Defining Key Questions on Adopting Quadruplet Regimens in NDMM

The treatment landscape for newly diagnosed multiple myeloma (NDMM) has transformed rapidly in recent years, with quadruplet regimens now dominating both guideline recommendations and clinical practice. Yet as daratumumab (Darzalex)- and isatuximab (Sarclisa)-based combinations become the standard for transplant-eligible and transplant-ineligible patients alike, the harder questions, including how long to treat, when to simplify a regimen, and how aggressively to incorporate minimal residual disease (MRD) testing into treatment decisions, remain unanswered by randomized trial data.

In an in-person Case-Based Roundtable event held at the 2026 ASCO Annual Meeting in Chicago, Gurbakhash Kaur, MD, assistant professor of medicine at the Mount Sinai Health System in New York, and Donna Catamero, ANP-BC, OCN, CCRC, associate director of the research program at Mount Sinai, moderated a discussion on frontline myeloma management that included a review of data from MAIA (NCT02252172), CEPHEUS (NCT03652064), and IMROZ (NCT03319667), as well as longer-range questions about maintenance therapy optimization and retreatment strategies in the relapsed/refractory setting. Kaur and Catamero emphasized that even as the field converges on quadruplets in induction, individualized decisions about therapy duration, frailty assessment, and MRD-guided deescalation are where meaningful practice variation still lives.

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CASE SUMMARY

• A 77-year-old woman presents to clinic with progressive fatigue, decreased appetite, and worsening back pain over the past 3 months. She reports she is less active and has difficulty walking long distances due to pain. Her past medical history includes hypertension, type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and mild peripheral neuropathy.
• Whole-body PET-CT showed multiple lytic lesions in the thoracic spine and ribs with mild compression fractures at T12. Bone marrow biopsy showed 52% clonal plasma cells and lambda light chain restriction. Notably, her ECOG performance status is 2; she is living independently but requires assistance to perform household tasks. Cytogenetics are notable for Gain 1q.
• Laboratory findings: Hemoglobin 9.1 g/dL; serum creatinine 2.1 mg/dL; calcium 11.2 mg/dL; albumin 3.1 g/dL; serum protein electrophoresis M-spike, 3.8 g/dL; immunofixation IgG lambda; serum free light chain ratio 0.09; beta-2 macroglobulin 5.6 mg/L; lactate dehydrogenase 200 IU/L
• The patient is considered ineligible for transplant.

EVENT RECAP

Before the data were presented, attendees split between daratumumab plus lenalidomide (Revlimid) and dexamethasone (Dara-Rd) and daratumumab plus bortezomib (Velcade), lenalidomide, and dexamethasone (Dara-VRd), with 64% initially choosing the quadruplet. After a review of the CEPHEUS and IMROZ trial data, support for quadruplet induction rose to 82%, with most of the triplet vote consolidating behind Dara-VRd.

Kaur acknowledged that a case like this one with hypercalcemia and elevated serum creatinine would often prompt an inpatient start, with intravenous fluids, bisphosphonate or denosumab, and early daratumumab initiation before lenalidomide is accessible. She noted that lenalidomide can take up to 2 weeks to obtain even in optimal circumstances, making bortezomib-based induction a practical bridging choice while outpatient approval is secured.

One participant noted that in patients with significant hypercalcemia and creatinine elevation, they prefer to defer lenalidomide until after the first cycle, once disease control has brought lab values closer to normal range.

MAIA: Establishing the Daratumumab-Rd Triplet in Transplant-Ineligible NDMM

Kaur reviewed updated data from the MAIA trial, a phase 3 study of Dara-Rd vs lenalidomide plus dexamethasone (Rd) in transplant-ineligible patients with NDMM.¹ At a median follow-up of 64.5 months, the triplet significantly extended progression-free survival (PFS), with a median PFS of 61.9 months vs 34.4 months favoring Dara-Rd. The estimated 60-month overall survival (OS) was 66.6% vs 53.6%, and overall response rate (ORR) was 92.9% vs 81.6%. Kaur highlighted subgroup analyses showing consistent PFS benefit across age groups, including patients 75 years and older. She emphasized that the MAIA data were what reoriented her practice away from doublet therapy in this population, and that she remains vigilant about managing lenalidomide dose intensity and dexamethasone in older patients, reducing or extending cycles proactively rather than waiting for toxicity.

