Tag: Multiple Myeloma

Expert Perspectives on MRD Testing in Multiple Myeloma

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Learn how leading oncologists use MRD to inform treatment strategy and predict relapse risk

Written by: Dr. Gary Simmons & Dr. Kashif Ali
This educational opportunity is sponsored by Adaptive Biotechnologies

Measurable residual disease (MRD) testing has become a valuable tool across the multiple myeloma disease continuum, offering unprecedented insight into disease burden, treatment response, and relapse risk.  NCCN guidelines define MRD negativity as the absence of clonal plasma cells by next generation flow cytometry or next generation sequencing (NGS), at a sensitivity of at least 1 in 10-5 cells, and recommend assessing MRD status after induction, post-transplant, post-consolidation and during maintenance therapy.1  MRD results are shaping key decisions ranging from the role and timing of autologous stem cell transplant to strategies for monitoring and treatment adjustment.  Notably, MRD may be measured from bone marrow or peripheral blood, with data indicating that blood-based testing complements – but does not replace – bone marrow-based testing.2  In this dual-perspective Thought Leader Article, Dr. Gary Simmons (Virginia Oncology Associates) explores how MRD guides transplant decision-making, and Dr. Kashif Ali (Maryland Oncology Hematology) examines the value of blood-based MRD in monitoring response and predicting relapse in multiple myeloma.

The Role of MRD in Informing Autologous Stem Cell Transplant Decision-Making

Despite remarkable advances in multiple myeloma therapy, autologous stem cell transplant still plays a role in the treatment of many patients.  Traditionally, clinical decision-making around transplant was limited to weighing patient-specific factors such as age, comorbidities, and the limited methods that existed to gauge response to induction therapy.  MRD testing provides unprecedented, personalized insight into the induction response achieved by each patient, which directly influences the decision of whether to follow up with transplant.  MRD does not diminish the value of transplant but is rather a stratification tool to identify patients who would derive additional benefit from transplant, from those for which monitoring would suffice.  Several clinical trials including Determination, Perseus and GMMG-HD7 have demonstrated that transplant increases achievement and duration of MRD negativity.3,4,5 Thus, there is a bi-directional relationship in which MRD negativity supports the therapeutic value of transplant, and MRD results help to ensure that patients receive the minimal level of treatment required to achieve optimal outcomes.

In my practice, I evaluate MRD status alongside several variables including patient age, comorbidities, and standard- vs high-risk cytogenetics per the International Myeloma Working Group, when deciding on upfront vs deferred vs no transplant following induction therapy.  In many cases, patient-specific factors significantly influence the weight of MRD results in guiding transplant decision-making.  Notable among these is patient age.  I tend to recommend transplant in young patients, even those who are MRD negative, given data showing a substantially increased disease-free survival6 and improved clinical outcomes in younger fit patients.7  Conversely, there are populations in which MRD negativity would lead me to defer upfront transplant, especially in patients demanding a conservative approach, such as those greater than 75-years-old and/or those with significant comorbidities.  In these patients, MRD negativity often leads me to delay transplant, with the understanding that if/when the patient relapses, there are alternative treatment options to pursue, such as CAR T-cell therapy.  In general, I encourage most standard-risk myeloma patients that if they are MRD negative over the next 5 years, the disease-free is similar with or without transplant; that is encouraging to patients.

As myeloma testing and treatment options rapidly evolve, it’s increasingly important to stay abreast of the gold standard MRD testing options and latest clinical guidelines, to ensure optimal patient outcomes.  We’re always reviewing the options and the depth of MRD testing in our myeloma patients.  At this point, I tend to exclusively use the clonoSEQ assay, as it has a depth of 1×10-6 cells.  We know that depth of MRD and duration of MRD are related to improved clinical outcomes.  Therefore, despite the clinical trials using a MRD cutoff of 1×10-5 cells, we prefer the increased sensitivity offered by clonoSEQ of 1×10-6, for optimal assurance that negativity accurately identifies patients who are truly “MRD negative”.  While this piece is focused on the value of MRD in guiding transplant decisions, it’s worth nothing that assay depth and sensitivity also come to be very important post-stem cell transplant – as MRD negativity after a few years of maintenance can be used to determine if patients can stop maintenance therapy.  In the MASTER trial, MRD status and cytogenetics could predict risk of relapse in two years, highlighting the utility of MRD to help guide continuing maintenance or identify patients who may be able to stop.8 Altogether, these insights underscore how MRD drives personalized care from transplant decision-making to maintenance, ensuring optimal outcomes for patients with multiple myeloma.

