In the fast-paced realm of multiple myeloma (MM) treatment, we're hurtling toward a breakthrough! The race to conquer myeloma is fueled by groundbreaking discoveries in disease biology and advancements in both diagnostics and therapeutics, and the excitement is palpable as we await the unveiling of long-term safety and efficacy data for these promising treatments. The 65th ASH annual meeting features several stand-out sessions on plasma cell dyscrasias that should undoubtedly be blocked off on your agenda.
First, understanding precursor conditions like monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) is crucial as they can signal active myeloma. A significant study, Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM), observed over 40,000 individuals for three-and-a-half years. It suggests revising serum-free light chain (FLC) reference levels, especially in those with preserved kidney function, aiming to decrease false-positive LC-MGUS diagnoses by over 80%. (Abstract entitled "Revised Definition of Free Light Chains in Serum and Light Chain Monoclonal Gammopathy of Undetermined Significance: Results of the Istopmm Study”). Careful monitoring remains the standard-of-care approach for SMM. Importantly, dynamic changes in serum biomarkers are predictive and may help identify patients at higher risk of progression, suggesting that risk stratification should also remain dynamic (“Evaluating the Effect of Evolving Changes in Serum Biomarkers on the Risk of Progression in Smoldering Multiple Myeloma”).
Let’s now delve into the world of bispecific antibodies, in which significant strides have been made since the approval of teclistamab in 2022 and talquetamab in 2023. These treatments have transitioned from clinical trials to real-world application, particularly for relapsed and refractory multiple myeloma (RRMM). Several presentations will share early data on the real-world use of teclistamab in patients who were ineligible for clinical trials ("Teclistamab in Relapsed Refractory Multiple Myeloma: Multi-institutional Real-world Study”and “Real-world Safety and Efficacy of Teclistamab for Patients with Heavily Pretreated Relapsed-refractory Multiple Myeloma”). Encouragingly, patients with poor performance status exhibited favorable responses; however, these studies also underscore the tangible risks of cytopenias and infections.
Another oral session (“Efficacy and Safety of Less Frequent/Lower Intensity Dosing of Talquetamab in Patients with Relapsed/Refractory Multiple Myeloma: Results from the Phase 1/2 MonumenTAL-1 Study”) will explore the efficacy of less frequent or limited-duration treatment with bispecific antibodies. Reassuringly, adjusting the dose intensity of talquetamab appears to maintain efficacy while significantly reducing treatment-related adverse effects.
Managing high-risk MM poses persistent challenges. That being said, the IFM 2018-04 study (“Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone Induction and Consolidation with Tandem Transplant in High-Risk Newly Diagnosed Myeloma Patients: Final Results of the Phase 2 Study IFM 2018-04”) targeting high-risk MM found that a regimen combining daratumumab, carfilzomib, lenalidomide, and dexamethasone, followed by tandem autologous hematopoietic transplants, resulted in high rates of minimal residual disease (MRD) negativity (94% among assessable patients). Notably, the data demonstrated a 24-month progression-free survival (PFS) rate of 87%, a 24-month overall survival (OS) rate of 94%, and progressively deeper responses over a median follow-up of 32 months.
Enhancing prognostic accuracy continues to be of utmost significance. A study comparing two new staging systems (i.e., the Mayo Additive Staging System [MASS] and the Second Revision of the International Staging System [R2-ISS]) with the widely used Revised International Staging System (R-ISS) found that MASS distinctly delineated survival stages in patients with MM, while R2-ISS showed overlap between certain stages (“Performance of Newer Staging Systems for Myeloma in a Contemporary, Large Cohort of Patients in the United States”). In parallel, diffusion-weighted whole-body MRI appears to outperform PET-CT in the assessment of prognostically relevant residual focal lesions post autologous stem cell transplant, suggesting the former may be the more accurate, and therefore preferred, modality (“Sequential Imaging with Diffusion-Weighted Whole-Body MRI (DW-MRI) and PET-CT Identifies Patients at High Risk of Relapse in Multiple Myeloma”).
Optimizing drug dosing to minimize adverse events also remains a critical research priority. Can we do more with less? A nationwide study noted a shift towards once-weekly bortezomib prescriptions; however, over 30% of patients received twice-weekly treatment, potentially contributing to higher rates of neuropathy as well as increased time in clinic and utilization of health care resources (“Retrospective Observational Study on Real-World Bortezomib Prescribing Patterns and Outcomes in Newly Diagnosed Multiple Myeloma”).
Turning attention to chimeric antigen receptor T-cell (CAR-T) therapy in MM, the KarMMa-3 phase III clinical trial showcased idecabtagene vicleucel (ide-cel) therapy. It demonstrated notably extended progression-free survival and deeper responses, with the interim analysis for overall survival pending (“Idecabtagene Vicleucel (ide-cel) Versus Standard (std) Regimens in Patients (pts) with Triple-Class–Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): Updated Analysis from KarMMa-3”). However, despite these strides, prolonged cytopenias remain a concern with CAR-T therapy. This issue has been explored in multiple presentations this year, shedding light on the significance of this complication, its underlying mechanisms, and strategies to manage and treat them “The Effect of Stem Cell Infusion on Immune Effector Cell Associated Hematotoxicity with BCMA CAR T in Multiple Myeloma”).
The use of quad based therapy will likely become the new standard of care for most transplant eligible patients given improved outcomes (take note of LBA-1.)
This round-up is just the beginning. While there are much more fascinating data to glean and discuss from the meeting, we'll leave the rest for you to hear directly from the speakers. The progress in treating these disorders has been substantial, and it's evident that this evolution will only continue, offering an even more promising future.
Drs. Rafae and Al Hadidi indicated no relevant conflicts of interest.