CEPHEUS: The Case for Quadruplets in Transplant-Ineligible and Transplant-Deferred Patients

The CEPHEUS trial randomized transplant-ineligible and transplant-deferred patients with NDMM to Dara-VRd vs VRd, with the primary end point of MRD-negativity rate.² Kaur noted that the patient population excluded frail patients and included a meaningful proportion of transplant-deferred younger patients, a nuance she flagged when applying the data to the case at hand. At a median follow-up of 58.7 months, MRD-negativity rates (10⁻⁵ sensitivity) were 60.9% with Dara-VRd vs 39.4% with VRd; CR or better rates were 81.2% vs 61.6%; and sustained MRD-negativity rates (12 months or longer) were 48.7% vs 26.3%. The PFS curve favored the quadruplet arm significantly, with median PFS not yet reached in the Dara-VRd arm vs 52.6 months with VRd. On safety, Kaur and Catamero called out the higher rates of grade 3 or 4 neutropenia (44% vs 30%) and infections with the quadruplet, noting that the addition of any anti-CD38 monoclonal antibody predictably increases respiratory infection risk.

IMROZ: Isatuximab-VRd in Transplant-Ineligible NDMM

Kaur reviewed the IMROZ trial, which randomly assigned transplant-ineligible patients at least 65 years of age or with comorbidities making them ineligible for autologous stem cell transplant (ASCT) to isatuximab plus bortezomib, lenalidomide, and dexamethasone (Isa-VRd) vs VRd.³ The study used an ECOG performance status of 0 to 2 and a 3:2 randomization. At a median follow-up of 59.7 months, the quadruplet significantly extended PFS; CR or better rates were 75% with Isa-VRd vs 64% with VRd. A subgroup analysis of patients older than 75 years showed consistent PFS benefit regardless of frailty status, though ORR dropped from 96% in non-frail younger patients to 88% in older frail patients, and CR rates fell from 87% to 57%, a pattern Kaur highlighted as a reminder that frailty meaningfully affects depth of response even with active regimens.⁴

Discussion at the table reflected the practical divide between daratumumab and isatuximab in this setting. Kaur pointed to payer dynamics: “I’ve had one practice where the insurance would not let them give [daratumumab]; it was actually [isatuximab] that they had to give.” On logistics, Catamero raised the pending subcutaneous isatuximab on-body injector (OBI), which is currently under FDA review with a decision date set for July 23, 2026, and has already received EU approval. “You stick on the device, press the button, and it infuses over 13 to 14 minutes,” Catamero explained. “It might free up your nurse. They can multitask; they can document while an infusion is going.” Participants noted that while the OBI would not change clinical efficacy, it could influence anti-CD38 selection in practices with constrained infusion chair time, with one attendee observing that cost and reimbursement arrangements were ultimately more determinative than administration logistics. Kaur noted that the OBI requires no order preparation and comes in a prepared vial, simplifying pharmacy workflow.

Treatment Duration, MRD, and the De-escalation Question

Participants were especially interested in the decision of what to do once a patient is responding. Catamero framed the tension directly: In the absence of prospective randomized data guiding when to discontinue agents or stop maintenance, real-world practice is shaped by toxicity, time burden, financial pressure, and patient preference.

Kaur described her current approach for transplant-ineligible patients: when running a MAIA-based regimen, she continues the triplet and removes lenalidomide if tolerated poorly, keeping patients on daratumumab and dexamethasone to progression. She checks MRD annually by bone marrow biopsy and uses PET and MRI imaging to monitor patients with exclusively skeletal or plasmacytoma-predominant disease. “I do check their MRD, but then what’s their next regimen going to be?” she noted, acknowledging that MRD status in this population does not yet have an established action threshold. She added that sustained MRD negativity data from ASCO 2026 suggested 2 years may be insufficient as a treatment-stopping point, and that 3 or more years of confirmed negativity may eventually support risk-adapted de-escalation, though the data are not yet practice-defining.