The Role of Peripheral Blood-Based MRD Assessment in Monitoring Disease Response

While bone marrow evaluation remains the standard method for MRD assessment, peripheral blood-based MRD testing is an increasingly valuable approach for guiding treatment decisions and monitoring response in multiple myeloma.  MRD negativity by both peripheral blood and bone marrow is associated with an improved progression-free survival (PFS) compared to one modality alone, underscoring their complementary nature.2 Notably, peripheral blood MRD positivity has a 100% positive predictive value of bone marrow MRD positivity.10  Understandably, the negative predictive value of peripheral blood MRD is lower, demonstrating that peripheral blood MRD negativity does not exclude bone marrow disease.11 Therefore, in my practice, blood-based MRD positivity does not prompt confirmatory bone marrow testing, whereas blood-based MRD negativity should be confirmed by bone marrow biopsy, if the goal is to alter treatment.

Confidence in blood-based MRD results is influenced by several factors, including myeloma disease biology and timing.  Patients who present with circulating plasma cells at diagnosis have more aggressive disease and worse outcomes.12,13,14 In the post-transplant setting, studies have shown that patients negative for circulating DNA at three months post-transplant had significantly better PFS (84 vs 31 months) with a positive predictive value of 93.3%.15,16 Those who achieve a complete response will have no detectable plasma cells, as opposed to those who have a relapse, and blood-based MRD testing opens the door to uncover previously undetectable levels of circulating plasma cells.  There are also situations, such as patients with patchy bone marrow involvement or extramedullary disease17, in which MRD assessment of blood is more informative and bone marrow testing alone would be insufficient.18

Timing is another important consideration.  The concordance between bone marrow and blood-based MRD is lowest early after transplant and increases with time, suggesting enhanced reliability of peripheral blood MRD during maintenance.19 Peripheral blood MRD is well suited for longitudinal monitoring post-induction, post-transplant, and especially during maintenance in situations where repeated bone marrow biopsies would not be feasible.10,20 I routinely incorporate peripheral blood MRD testing at these timepoints and find it to be a less invasive alternative that enables more frequent assessment of patients who are reluctant to undergo repeat bone marrow biopsies.20,21 When the goal is to continue maintenance treatment, I utilize serial peripheral blood MRD testing and myeloma-related lab tests.  In these scenarios, I would only check a bone marrow biopsy if the goal were to discontinue or de-escalate treatment.  In the case of a blood-based MRD positivity, given the high concordance between peripheral blood and bone marrow, I would not mandate that an unwilling patient also undergo bone marrow-based MRD.  In my practice and outside of a clinical trial, most patients with blood-based MRD positivity, after hearing about data on concordance, decide not to undergo bone marrow confirmation although I do offer it to them.  Together, the expanding clinical utility of MRD assessment by blood and bone marrow underscores its value for guiding treatment decisions, monitoring response and prognosticating outcomes in multiple myeloma.

References:

