L, et al. Initial Results from the Frailty-Stratified, Randomised Controlled Bayesian Adaptive Trial of Bortezomib Versus Lenalidomide in Transplant Ineligible Myeloma (TI-NDMM) - the FRAIL-M Study (AMaRC 19-01; ALLG MM22). Blood. 2024;144 (Supplement 1):4755. doi: https://doi.org/10.1182/blood-2024-209640
Abstract 769: Goldschmidt H, et al. (2024, December 9). Isatuximab, Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy for Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma: Final Progression-Free Survival Analysis of Part 1 of an Open-Label, Multicenter, Randomized, Phase 3 Trial (GMMG-HD7). [Conference presentation abstract]. American Society of Hematology Annual Meeting and Exposition, San Diego, California. https://ash.confex.com/ash/2024/webprogram/Paper193308.html
Abstract 258: Filho JTDS, et al. Daratumumab-Based Quadruplet Versus Triplet Induction Regimens in Frontline Transplant-Eligible Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis. Blood. 2024;144 (Supplement 1):258. doi: https://doi.org/10.1182/blood-2024-202677
Abstract 250: O'Dwyer M, et al. Increased Expression of the Sialyltransferase Gene ST3GAL1 Predicts Lack of Sustained MRD Negativity and Increased Risk of Progression in Newly Diagnosed, Transplant Eligible Multiple Myeloma Patients in the Maintenance/Observation Phase of Cassiopeia Study. Blood. 2024;144 (Supplement 1):250. doi: https://doi.org/10.1182/blood-2024-193955
Abstract 770: Orlowski RZ, et al. Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone (Isa-VRd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Analyses of Minimal Residual Disease (MRD) Negativity Dynamics in the Phase 3 Imroz Study. Blood. 2024;144 (Supplement 1):770. doi: https://doi.org/10.1182/blood-2024-203818
Abstract 2281: Mohyuddin GR et al. Patient Preferences on Clinical Decision-Making in Myeloma: A 747-Patient Survey. Blood. 2024;144 (Supplement 1):2281. doi: https://doi.org/10.1182/blood-2024-208803
Abstract 763: Bolomsky A, et al. Proteogenomic Screens Identify Plasma Cell Specific Vulnerabilities to Halt Oncogenic Transcription in Multiple Myeloma. Blood. 2024;144 (Supplement 1):763. doi: https://doi.org/10.1182/blood-2024-208485
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