Daratumumab-VRd for Newly Diagnosed Multiple Myeloma: Oncology NPs Review Frontline CD38 Therapy and AE Management

Suzan Rosen, APRN, from the Sylvester Myeloma Institute at Sylvester Comprehensive Cancer Center, University of Miami Miller Health System, led a case-based roundtable discussion with oncology nurse practitioners to examine optimal frontline treatment strategies for patients with newly diagnosed multiple myeloma (NDMM). The session focused on CD38-targeted monoclonal antibody regimens through 2 distinct patient cases—one transplant-ineligible and one transplant-eligible.

The Shift to Quadruplet Therapy

The discussion emphasized a fundamental shift in treatment philosophy: using the most effective drugs upfront rather than reserving them for later lines of therapy. "We're learning now that it's not always the best to save drugs for later on, because later on the disease can be sometimes a little more resistant to treat," Rosen explained. This approach aims to achieve deeper, more durable remissions that may ultimately lead to cure.

When polling participants on their most frequently prescribed NDMM regimen, 10 of 11 participants (91%) reported using daratumumab (Darzalex)-bortezomib (Velcade)-lenalidomide (Revlimid)-dexamethasone (Dara-VRd), reflecting widespread adoption of quadruplet therapy in clinical practice.

Case 1: Transplant-Ineligible Patient

The first case presented a 75-year-old male with multiple comorbidities including diabetes, hypertension, controlled coronary artery disease, heart failure, and chronic obstructive pulmonary disease. His workup revealed 50% to 60% plasma cells, standard-risk cytogenetics, and International Staging System (ISS) stage 3 disease with an ECOG performance status of 2.

Despite his age and comorbidity burden, 80% of participants recommended Dara-VRd over triplet therapy. This preference aligns with data from the CEPHEUS trial (NCT03652064), which demonstrated superior outcomes with Dara-VRd versus VRd in transplant-ineligible patients: minimal residual disease (MRD) negativity rates of 60% versus 39%, complete remission rates of 81% versus 61%, and progression-free survival at 58 months of 68% versus 49%.¹

Similar results were observed in the IMROZ trial (NCT03319667) evaluating isatuximab-irfc (Sarclisa)-VRd (Isa-VRd), with 63.2% versus 45.2% progression-free survival (PFS) at 60 months.² However, Isa-VRd showed notably higher grade 3 or higher infection rates (53% vs 23%), raising important safety considerations.

Case 2: Transplant-Eligible Patient

The second case featured a 61-year-old professionally active female with no significant medical history who presented with symptomatic disease and favorable hyperdiploid cytogenetics. She prioritized quality of life and did not want to spend time in the clinic.

Participants initially showed mixed preferences (54% Dara-VRd, 27% VRd), but discussion centered on balancing treatment intensity with patient priorities. The PERSEUS trial (NCT03710603) data, as an example, demonstrating superior PFS with Dara-VRd followed by transplant and maintenance versus VRd-based treatment.³

Rosen emphasized presenting patients with outcome, "I would want to show her that progression-free survival increases when you're having 4 drugs versus 3. You may relapse sooner, and then you have to kind of restart again and be back to the clinic."

Managing Adverse Events

Peripheral neuropathy emerged as the most challenging adverse event (AE), identified by 63% of participants. Management strategies included baseline assessment—particularly in patients with diabetes—functional impact evaluation, dose modifications, and switching from bortezomib to carfilzomib (Kyprolis) when necessary.

One participant noted the nuanced approach required: "It's a real art because certain patients are minimizers or patients who are maximizers. You really have to know who you're talking to."

Infection risk represents another significant concern with CD38-targeted therapy. Participants emphasized patient education, antimicrobial prophylaxis, immunoglobulin (IG) monitoring, and consideration of intravenous IG supplementation for hypogammaglobulinemia—a common complication as CD38 antibodies affect both malignant and healthy plasma cells.