  1. National Comprehensive Cancer Network. Multiple Myeloma. Updated 2025-11-26.
  2. Langerhorst P, Noori S, Zajec M, et al. Multiple Myeloma Minimal Residual Disease Detection: Targeted Mass Spectrometry in Blood vs Next-Generation Sequencing in Bone Marrow. Clinical Chemistry.  2021;67(12):1689-1698.  doi:10.1093/clinchem/hvab187.
  3. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma.  The New England Journal of Medicine.  2022;387(2):132–147. doi:10.1056/NEJMoa2204925.
  4. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. The New England Journal of Medicine.  2024;390(4):301-313.   doi:10.1056/NEJMoa2312054.
  5. Goldschmidt H, Bertch U, Pozek E, et al. 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). Blood.  2024;144(Supplement 1): 769.  doi: https://doi.org/10.1182/blood-2024-193308.
  6. Ebraheem M, Kumar SK, Dispenzieri A, et al. Deepening Responses after Upfront Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma in the Era of Novel Agent Induction Therapy. Transplant Cell Ther.  2022;28(11):760.e1-760.e5.  doi:10.1016/j.jtct.2022.07.030.
  7. Liu J, Yan W, Fan H, et al. Clinical Benefit of Autologous Stem Cell Transplantation for Patients with Multiple Myeloma Achieving Undetectable Minimal Residual Disease after Induction Treatment. Cancer Res Commun.  2023;3(9):1770-1780.  doi:10.1158/2767-9764.CRC-23-0185.
  8. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. J Clin Oncol.  2022;40(25):2901-2912.  doi:10.1200/JCO.21.01935.
  9. Terpos E, Malandrakis P, Ntanasis-Stathopoulos I, et al. Sustained bone marrow and imaging MRD negativity for 3 years drives discontinuation of maintenance post-ASCT in myeloma. Blood.  2025;145(20):2353-2360.  doi:10.1182/blood.2024027686.
  10. Lasa M, Notarfranchi L, Agullo C, et al. Minimally Invasive Assessment of Peripheral Residual Disease During Maintenance or Observation in Transplant-Eligible Patients With Multiple Myeloma. J Clin Oncol.  2025;43(2):125-132.  doi:10.1200/JCO.24.00635.
  11. Chandhok NS, Sekeres MA. Measurable residual disease in hematologic malignancies: a biomarker in search of a standard. EClinicalMedicine.  2025;86:103348.  doi:10.1016/j.eclinm.2025.103348.
  12. Bertamini L, Oliva S, Rota-Scalabrini D, et al. High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol.  2022;40(27):3120-3131.  doi:10.1200/JCO.21.01393.
  13. Li Q, Ai L, Zuo L, et al. Circulating plasma cells as a predictive biomarker in Multiple myeloma: an updated systematic review and meta-analysis. Ann Med.  2024;56(1):2338604.  doi:10.1080/07853890.2024.2338604.
  14. Li J, Wang N, Tesfaluul N, Gao X, Liu S, Yue B. Prognostic value of circulating plasma cells in patients with multiple myeloma: A meta-analysis. PLoS One.  2017;12(7):e0181447.  doi:10.1371/journal.pone.0181447.
  15. Dhakal B, Sharma S, Balcioglu M, et al. Assessment of Molecular Residual Disease Using Circulating Tumor DNA to Identify Multiple Myeloma Patients at High Risk of Relapse. Frontiers in Oncology.  2022;12:786451.  doi:10.3389/fonc.2022.786451.
  16. Dhakal B, Sharma S, Shchegrova S, et al. Personalized, ctDNA analysis to detect minimal residual disease and identify patients at high risk of relapse with multiple myeloma. Journal of Clinical Oncology.  2021;39(Suppl 15):8029.  doi:10.1200/JCO.2021.39.15_suppl.8029.
  17. van de Donk NWCJ, Pawlyn C, Yong KL. Multiple myeloma. Lancet.  2021;397(10272):410-427.  doi:10.1016/S0140-6736(21)00135-5.
  18. Manasanch EE. What to do with minimal residual disease testing in myeloma. Hematology Am Soc Hematol Educ Program.  2019;2019(1):137-141.  doi:10.1182/hematology.2019000080.
  19. Kubicki T, Dytfeld D, Barnidge D, et al. Mass spectrometry-based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma. Blood.  2024;144(9):955-963.  doi:10.1182/blood.2024024041.
  20. Wijnands C, Noori S, Donk NWCJV, VanDuijn MM, Jacobs JFM. Advances in minimal residual disease monitoring in multiple myeloma. Crit Rev Clin Lab Sci.  2023;60(7):518-534.  doi:10.1080/10408363.2023.2209652.
  21. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group Consensus Criteria for Response and Minimal Residual Disease Assessment in Multiple Myeloma. Lancet Oncology.  2016;17(8):e328-e346.  doi:10.1016/S1470-2045(16)30206-6.

LYNOZYFIC® (Linvoseltamab-gcpt)

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The FDA on July 2, 2025, granted accelerated approval to LYNOZYFIC®, a bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adults with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. LYNOZYFIC® is a product of Regeneron Pharmaceuticals, Inc.

Late Breaking Abstract – ASH 2025: Teclistamab Plus Daratumumab Redefines Outcomes in Early Relapsed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.

Relapsed or Refractory Multiple Myeloma (RRMM) remains a complex clinical challenge, even as therapeutic options continue to expand. Progressive immune dysfunction, cumulative treatment toxicity, and repeated relapses often limit the durability of benefit with conventional salvage regimens. Moreover, the increasingly effective frontline landscape has raised the bar for second- and later-line therapy, leaving fewer highly active, well-tolerated options for patients early in relapse.

BCMA-directed therapies have transformed expectations in advanced disease, particularly with CAR-T cell approaches demonstrating deep responses and prolonged disease control. However, manufacturing timelines, resource intensity, and patient fitness requirements limit universal access. Consequently, there is a critical need for off-the-shelf, immunotherapy-based regimens that deliver CAR-T–like efficacy with broader applicability.

Teclistamab (TECVAYLI®), a bispecific T-cell engaging antibody targeting CD3 on T cells and BCMA on myeloma cells, has previously shown meaningful and durable responses in heavily pretreated RRMM. Daratumumab (DARZALEX®), an anti-CD38 monoclonal antibody, remains a foundational therapy across all disease stages, offering both direct antimyeloma activity and immune modulation. Preclinical and clinical observations suggest that Daratumumab-mediated depletion of immunosuppressive cellular subsets enhances T-cell fitness, providing a strong biological rationale for combination with BCMA-directed bispecific antibodies.

The MajesTEC-3 trial was designed to test whether combining Teclistamab with Daratumumab could improve outcomes compared with established Daratumumab-based regimens in patients with earlier-line RRMM.

