Daratumumab Retreatment Displays Activity in Relapsed Myeloma Following Continuous Frontline Therapy

Second-line therapy comprising daratumumab and hyaluronidase-fihj (Darzalex Faspro) plus lenalidomide (Revlimid) and dexamethasone (DRd) drove responses in older, frailer patients with multiple myeloma who received continuous daratumumab-based induction and maintenance therapy as frontline treatment, according to data from the phase 2 GMMG-DADA trial (NCT04656951) presented at the 2026 EHA Congress.¹

The efficacy population included patients more reflective of the real-world multiple myeloma population, including those with renal failure, frailty, or a higher performance status who are often excluded from clinical trials.

Findings showed that among patients who relapsed (n = 27), DRd produced an overall response rate (ORR) of 77%. Patients relapsing at least 12 months after frontline initiation achieved an ORR of 88%, with complete response (CR) or very good partial response (VGPR) reported at a rate of 56%; the progressive disease rate was 6% at a median follow-up of 11.6 months from second-line initiation. Patients relapsing within 12 months of the start of frontline treatment had an ORR of 60%, including CR or VGPR in 20%, and progressive disease in 20%. Median progression-free survival (PFS) from relapse therapy was NR, with a 12-month rate of 59.3%. The median time to second progression (PFS2) and overall survival (OS) were also NR.

In the frontline setting (n = 62), treatment with daratumumab plus bortezomib (Velcade), cyclophosphamide, and dexamethasone (DVCd) yielded an ORR of 82.3% after 8 cycles of induction therapy, and 54.0% of evaluable patients (n = 50) achieved minimal residual disease (MRD) negativity by next-generation sequencing at a threshold of 1×10⁻⁵, corresponding to 43.5% of the full efficacy population. Across frontline DVCd induction plus DVd maintenance, the best ORR was 83.9%, and the VGPR or better rate was 71.0%, including a CR rate of 21.0% and a VGPR rate of 50.0%.

Median PFS in the efficacy population was 29.9 months, with 12- and 24-month rates of 77.6% and 57.5%, respectively. Median OS was NR; the 12-month OS rate was 95.2%.

“GMMG-DADA provides unique prospective data on daratumumab retreatment after continuous frontline exposure until progression with protocol-defined backbone switching in a frail, [older] newly diagnosed multiple myeloma population including patients with renal dysfunction,” lead study author Tim Richardson, MD, of the University of Cologne in Germany, and colleaues wrote in a poster presentation of the data. “Daratumumab retreatment with DRd was feasible and showed clinically meaningful activity, particularly in patients with relapses after 12 months. Functional high-risk patients relapsing within 12 months may not benefit from such a retreatment.”

How was the GMMG-DADA trial designed?

GMMG-DADA was a single-arm, phase 2 investigator-initiated trial conducted across 24 German sites between 2021 and 2024. Eligible patients had transplant-ineligible newly diagnosed multiple myeloma and an ECOG performance status of 3 or lower, with no exclusion for renal impairment.^1,2

Investigators selected the DVCd backbone to avoid lenalidomide in the frontline setting, which they noted is critical for patients with an eGFR below 30 mL/min or those on dialysis, because bortezomib and cyclophosphamide require no dose adjustment in this setting.¹

Induction comprised 8 cycles of subcutaneous daratumumab, subcutaneous bortezomib at 1.3 mg/m² weekly, intravenous cyclophosphamide at 500 mg/m² on day 1, and dexamethasone at 20 mg weekly. Patients then proceeded to DVd maintenance with daratumumab every 4 weeks, bortezomib every 2 weeks, and dexamethasone 20 mg per day until progression or intolerance. At relapse, patients received DRd for 12 cycles.

The primary end point was the VGPR or better rate after 8 DVCd induction cycles.

How did the data break down across the patient population?

Among the 67 enrolled patients, the median age was 74 years (range, 56-85), and 58.2% were male. ECOG performance status was 0 in 25.4% of patients, 1 in 50.7%, 2 in 22.4%, and 3 in 1.5%. By R-ISS stage, 25.4% had stage I disease, 35.8% had stage II, and 22.4% had stage III. High-risk cytogenetic aberrations included del(17p) in 17.9% of patients, t(4;14) in 9%, t(14;16) in 9%, and amp1q21 (more than 3 copies) in 29.9%. Osteolysis was present in 74.6% of patients, and 13.4% had extramedullary lesions.

Regarding renal function, the median eGFR was 62 mL/min/1.73m² (range, 5-158). An eGFR below 30 mL/min was present in 17.9% of patients, 25.4% had an eGFR of 30 to less than 60 mL/min, and 53.7% had 60 mL/min or higher. A total of 77.6% of patients completed all 8 DVCd induction cycles.

What was the safety profile during induction?

Through the end of 8 induction cycles (n = 65), 93.8% of patients experienced any adverse effect (AE), and 60.0% had a grade 3 or higher AE. No unexpected safety signals were observed during retreatment.

The most common hematologic AEs were anemia (any-grade, 21.5%; grade ≥3, 12.3%), lymphopenia (15.4%; 15.4%), and neutropenia (13.8%; 6.2%). The most common nonhematologic AEs of any grade were infections (53.8%; 15.4%), gastrointestinal events (41.5%; 4.6%), neuropathy (36.9%; 3.1%), cardiac events (12.3%; 4.6%), hypertension (10.8%; 6.2%), and renal events (9.2%; 6.2%).

References

1. Richardson T, Theisen C, Benner A, et al. Daratumumab re-treatment after continuous frontline daratumumab-VCd with backbone switching in transplant-ineligible patients with newly diagnosed multiple myeloma: results from the multicenter GMMG-DADA study. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract PF779.
2. Daratumumab for first line treatment of transplant-ineligible myeloma patients followed by daratumumab retreatment at first relapse (GMMG-DADA). ClinicalTrials.gov. Updated March 5, 2026. Accessed June 24, 2026. https://clinicaltrials.gov/study/NCT04656951