Several participants had already moved to active MRD-guided decision-making, particularly in transplant-eligible patients on maintenance. One attendee described stopping maintenance after 2 years of sustained MRD negativity. Others were more cautious, citing the MASTER trial (NCT03224507) experience in which deescalation in high cytogenetic-risk patients, even after achieving MRD negativity, led to relapse, and reserving continued doublet maintenance for that group. “The one group that I would probably hesitate to deescalate is the high-risk cytogenetics group,” Kaur noted.

Catamero asked whether peripheral blood MRD testing had begun to supplant bone marrow sampling in attendee practice. Most had not yet incorporated it as a primary decision tool. Kaur flagged how they can detect meaningful changes in MRD but are not perfect: “If they’re positive, it tells you something. If they’re negative, it doesn’t tell you anything.” Several attendees mentioned exploring clonal tracking and mass spectrometry as potential future surrogates.

MajesTEC-3 and the Second-Line Landscape

The discussion extended to data from the MajesTEC-3 trial (NCT05083169), a phase 3 study of teclistamab-cqyv (Tecvayli) plus subcutaneous daratumumab vs investigator’s choice of daratumumab, pomalidomide (Pomalyst), and dexamethasone (DPd) or daratumumab, bortezomib , and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy including a proteasome inhibitor (PI) and lenalidomide.⁵ Anti-CD38-refractory patients were excluded. At a median follow-up of 34.5 months, 36-month PFS was 83.4% with teclistamab plus daratumumab vs approximately 30% in the control arm; 36-month OS was 83.3% vs 65%; and duration of response at 36 months was 88.4%. Kaur called the efficacy curve “quite revolutionary,” noting that a sustained plateau at 3 years, rather than a continuous decay, represents something the field has not previously seen with standard regimens in this setting.

Catamero flagged the protocol amendment that added mandatory infection prophylaxis including intravenous immunoglobulin (IVIG), Pneumocystis jirovecii pneumonia prophylaxis, and antiviral coverage after the Kaplan-Meier OS curves crossed early in the trial due to infection-related mortality in the teclistamab arm. Once prophylaxis was instituted, the curves separated in favor of the combination. Kaur noted that she now checks cytomegalovirus PCR levels at the start of therapy for patients on T-cell–redirecting agents and maintains a low threshold for IVIG. Attendees who expressed concern about late CAR T toxicities, including delayed neurotoxicity and immune-mediated colitis, discussed using teclistamab plus daratumumab as a bridging or alternative strategy for patients who are chimeric antigen receptor (CAR) T-cell therapy eligible but not yet ready to proceed, preserving CAR T for a later line after the disease is better controlled. “If they’re going to be a CAR T candidate, and if they agree, great,” Kaur said. “If they want to take their time, they go on to a non-immune-therapy based regimen first.”

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_{DISCLOSURES: Kaur previously reported research funding from Arcellx and AbbVie; consultancy or advisory roles with Karyopharm, BMS, Janssen, Kite/Arcellx. Catamero previously reported consulting fees from Johnson & Johnson, Bristol-Myers Squibb, and Legend Biotech, and has served on the speakers bureau for Johnson & Johnson.}

REFERENCES

1. Facon T, Moreau P, Weisel K, et al. Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. Leukemia. 2025;39(4):942-950. doi:10.1038/s41375-024-02505-2

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, Dimopoulos MA, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(17):1597-1609. doi:10.1056/NEJMoa2400712

4. Manier S, Dimopoulos MA, Leleu XP, et al. Isatuximab plus bortezomib, lenalidomide, and dexamethasone for transplant-ineligible newly diagnosed multiple myeloma patients: a frailty subgroup analysis of the IMROZ trial. Haematologica. 2025;110(9):2139-2150. doi:10.3324/haematol.2024.287200

5. Costa LJ, Bahlis NJ, Perrot A, et al. Teclistamab plus daratumumab in relapsed or refractory multiple myeloma. N Engl J Med. 2026;394(8):739-752. doi:10.1056/NEJMoa2514663