Study Design and Patient Population

MajesTEC-3 (NCT05083169) is an ongoing, randomized, open-label, Phase 3 trial conducted across 150 centers in 20 countries. Eligible patients had relapsed or refractory multiple myeloma after one to three prior lines of therapy, including prior exposure to both an immunomodulatory agent and a proteasome inhibitor. Patients with prior BCMA-directed therapy or anti-CD38–refractory disease were excluded.

A total of 587 patients were randomized 1:1 to receive either:

  • Teclistamab plus subcutaneous Daratumumab, or
  • Investigator’s choice of standard Daratumumab-based therapy, consisting of Daratumumab and Dexamethasone combined with either Pomalidomide (DPd) or Bortezomib (DVd).

Randomization was stratified by choice of control regimen, International Staging System stage, prior exposure to anti-CD38 antibodies, and number of prior treatment lines. The median patient age was approximately 64–65 years, with a median of two prior lines of therapy. Importantly, more than one-third of enrolled patients had high-risk cytogenetic features, reflecting a clinically relevant population.

Treatment Administration: A Patient-Centered, Steroid-Sparing Approach

Patients in the investigational arm received subcutaneous Teclistamab using a step-up dosing strategy, followed by a progressively extended dosing interval, transitioning to monthly administration from cycle 7 onward. Daratumumab was administered subcutaneously according to its approved schedule.

Notably, the regimen became steroid-free after cycle 1, an important quality-of-life consideration for patients requiring long-term therapy. Infection prophylaxis, immunoglobulin supplementation, and monitoring of IgG levels were mandated, with protocol amendments reinforcing best practices for infection prevention during BCMA-directed therapy. The Primary end point was Progression-Free Survival (PFS), as assessed by an Independent Review Committee.

Primary Endpoint: Striking Improvement in Progression-Free Survival

At a median follow-up of 34.5 months, Teclistamab plus Daratumumab demonstrated a highly significant and clinically transformative improvement in PFS compared with DPd or DVd.

  • The estimated 36-month PFS rate was 83.4% with Teclistamab–Daratumumab versus 29.7% with standard Daratumumab-based therapy.
  • This translated into an 83% reduction in the risk of disease progression or death (HR 0.17; 95% CI, 0.12–0.23; P<0.001).
  • The prespecified boundary for superiority was crossed at the first interim analysis.

Importantly, the PFS advantage was consistent across all prespecified and clinically relevant subgroups, including patients with high-risk cytogenetics and those treated in earlier versus later relapse.

Depth and Durability of Response

Beyond delaying progression, Teclistamab–Daratumumab induced exceptionally deep and durable responses:

  • Complete Response or better was achieved in 81.8% of patients receiving the combination, compared with 32.1% in the control arm.
  • Overall Response Rates were also higher (89.0% vs. 75.3%).
  • Rates of Minimal Residual Disease negativity at a sensitivity of 10⁻⁵ were more than threefold higher with Teclistamab–Daratumumab (58.4% vs. 17.1%).

Responses occurred rapidly, with a median time to first response of just over one month, and deepened over time. At three years, nearly 90% of responders in the investigational arm remained in response, suggesting the emergence of a plateau in disease control.

Overall Survival and Symptom Outcomes

Although follow-up for overall survival continues, early analyses favored Teclistamab–Daratumumab, with a high proportion of patients remaining alive beyond two years. Improvements were also observed in time to worsening of myeloma-related symptoms, underscoring the regimen’s clinical and patient-reported benefit.

Safety and Tolerability: Manageable With Established Protocols

The safety profile of Teclistamab–Daratumumab was consistent with the known risks of BCMA-directed bispecific antibodies and Daratumumab. Serious adverse events occurred more frequently in the investigational arm, driven primarily by cytopenias and infections.

  • Cytokine Release Syndrome was common but predominantly low grade and largely confined to the step-up dosing period.
  • Importantly, the incidence of CRS was lower than that reported with Teclistamab monotherapy, supporting a favorable interaction between the two agents.
  • Fatal adverse events were infrequent and decreased following protocol-reinforced infection-prevention strategies.

The trial highlights the critical importance of early immunoglobulin replacement, antimicrobial prophylaxis, and vigilant monitoring, now well established in guidelines for patients receiving BCMA-targeted therapies.

Context Within the Evolving Treatment Landscape

The magnitude of benefit observed with Teclistamab–Daratumumab is particularly notable given the strong performance of the control arm, which exceeded historical expectations from prior DPd and DVd studies. Even in this context, the combination delivered superior depth, durability, and consistency of response. As CAR-T therapies move earlier in the disease course, off-the-shelf immunotherapies such as Teclistamab–Daratumumab offer a complementary strategy, one that combines accessibility, scalability, and sustained disease control. Monthly dosing after the initial treatment phase further supports feasibility in community oncology settings.

