How Do Long-Term MAIA and CEPHEUS Data Reinforce Daratumumab Use in NDMM?

In a recent CancerNetwork® Between the Lines program, experts in multiple myeloma read long-term follow-up data from the phase 3 MAIA (NCT02252172) and CEPHEUS trials (NCT03652064), both of which evaluated daratumumab (Darzalex)-based regimens in newly diagnosed multiple myeloma (NDMM).^1,2 Despite this body of evidence, an estimated 30% of frontline patients in the US still are not receiving a CD38-directed monoclonal antibody. The panel considered why that gap persists along with what the data mean for regimen selection, treatment duration, and long-term disease management.

The program was led by Ajai Chari, MD, a professor of clinical medicine and director of the Multiple Myeloma Program at the University of California, San Francisco (UCSF), and he was joined by Samantha Shenoy, NP, MS, MSN, ACNP-BC, a nurse practitioner at UCSF Medical Center who works with patients with multiple myeloma enrolled in clinical trials.

Moving Past a Binary Transplant-Eligibility Framework

Chari opened by questioning the field’s traditional split of patients into transplant-eligible and transplant-ineligible categories for frontline treatment selection. Shenoy said that framework deserves reassessment in favor of a more dynamic approach. “It’s important to think about things such as frailty,” she said, pointing to the International Myeloma Working Group (IMWG) frailty index, which stratifies patients as fit, intermediate fit, or frail. “It’s important to remember that this can change. Someone who might be frail at the beginning may no longer fit into that category after 3 to 6 months of treatment.”

Chari added that multiple myeloma’s disease burden—hypercalcemia, renal impairment, anemia-related fatigue, and bone pain—means every patient, fit or frail, benefits from rapid cytoreduction. Despite that rationale and a substantial body of supporting data, he noted that roughly 30% of frontline patients in the US are still not receiving a CD38 monoclonal antibody. Many are treated with regimens such as lenalidomide (Revlimid) plus dexamethasone (Rd) or bortezomib (Velcade) plus lenalidomide/dexamethasone (VRd) alone. Shenoy attributed this in part to outdated tolerability concerns. “Adding a CD38 [antibody] is very well tolerated,” she said. “We know it carries infection risk and neutropenia risk, but those are easy to manage...we have so many trials that demonstrate the improved efficacy when we add [daratumumab], so you can’t really argue with those data.”

The Rationale for CD38-Directed Therapy in Frontline Disease

Beyond direct antitumor killing, Chari pointed to daratumumab’s immunomodulatory effects on the tumor microenvironment as an underappreciated part of its mechanism. He noted that in patients already refractory to CD38 antibodies, combining daratumumab with newer immunotherapies has produced better responses than would be expected from re-exposure alone. He attributed this effect in part to depletion of regulatory T cells that otherwise inhibit T-cell activation. “These aren’t just theoretical” effects, he said, characterizing daratumumab’s target as “pleiotropic” by acting on the immune microenvironment as well as the multiple myeloma cell itself.

Shenoy agreed, noting she has observed daratumumab-exposed and -refractory patients on clinical trials “do very well when you combine daratumumab with another agent.” Chari cautioned that these findings still require confirmatory phase 3 data but called them proof of concept for the target’s broader immunologic relevance.

The panel also discussed how daratumumab’s logistics have evolved. The subcutaneous formulation reduced what was once an 8-hour first infusion to a 3- to 5-minute injection, easing the burden on infusion centers that Chari recalled from daratumumab’s early intravenous era. Between direct killing; immune effects; and now a favorable administration schedule involving dosing weekly for 2 months, every other week for 4 months, then monthly, Chari sees no reason why “a patient can’t get CD38 [in the] front line.”

MAIA: A New Overall Survival Benchmark in Transplant-Ineligible NDMM

The MAIA trial randomly assigned transplant-ineligible patients with NDMM to daratumumab plus lenalidomide/dexamethasone (D-Rd) or Rd alone, treating to progression.¹ At long-term follow-up, median progression-free survival (PFS) was 61.9 months with D-Rd vs 34.4 months with Rd (HR, 0.55); minimal residual disease (MRD) negativity at a sensitivity of 10⁻⁵ was reached in 32.1% vs 11.1% of patients, respectively.³ At final survival analysis, median overall survival (OS) was 90.3 months with D-Rd vs 64.1 months with Rd (HR, 0.67; 95% CI, 0.55-0.82; P <.0001).⁴

“It’s remarkable to see an OS benefit,” Chari said, noting that the control arm reached a 5-year median OS, with D-Rd extending that by more than 2 additional years in a population with a median age of 73 years. Shenoy called the durability “pretty impressive,” adding that the once-monthly maintenance schedule matters practically for patients: “We have patients coming from all over, 3 to 5 hours away…and for patients like that, receiving a monthly treatment like daratumumab is much more feasible.”

