Recent developments and key clinical trial data suggest that the role of CD38-targeted therapies is continuing to evolve, and has the potential to reshape clinical practice even further. New combinations and administration methods not only offer improved convenience and reduced infusion times, but also have the potential for deeper responses and improved disease control among previously challenging patient populations.

For clinicians treating patients with multiple myeloma, remaining current with evolving therapeutic strategies and new advancements is crucial, as emerging data may offer new strategies to enhance patient outcomes and refine treatment decisions, particularly for those with high-risk disease. The following discussion will explore the most recent advances, including key trial results and newly approved regimens, and will provide insights into how these developments may be applied in everyday clinical practice.

Advancing Frontline Care with Isatuximab: New Data and Insights
Isatuximab, an anti-CD38 monoclonal antibody, has emerged as a powerful therapeutic option, particularly for newly diagnosed and transplant-ineligible patients.4,5 One of the most significant studies showcasing isatuximab's potential is the phase 3 BENEFIT trial5 which evaluated the combination of isatuximab with lenalidomide, dexamethasone, and weekly bortezomib (Isa-VRd) in transplant-ineligible patients with newly diagnosed multiple myeloma. The results demonstrated that Isa-VRd led to markedly higher minimal residual disease (MRD) negativity rates (53% versus 26% with IsaRd) and superior complete response (CR) rates. These findings support Isa-VRd as a new standard of care for older or more frail patients who are not candidates for stem cell transplant, providing a deeper and more durable response with manageable toxicity.5,7

The real-world applicability of isatuximab has also been highlighted in retrospective studies, such as an Italian multicenter analysis, which evaluated Isa-Kd (isatuximab plus carfilzomib and dexamethasone) in relapsed/refractory multiple myeloma.6 With an overall response rate (ORR) of 85% and 1-year progression-free survival (PFS) of 72%, the study confirmed the effectiveness of isatuximab in difficult-to-treat populations, including those previously exposed to lenalidomide.6 Notably, in patients receiving Isa-Kd as second-line therapy, the ORR rose to 88%, and the 1-year PFS was 92%, further supporting the efficacy of isatuximab in relapsed settings.6

The September 20, 2024, FDA approval of isatuximab in combination with VRd for transplant-ineligible newly diagnosed patients is a milestone for the multiple myeloma community.7 This approval was driven by the robust data from the IKEMA trial, which evaluated the addition of isatuximab to the standard VRd regimen. In the IKEMA trial, isatuximab demonstrated a significant improvement in PFS compared to VRd alone, with a median PFS of 41.7 months versus 29.6 months in the control group.7 This difference underscores the potential for isatuximab to offer more durable responses in patients who are not candidates for stem cell transplantation.

Moreover, MRD negativity rates were also notably higher in the isatuximab arm, with a 29.6% MRD negativity rate compared to 13% in the control group, reflecting a deeper and more sustained response to treatment.7 Importantly, the safety profile of isatuximab was consistent with previous studies, and no new safety concerns were identified, supporting its potential as a manageable therapeutic option, even for frail patients.7

Given these findings, the role of isatuximab in frontline treatment for multiple myeloma is expected to expand, particularly for patients who may benefit from deeper responses earlier in their disease course. For community hematologists/oncologists, isatuximab should now be viewed as a highly valuable option, particularly in patients with high-risk features or those who may require a regimen with more potent and durable outcomes.5,7 The addition of isatuximab to VRd not only enhances PFS but also offers the potential for improved long-term disease control in this challenging population.7

Expanding Treatment Opportunities with Daratumumab
Daratumumab, another CD38-targeting monoclonal antibody, continues to play a pivotal role across multiple myeloma treatment paradigms.8 In newly diagnosed, transplant-eligible patients, the GRIFFIN trial has underscored the benefits of incorporating daratumumab into frontline treatment.9 In this phase 2 study, patients receiving daratumumab plus lenalidomide, bortezomib, and dexamethasone (D-RVd) achieved significantly higher MRD negativity rates compared to those receiving RVd alone (64.4% vs. 30.1%).9 Furthermore, daratumumab demonstrated a marked improvement in complete response (CR) rates and a 55% reduction in the risk of disease progression or death.9 These benefits were particularly pronounced in patients with high-risk cytogenetic abnormalities, such as del(17p) and t(4;14), reinforcing the use of daratumumab in patients with poor prognostic features.9

The long-term follow-up data from the CASSIOPEIA trial further supports daratumumab’s role in the transplant-eligible population.10 Daratumumab added to bortezomib, thalidomide, and dexamethasone (D-VTd) as induction and consolidation therapy led to significantly improved PFS and overall survival compared to VTd alone.10 Patients who received daratumumab maintenance therapy also experienced improved MRD negativity and prolonged disease control.10 Importantly, these data establish daratumumab-based regimens as a critical option for transplant-eligible patients, particularly those with high-risk disease features who require deeper and more sustained responses.10