Clinical Implications

The MajesTEC-3 trial establishes Teclistamab plus Daratumumab as a highly effective immunotherapy-based option for patients with early relapsed multiple myeloma, delivering unprecedented Progression-Free Survival and deep molecular responses without the logistical barriers of cellular therapy. With appropriate supportive care and infection-prevention strategies, this regimen may meaningfully reset expectations for long-term disease control in a population historically characterized by inevitable relapse.

Conclusion

In patients with multiple myeloma who had received one to three prior lines of therapy, Teclistamab combined with Daratumumab significantly outperformed established Daratumumab-based regimens, offering durable disease control, deep responses, and a manageable safety profile. These findings position Teclistamab–Daratumumab as a potential new standard in earlier-line Relapsed or Refractory Multiple Myeloma, and signal continued progress toward prolonged survival in this traditionally incurable disease.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma. Costa LJ,  Bahlis NJ, Perrot A, et al. for the MajesTEC-3 Trial Investigators. N Engl J Med. Published December 9, 2025. DOI: 10.1056/NEJMoa2514663

 

 

 

 

FDA Approves BLENREP® Combination for Relapsed or Refractory Multiple Myeloma

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SUMMARY: The FDA on October 23, 2025, approved Belantamab mafodotin-blmf (BLENREP®), a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor conjugate, with Bortezomib and Dexamethasone for adults with Relapsed or Refractory Multiple Myeloma (RRMM) who have received at least two prior lines of therapy, including a Proteasome Inhibitor and an immunomodulatory agent.

Context and Rationale

Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.

Patients with newly diagnosed multiple myeloma often receive triplet and quadruplet regimens that incorporate Proteasome Inhibitors, immunomodulators, and anti-CD38 antibodies as first line therapy, as these regimens are associated with prolonged Progression Free Survival (PFS) and Overall Survival (OS). However, most patients relapse and frontline use of Lenalidomide therapy has increased the number of patients with Lenalidomide-refractory disease at the time of the first relapse. New novel combinations are needed for patients who have relapsed or refractory myeloma, after disease progression during frontline therapy.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and multiple myeloma. B-Cell Maturation Antigen is therefore an established target in myeloma.

Belantamab Mafodotin: A Multimodal Antibody-Drug Conjugate

Belantamab mafodotin is a BCMA-targeting antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. Auristatin F induces cytotoxicity, Antibody-Dependent Cellular Cytotoxicity and phagocytosis, and induction of immunogenic cell death. Early-phase data demonstrated sustained, deep responses in heavily pretreated populations, suggesting potential benefit when used earlier in the disease course in combination with established backbones.

Study Design: DREAMM-7

The Phase III DREAMM-7 trial (DRiving Excellence in Approaches to Multiple Myeloma) was an open-label, multicenter, randomized study comparing Belantamab mafodotin plus Bortezomib and Dexamethasone (BVd) versus Daratumumab plus Bortezomib and Dexamethasone (DVd) in patients with RRMM who had received at least one prior line of therapy. A total of 494 patients were randomized 1:1 to BVd (N=243) or DVd (N=251). Baseline characteristics were well balanced between arms: approximately half of participants (51%) had received one prior line of therapy, 52% had prior Lenalidomide exposure, 34% were Lenalidomide-refractory, and 28% harbored high-risk cytogenetic abnormalities. The Primary endpoint was PFS as assessed by an Independent Review Committee. Key Secondary endpoints included OS, Duration of Response (DOR), Minimal Residual Disease (MRD) negativity by Next-Generation Sequencing, Overall Response Rate (ORR), and safety.

Primary Analysis: Robust Progression-Free Survival Benefit

At a median follow-up of 28.2 months, the trial met its Primary endpoint. The median PFS was 36.6 months (95% CI, 28.4–not reached) in the BVd arm versus 13.4 months (95% CI, 11.1–17.5) in the DVd arm, corresponding to a 59% reduction in risk of progression or death (HR=0.41; 95% CI, 0.31–0.53; P<0.00001).

BVd achieved higher rates of Complete Response or better with MRD negativity (25% vs 10%) and a more favorable DOR distribution (P<0.001). Median DOR was 35.6 months with BVd compared to 17.8 months with DVd. Treatment benefits with BVd were preserved even after subsequent therapy (PFS2 HR= 0.56; 95% CI, 0.41–0.76). Although median OS was not reached at this time point, a strong trend favored BVd (HR=0.57; 95% CI, 0.40–0.80).