Discontinuation rates due to treatment-emergent adverse events (TEAEs) were lower with D-Rd than Rd (14.6% vs 23.8%), and analyses showed that lenalidomide discontinuation did not compromise efficacy.³ Chari attributed this in part to lenalidomide’s cumulative toxicity, citing cytopenias, fatigue, diarrhea, and rash that many patients associate with specific days of their dosing cycle. He argued that the triplet’s superior disease control allowed for more dose modification without loss of control. Grade 3/4 TEAEs of note included neutropenia (54.1%) and pneumonia (19.5%). Comparing MAIA with the phase 3 SWOG S0777 study (NCT00644228) of VRd, which did not show an OS benefit in its older-patient subgroup, Chari said: “If you’re practicing evidence-based medicine, I don’t see the role for VRd anymore.” Shenoy agreed.

CEPHEUS: Quadruplet Therapy and MRD Negativity as an Endpoint

CEPHEUS enrolled patients with transplant-ineligible or transplant-deferred NDMM, randomly assigning them to daratumumab plus VRd (D-VRd) or VRd alone, with MRD negativity at 10⁻⁵ as the primary end point.² At a median follow-up of 58.7 months, MRD negativity was achieved in 60.9% of patients receiving D-VRd vs 39.4% with VRd (OR, 2.37; 95% CI, 1.58-3.55; P <.0001); rates of complete response (CR) or better were 81.2% vs 61.6% (P <.0001). PFS was significantly improved with the quadruplet (HR, 0.57; 95% CI, 0.41-0.79; P = .0005).

Chari noted that the choice of an MRD primary end point reflected the field’s need to “keep pushing the envelope” without waiting years for survival readouts. He also raised a design question about CEPHEUS’s comparator; since MAIA had established D-Rd as an effective triplet, he suggested a more informative control arm might have tested whether bortezomib adds meaningful benefit on top of daratumumab, rather than confirming daratumumab’s benefit on top of VRd. Both panelists agreed that twice-weekly bortezomib dosing, used in CEPHEUS’s first cycle, is difficult to justify. “I don’t think we should do that in any patient,” Shenoy said, citing the risk of rapidly progressive neuropathy. Chari noted a precedent from the phase 3 ALCYON trial (NCT02195479), in which bortezomib was given twice weekly only in cycle 1 before moving to a weekly schedule.

Despite that critique of trial design, both panelists said the results support quadruplet therapy as a new standard in this setting. “Everyone should get a quad upfront,” Shenoy said. “You want to give them everything that you can.”

Managing Therapy Duration and Adverse Effects Over Time

A substantial portion of the discussion focused on how each drug in a daratumumab-based regimen should be modified over months and years of continuous therapy. Chari described an approach of tapering corticosteroids as early as possible once the infusion-related reaction risk subsides, typically after daratumumab’s first 3 doses, while acknowledging dexamethasone’s early role in augmenting responses and premedication. For bortezomib, both panelists favored moving quickly from twice-weekly to weekly dosing and stopping altogether once any hint of neuropathy appears, given that the toxicity does not always fully reverse. Lenalidomide dosing, Shenoy said, should be adjusted based on creatinine clearance and individualized for diarrhea, rash, and fatigue, often stepping down to 10 mg for long-term maintenance. Daratumumab’s dose and schedule, by contrast, typically does not require modification.

On safety, the panel discussed infection risk and hypogammaglobulinemia associated with CD38-targeted therapy. Chari mentioned that not every patient on daratumumab needs intravenous immunoglobulin (IVIG); rather, IVIG should be reserved for patients with recurrent infections and low immunoglobulin G levels rather than used reflexively based on lab values alone. “It’s as we always say: treat the patient, not the number,” he said. Shenoy added that all patients should remain on herpes simplex virus/varicella-zoster virus prophylaxis, with Pneumocystis jirovecii pneumonia prophylaxis reserved for patients receiving more substantial corticosteroid dosing.

Practical Considerations for Long-Term Disease Management

The panel closed by discussing how to sustain patients on effective therapy over years, emphasizing shared decision-making, proactive symptom management, and collaboration between physicians, advanced practice providers (APPs), and community sites. Shenoy noted that patients often disclose treatment-related burdens, such as a caregiver reporting sleeplessness or irritability from dexamethasone, more readily to APPs than physicians. This underscores the value of a multidisciplinary team that communicates closely, including with community-based colleagues managing shared patients through a hub-and-spoke model.

Both panelists agreed that CD38-directed therapy has changed the trajectory of frontline multiple myeloma care. “They have revolutionized [multiple] myeloma care up front,” Shenoy said. “I absolutely cannot think of any reason not to give a CD38 monoclonal antibody up front.” Chari closed by framing the value proposition beyond survival alone. “The take-home message is CD38 monoclonal antibodies help us improve not just quantity of life but also quality of life,” he said.

References

1. Facon T, Kumar SK, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249
2. 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. Nat Med. 2025;31(4):1195-1202. doi:10.1038/s41591-024-03485-7
3. Facon T, Moreau P, Weisel K, et al. Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. Leukemia. Published online February 27, 2025. doi:10.1038/s41375-024-02505-2
4. Facon T, Kumar SK, Orlowski RZ, et al. Daratumumab, lenalidomide, and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: MAIA final survival analysis. Leukemia. Published online August 24, 2026. doi:10.1038/s41375-026-03097-9