Daratumumab’s efficacy extends beyond the newly diagnosed setting. In relapsed/refractory multiple myeloma, daratumumab combined with carfilzomib and dexamethasone (D-Kd) has demonstrated a significant PFS advantage, as seen in the CANDOR trial.11 The subcutaneous formulation of daratumumab, which reduces infusion times and improves patient convenience, has been an important development, particularly in the community oncology setting where ease of administration is crucial.12 The approval of subcutaneous daratumumab provides an opportunity to further integrate this therapy into clinical practice, offering a convenient and effective treatment for both newly diagnosed and relapsed patients.12

Incorporating These Advances into Clinical Practice in the Community Setting
For community hematologists and oncologists, the expanding role of anti-CD38 therapies offers significant opportunities to optimize treatment outcomes for patients across the multiple myeloma disease spectrum.13 The use of isatuximab and daratumumab earlier in the disease course has clear benefits in achieving deeper responses, delaying disease progression, and improving overall survival.13,14 In particular, regimens such as Isa-VRd for transplant-ineligible patients and D-RVd or D-VTd for transplant-eligible patients provide new avenues for enhancing care in various patient populations.5,9

MRD status is emerging as an important tool in guiding treatment decisions and evaluating patient responses.14 The high rates of MRD negativity seen in patients treated with isatuximab and daratumumab-based regimens suggest that these therapies can be key to long-term disease control, especially among patients with high-risk cytogenetic abnormalities.5,9,14 Community oncologists should consider incorporating MRD testing into routine practice, using it as a marker to evaluate treatment success and potentially adjust therapy accordingly.14 Finally, the growing convenience of subcutaneous daratumumab also offers significant benefits in the community setting, reducing infusion times and enhancing patient compliance.12

With multiple trials and real-world data supporting the efficacy of anti-CD38 therapies, community oncologists are well-positioned to integrate these advances into their practices.1,13 By remaining current with the latest data and leveraging these therapies, physicians have therapeutic options with the potential to improve both survival outcomes and quality of life for patients at all stages of multiple myeloma.1

For additional information on this important topic, Managing Myeloma.com is hosting an accredited, fast-paced and dynamic podcast series entitled The Cutting Edge of MM: The Evolving Role of CD38-directed Strategies. This series, led by nationally recognized myeloma experts Dr. Joshua Richter and Dr. Andrew Yee, addresses the evolving role of CD38-targeting agents across multiple myeloma’s treatment landscape, from frontline therapy to relapsed/refractory settings and beyond. Visit Managing Myeloma.com to stay up to date with the latest clinical insights and trial data that are shaping the future of multiple myeloma management today.

References

1. Hashmi H, et al. CD38-Directed Therapies for Management of Multiple Myeloma. Immunotargets Ther. 2021 Jun 29;10:201-211.
2. van de Donk NWCJ, Usmani SZ. CD38 Antibodies in Multiple Myeloma: Mechanisms of Action and Modes of Resistance. Front Immunol. 2018 Sep 20;9:2134.
3. Bisht K, et al. Immunomodulatory properties of CD38 antibodies and their effect on anticancer efficacy in multiple myeloma. Cancer Med. 2023 Oct;12(20):20332-20352.
4. Frampton JE. Isatuximab: A Review of Its Use in Multiple Myeloma. Target Oncol. 2021 Sep;16(5):675-686. Erratum in: Target Oncol. 2021 Nov;16(6):867.
5. Leleu X, et al. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nat Med. 2024 Aug;30(8):2235-2241.
6. De Novellis D, et al. Clinical Efficacy of Isatuximab Plus Carfilzomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients. Eur J Haematol. 2024 Oct 6.
7. FDA approves isatuximab-irfc with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. September 20, 2024. Accessed at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-bortezomib-lenalidomide-and-dexamethasone-newly-diagnosed-multiple, October 13, 2024.
8. Atrash S, et al. Treatment patterns and effectiveness of patients with multiple myeloma initiating Daratumumab across different lines of therapy: a real-world chart review study. BMC Cancer. 2021 Nov 12;21(1):1207. Erratum in: BMC Cancer. 2021 Dec 2;21(1):1291.
9. Chari A, et al. Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN. Blood Cancer J. 2024 Jul 8;14(1):107.
10. Moreau P, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024 Aug;25(8):1003-1014.
11. Usmani SZ, et al. Final analysis of carfilzomib, dexamethasone, and daratumumab vs carfilzomib and dexamethasone in the CANDOR study. Blood Adv. 2023 Jul 25;7(14):3739-3748.
12. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide and dexamethasone for multiple myeloma. July 30, 2024. Accessed at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-multiple, October 13, 2024.
13. Badros AZ, et al. Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study. Blood 2024; blood.2024025746.
14. Lonial S, et al. Expert Consensus on the Incorporation of Anti-CD38 Monoclonal Antibody Therapy Into the Management of Newly Diagnosed Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2023 Nov;23(11):815-824.
15. Usmani SZ, et al. Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematologica. 2022 Oct 1;107(10):2408-2417.

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