Second Interim Analysis: Statistically Significant OS Advantage

At the second interim analysis, conducted at a median follow-up of 39.4 months, BVd demonstrated a 42% reduction in the risk of death versus DVd (HR=0.58; 95% CI, 0.43–0.79; P=0.00023). Median OS was not reached in either arm, but projected estimates were striking, 84 months for BVd compared with 51 months for DVd. The 3-year OS rate was 74% with BVd versus 60% with DVd, with survival separation evident as early as 4 months and sustained over time.

Subgroup Analysis and FDA Approval

In the subset of patients who had received two or more prior lines of therapy (the population used for regulatory evaluation, N=108 in the BVd and N=109 in the DVd groups), BVd maintained substantial efficacy. Median PFS was 31.3 months (95% CI, 23.5–NR) compared with 10.4 months (95% CI, 7.0–13.4) with DVd (HR, 0.31; 95% CI, 0.21–0.47). Median OS was not reached with BVd and 35.7 months with DVd (HR, 0.49; 95% CI, 0.32–0.76), representing a 51% reduction in risk of death.

Depth of Response and MRD Negativity

The BVd regimen achieved statistically significant improvements in MRD negativity, with rates more than 2.5 times higher than those observed with DVd (P<0.00001). Superior depth and durability of response were reflected in all major efficacy endpoints, including DOR and PFS2, underscoring the potential for more sustained disease control with the Belantamab-containing triplet.

Safety Profile and Ocular Events

Adverse events were consistent with prior experience for the individual agents. Grade ≥3 thrombocytopenia occurred in 56% of patients receiving BVd versus 35% with DVd; grade ≥3 anemia and neutropenia were comparable between groups. Ocular events, a known risk associated with Belantamab mafodotin, were manageable with dose modifications and rarely led to discontinuation. Only 10% of patients in the BVd arm discontinued therapy due to ocular toxicity.

Clinical Implications

The DREAMM-7 results represent the first head-to-head Phase III evidence of a statistically significant OS advantage for a BCMA-targeting therapy in RRMM compared with a Daratumumab-based regimen. The combination of Belantamab mafodotin with Bortezomib and Dexamethasone delivered a tripling of median PFS, a clinically meaningful OS benefit, and deeper MRD-negative responses, establishing a compelling new benchmark for patients experiencing their first relapse or later. These data reinforcing the OS benefit and may solidify BVd as a new standard of care for relapsed or refractory multiple myeloma.

Belantamab Mafodotin, Bortezomib, and Dexamethasone Vs Daratumumab, Bortezomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Overall Survival Analysis and Updated Efficacy Outcomes of the Phase 3 Dreamm-7 Trial. Hungria V, Robak P, Hus M, et al. Blood (2024) 144 (Supplement 1): 772. https://doi.org/10.1182/blood-2024-200336

Innovating Multiple Myeloma Care: IRAKLIA Confirms On-Body Injector for Subcutaneous Isatuximab as a Safe, Effective Alternative to IV Delivery

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity.

Newly diagnosed multiple myeloma patients are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd), after the SWOG S0777 trial established this regimen as a standard first-line treatment, regardless of their transplantation eligibility. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Isatuximab-irfc (SARCLISA®) is a CD38-targeting IgG1monoclonal antibody, similar to Daratumumab (DARZALEX®), but unlike Daratumumab, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from Daratumumab allows use of Isatuximab in cases when Daratumumab fails.

With prevalence of multiple myeloma expected to climb further, disparities in care delivery remain a concern, often linked to treatment access, infusion-center capacity, and patient convenience. Advances in drug delivery technology, particularly subcutaneous (SC) administration, offer an opportunity to bridge these gaps. Compared with intravenous (IV) therapy, SC approaches can shorten administration time, improve comfort, and reduce healthcare resource demands.

However, conventional SC delivery of large-volume biologics can be challenging, often requiring high manual pressure over several minutes and the use of larger needles, both of which may cause discomfort and anxiety for patients and increase the physical burden for nurses. The IRAKLIA trial is the first Phase III study in multiple myeloma to evaluate an On-Body Injector (OBI) for delivering SC Isatuximab (Isa) in combination with Pomalidomide and Dexamethasone (Pd) in Relapsed/Refractory MM (RRMM).

Study Design
IRAKLIA was a global, open-label, randomized, noninferiority Phase III trial enrolling adults with 1 or more prior lines of therapy, including Lenalidomide and a Proteasome Inhibitor. A total of 531 patients were randomized (OBI, N=263; IV, N=268). Participants were assigned 1:1 to receive either:

  • Isa OBI: 1,400 mg SC via an OBI device (Enable Injections, Inc.)
  • Isa IV: 10 mg/kg IV infusion once weekly during cycle 1, then on days 1 and 15 of subsequent cycles.