Subcutaneous Daratumumab Administration

The transition from intravenous to subcutaneous daratumumab (Darzalex Faspro) administration has dramatically improved patient experience. The COLUMBA study (NCT03277105) demonstrated equivalent efficacy and administration time was reduced from 3 to 8 hours to approximately 5 minutes.⁴

The transition from intravenous to subcutaneous daratumumab administration has dramatically improved patient experience. The COLUMBA study demonstrated equivalent efficacy between subcutaneous and intravenous formulations with approximately 33% fewer infusion reactions.

Successful subcutaneous daratumumab administration requires attention to four key phases:

• Pre-medications (1-3 hours before each dose): Patients receive corticosteroid (long or intermediate acting), acetaminophen 650 to 1000 mg, and diphenhydramine 25 to 50 mg to minimize infusion-related reactions.
• Preparation: The fixed dose consists of 1800 mg daratumumab combined with 30,000 units hyaluronidase per 15 mL vial. Critical preparation steps include avoiding shaking the vial, inspecting for colorless to yellow and clear to opalescent solution (discarding if particles or discoloration are present), warming to room temperature, and discarding any unused portion from the single-dose vial.
• Injection technique: The injection site is the abdomen, approximately 3 inches from the navel, with rotation of sites for each injection. Administration occurs subcutaneously over 3 to 5 minutes. Practitioners must avoid injecting into bruised, red, tender, or hard skin. A winged infusion kit may be used per institutional protocol.
• Post-injection monitoring: Patients receive post-dose methylprednisolone 20 mg (or equivalent corticosteroid dose) for 2 days starting after administration to manage delayed reactions.

Butterfly Infusion Kit Considerations

Patients preferred this method due to reduced injection site pressure; additionally, institutions identified factors to take into consideration, such as the requirement for an additional 1 mL of medication to prime tubing, medication spillage risk, potential needle dislodgement, and the need for uniform adoption across satellite locations.

Despite these operational challenges, the overall shift to subcutaneous administration has fundamentally improved the treatment experience, reducing what was previously a 3- to 8-hour intravenous infusion to a brief 3- to 5-minute subcutaneous injection.

Maintenance Therapy Strategies

For transplant-eligible patients, lenalidomide monotherapy remains the preferred maintenance approach (NCCN Category 1), with daratumumab plus lenalidomide as an alternative. Participants recommended 1.5 to 2 years of daratumumab for transplant-ineligible patients, with monthly administration as the minimum effective frequency.

The discussion highlighted quality-of-life benefits of transitioning to less intensive regimens. Some patients with favorable cytogenetics, particularly hyperdiploid disease, maintain excellent disease control on lenalidomide alone for years, requiring only quarterly clinic visits with local laboratory monitoring.

Patient Education and Expectations

Setting realistic expectations from diagnosis proved crucial. Participants emphasized counseling patients that multiple myeloma remains incurable but highly treatable, with response rates exceeding 90% for current quadruplet regimens.

The group acknowledged the challenge of continuous therapy, describing it as "not your life, but it's a part-time job, at least in the beginning." This framing helps patients understand the chronic disease management model while maintaining hope for extended, high-quality remissions.

Next Steps of CD38-Based Regimens in Multiple Myeloma

The roundtable demonstrated strong consensus supporting CD38-based quadruplet regimens as frontline therapy for NDMM regardless of transplant eligibility. Subcutaneous daratumumab has become the predominant delivery method, significantly reducing treatment burden. While AE requires ongoing vigilance—particularly for peripheral neuropathy and infections—current regimens achieve unprecedented outcomes with manageable toxicity.

References

1. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nature. 2025;31:1195-1202
2. Facon T, Dimopoulos M-A, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Eng J Med. 2024;391(17):1597-1609. doi:10.1056/NEJMoa2400712
3. Sonneveld P, Dimopoulos M-A, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054
4. Usmani SV, Nahi H, Legiec W, 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;1-7(10):2408-2417.doi:10.3324/haematol.2021.279459