Both arms received Pomalidomide 4 mg orally, days 1–21 and Dexamethasone 40 mg orally weekly and 20 mg if 75 years or older. Baseline characteristics were generally balanced, although the OBI group had slightly more patients ≥75 years, with higher rates of advanced disease features (soft-tissue plasmacytomas, ISS stage III, reduced renal function, and Lenalidomide-refractory status).

Key coPrimary endpoints were Overall Response Rate (ORR) and steady-state trough concentration (Ctrough) at cycle 6 day 1. The trial also assessed ≥Very Good Partial Response (≥VGPR) rate, pharmacokinetics at week 4, incidence of Infusion-related Reactions (IRs), and patient-reported satisfaction.

Efficacy after 12 Month Median Follow-Up

  • ORR: 71.1% (OBI) vs 70.5% (IV); noninferiority demonstrated (RR 1.008; 95% CI, 0.903–1.126).
  • Ctrough: Higher with OBI (geometric mean ratio 1.532; 90% CI, 1.316–1.784), meeting noninferiority criteria.
  • ≥VGPR rate: Comparable-46.4% (OBI) vs 45.9% (IV).
  • Results were consistent across most subgroups, with a lower response in patients ≥75 years in the OBI arm, likely due to baseline disease imbalances.

Safety

  • Grade ≥3 treatment-emergent adverse events occurred in 81.7% (OBI) vs 76.1% (IV).
  • Infusion-related Reactions were dramatically reduced with OBI (1.5%) compared with IV (25%).
  • Injection site reactions with OBI were rare (0.4%, all grade 1–2).
  • No unexpected safety signals emerged; the profile aligned with prior Isa studies.

Patient Experience

  • Satisfaction rates were higher with OBI (70.0%) than IV (53.4%).
  • Nearly all OBI doses (99.9%) were completed without interruption.

Clinical Implications

Reduced Infusion Reactions and Improved Workflow
The marked drop in Infusion-related Reactions incidence with OBI is likely related to slower systemic absorption from interstitial tissue compared with rapid IV exposure. This improvement not only enhances patient comfort but also reduces infusion chair time and the need for monitoring, potentially enabling at-home administration by healthcare professionals in select patients.

Efficiency for Nursing Staff
OBI eliminates the sustained manual pressure required for large-volume SC pushes and replaces large-bore needles with a smaller, hidden 30-gauge needle. This reduces nurse fatigue, frees up clinical resources, and may lower patient anxiety during injections.

Potential for Home Administration and Broader Access
Given the convenience and safety profile, OBI administration could be extended beyond the infusion center. This aligns with ongoing efforts to decentralize cancer care, expand access to anti-CD38 therapy, and improve treatment adherence in multiple myeloma.

Future Directions
Isa OBI is being further evaluated in other multiple myeloma settings, including:

  • IZALCO: Isa-Kd in RRMM (NCT05704049)
  • IsaSoCut: Isa-VRd in transplant-ineligible NDMM (NCT05889221)
  • GMMG-HD8: Isa-VRd in NDMM (NCT05804032)

Upcoming analyses from IRAKLIA will also explore the feasibility of at-home dosing.

Conclusion
The Phase III IRAKLIA trial demonstrates that Isa SC delivered via OBI is noninferior to IV administration in RRMM, with equivalent efficacy, favorable pharmacokinetics, and a significantly lower Infusion-related reaction rate. This hands-free delivery method offers a practical, patient-preferred, and resource-efficient alternative to standard IV infusion, potentially transforming anti-CD38 therapy administration in multiple myeloma.

Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study. Ailawadhi S,  Špička I, Spencer A, et al. J Clin Oncol. 2025;43:2527-2537.

 

 

Practice-Changing Insights in Myeloma Prevention: DARZALEX® Shows Landmark Results in High-Risk Smoldering Myeloma (AQUILA Trial)

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Multiple Myeloma evolves from a precursor stage called Monoclonal Gammopathy of Unknown Significance (MGUS) to MM.

Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. The risk of MGUS transforming into MM is approximately 1% per year. Smoldering Multiple Myeloma or asymptomatic MM is a precursor to MM and is characterized by at least 10% plasma cells in the bone marrow or M-spike of at least 3 g/dl, or both, but these patients have no evidence of active symptomatic Myeloma with associated end-organ damage such as hypercalcemia, renal insufficiency, anemia or bone lesions. Even though only 10% of patients with SMM progress to MM annually, over 50% of the SMM patients with high risk features will progress to MM in the first 2 years.

The current recommendations for those with SMM are periodic monitoring and treatment intervention only when disease progresses to MM. SMM patients with high risk features include those with at least 10% plasma cells in the bone marrow, a Monoclonal component (IgG monoclonal spike of at least 3 g/dL, IgA M-spike of at least 2 g/dL or a urinary Bence Jones protein level of more than 1 g per 24 hours) or only one of the above two criteria plus at least 95% abnormal plasma cells in the bone marrow, with a reciprocal decrease in one or two uninvolved immunoglobulins of more than 25%, compared to normal values. Immunoparesis describes the reduction of normal/polyclonal immunoglobulin levels and is commonly seen in conditions such as MM, SMM, and MGUS. This phenomenon involves a decline in immunoglobulins not associated with the malignant clone-for instance, in IgG-type myeloma, levels of IgA and IgM are typically decreased. The severity of immunoparesis at diagnosis serves as an independent prognostic indicator in newly diagnosed multiple myeloma. Patients presenting with lower levels of uninvolved immunoglobulins tend to experience shorter Progression-Free Survival (PFS) and Overall Survival (OS).

High-risk SMM has long posed a therapeutic dilemma—patients face a substantial risk of progression to symptomatic disease, yet no standard treatment has been approved. Traditionally, observation has remained the mainstay approach, despite the documented risk of end-organ damage. Daratumumab (DARZALEX®), a CD38-targeting monoclonal antibody already approved for multiple myeloma, has now been evaluated in this pre-malignant population through the pivotal Phase 3 AQUILA trial.

Study Design: The AQUILA Trial
AQUILA was a global, multicenter, open-label, randomized Phase 3 study, evaluating the efficacy of subcutaneous Daratumumab monotherapy versus active monitoring in patients with high-risk SMM. Conducted across 124 sites in 23 countries, the trial enrolled 390 patients, randomized 1:1 to receive either subcutaneous Daratumumab 1800 mg with recombinant Hyaluronidase PH20 weekly during cycles 1–2, biweekly during cycles 3–6, and monthly thereafter for 39 cycles for 36 months, or until disease progression (N=194), or active monitoring (N=196).

Eligibility criteria included:

  • 10% or more clonal plasma cells in bone marrow
  • At least one high-risk feature, such as:
    • Serum M-protein 30 g/L or more
    • IgA subtype
    • Immunoparesis (2 or more uninvolved Ig isotypes)
    • FLC ratio between 8 and 100
    • Clonal plasma cells more than 50% but less than 60%

The Primary end point was Progression-Free Survival (PFS) defined as progression to active multiple myeloma as assessed by an Independent Review Committee in accordance with International Myeloma Working Group (IMWG) diagnostic criteria.

Efficacy Outcomes
After a median follow-up of 65.2 months, results demonstrated a clear and significant benefit for Daratumumab over observation:

  • Progression-Free Survival (PFS):
    • 5-year PFS: 63.1% with Daratumumab vs 40.8% with active monitoring
    • Hazard ratio (HR): 0.49 (95% CI: 0.36–0.67; P<0.001)
  • Overall Survival (OS):
    • 5-year OS: 93.0% with Daratumumab vs 86.9% with active monitoring
    • HR for death: 0.52 (95% CI: 0.27–0.98)

These results support a 51% reduction in risk of progression to active multiple myeloma or death with early Daratumumab intervention.

Safety Profile
Daratumumab was well tolerated:

  • Grade 3–4 hypertension was the most frequent serious AE (5.7%)
  • Treatment discontinuation due to AEs occurred in only 5.7%
  • No new safety signals were observed
  • Quality of life was maintained throughout treatment and comparable to active monitoring

Clinical Interpretation
The AQUILA trial provides the strongest evidence to date supporting early therapeutic intervention in high-risk SMM. Unlike prior trials (e.g., QuiRedex, ECOG E3A06), which demonstrated benefit with Lenalidomide-based regimens but did not lead to regulatory approval, AQUILA offers compelling long-term survival and disease control data using a well-tolerated, single-agent regimen. Importantly, patient-reported outcomes indicated no decline in quality of life, reinforcing the feasibility of early intervention.

Context & Historical Comparison

  • In QuiRedex (Rd vs monitoring), median time to progression was prolonged (9.5 vs 2.1 years), but approval was not pursued
  • ECOG E3A06 (Lenalidomide vs monitoring) showed improved PFS but no OS benefit
  • AQUILA uniquely demonstrates both PFS and OS advantages with a favorable safety profile, positioning Daratumumab as a potential new standard for early treatment of high-risk SMM

Conclusion
The AQUILA study marks a paradigm shift in the management of high-risk Smoldering Multiple Myeloma. Subcutaneous Daratumumab monotherapy not only halved the risk of progression or death but also preserved quality of life, supporting its consideration as the first active treatment option for this high-risk population. Oncologists should engage in shared decision-making with high-risk SMM patients regarding early therapeutic intervention, particularly in the context of these compelling new data.

Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma. Dimopoulos MA, Voorhees PM,  Schjesvold F, et al. for the AQUILA Investigators. N Engl J Med 2025;392:1777-1788