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Daratumumab Plus VRd Improves MRD Negativity in Newly Diagnosed, Transplant-Ineligible or -Deferred Myeloma

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Daratumumab plus VRd improved MRD-negativity rates in transplant-ineligible or -deferred, newly diagnosed multiple myeloma.

Saad Z. Usmani, MD, FACP

Saad Z. Usmani, MD, FACP

The addition of daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) to bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) led to improvements in the rates of minimal residual disease (MRD) negativity compared with VRd alone in patients with newly diagnosed multiple myeloma who were ineligible for or deferred transplant, according to data from the phase 3 CEPHEUS trial (NCT03652064).1,2

Findings presented at the 21st International Myeloma Society Annual Meeting showed that at a 10-5 sensitivity, the overall MRD-negativity rate was 60.9% for patients treated with daratumumab plus VRd (n = 197) vs 39.4% for those given VRd alone (n = 198; odds ratio [OR], 2.37; 95% CI, 1.58-3.55; P < .0001).1

The complete response (CR) or better rate was 81.2% in the daratumumab arm vs 61.6% in the VRd arm (OR, 2.73; 95% CI, 1.71-4.34; P < .0001). In the daratumumab plus VRd arm, the stringent CR, CR, very good partial response (PR), and PR rates were 65.0%, 16.2%, 11.7%, and 4.1%, respectively. In the VRd arm, these respective rates were 44.4%, 17.2%, 25.3%, and 6.1%.

“The CEPHEUS study results show that [60.9%] of patients [in the experimental arm] achieved MRD negativity, which is clinically important for physicians treating patients with multiple myeloma and, in general, a strong predictor of improved long-term outcomes, including progression-free survival [PFS] and overall survival [OS],” lead study author Saad Z. Usmani, MD, FACP, chief of Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, New York, stated in a news release.2 “The subcutaneous daratumumab–based quadruplet regimen has compelling efficacy characterized by deep, durable responses and reduced risk of disease progression in the frontline population of patients not undergoing transplant, supporting the potential of this quadruplet to become a new regimen in this treatment setting.”

In July 2024, the FDA approved subcutaneous daratumumab plus VRd for induction and consolidation in patients with newly diagnosed multiple myeloma who are candidates for autologous stem cell transplant (ASCT), based on data from the phase 3 PERSEUS trial (NCT03710603).3

During his presentation, Usmani noted that triplet therapy consisting of VRd or daratumumab plus Rd is the current standard of care for patients with newly diagnosed multiple myeloma who are not eligible for ASCT.1

CEPHEUS Design and Methods

The phase 3 study evaluated the efficacy and safety of subcutaneous daratumumab plus VRd in patients with newly diagnosed multiple myeloma who were ineligible for ASCT or deferred transplant. Patients were required to have an ECOG performance status (PS) of 0 to 2 and a frailty score of 0 or 1.

Investigators randomly assigned patients 1:1 to receive daratumumab at 1800 mg once per week in cycles 1 and 2, then once every 3 weeks in cycles 3 to 8, plus 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 of each 21-day cycle, 25 mg of lenalidomide on days 1 to 14 of each cycle, and 20 mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle for 8 cycles; or VRd alone at the same dosing schedule. Starting in cycle 9, patients in the experimental arm received 1800 mg of daratumumab once every 4 weeks plus 25 mg of lenalidomide on days 1 to 21 and 40 mg of dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle; those in the control arm received Rd at the same dosing schedule.

The overall MRD-negativity rate with a CR or better served as the trial’s primary end point. Secondary end points included PFS; the proportion of patients with sustained MRD negativity with a CR or better for at least 12 months; CR or better rate; and OS.

Usmani explained that the 2 treatment arms were well balanced. The median age was 70.0 years (range, 42-79) in the daratumumab arm vs 70.0 years (range, 31-80) in the VRd arm. Most patients were at least 70 years of age in both the experimental arm (55.3%) and the control arm (55.6%). In the daratumumab arm, 44.2% of patients were male; 56.1% of patients were male in the VRd arm. Most patients had an ECOG PS of 1 (daratumumab arm, 52.3%; VRd arm, 50.5%), had a frailty score of 0 (62.9%; 66.7%), were transplant ineligible (73.1%; 73.2%), and had IgG myeloma per immunofixation or serum free light chain assay (66.0%; 57.6%).

Additionally, 5.6% of patients in the daratumumab arm and 6.6% of patients in the VRd arm had extramedullary plasmacytomas at baseline. International Staging System disease stage included stage I (daratumumab arm, 34.5%; VRd arm, 34.3%), stage II (37.1%; 37.9%), and stage III (28.4%; 27.8%). Most patients had standard-risk disease in the experimental arm (75.6%) and control arm (75.3%). The rates of patients with high-risk cytogenetics were 12.7% and 13.6% in the daratumumab and control arms, respectively.

All patients randomly assigned to the daratumumab arm received treatment compared with 195 of the 198 patients randomly assigned to receive VRd alone. The median duration of treatment was 56.3 months (range, 0.1-64.6) in the experimental arm vs 34.3 months (range, 0.5-63.8) in the control arm. Rates of treatment discontinuation were 48.2% and 65.6%, respectively. Reasons for treatment discontinuation in the daratumumab arm included progressive disease (13.7%); adverse effects (AEs; 8.1%); death (17.3%), including death due to COVID-19 (6.1%); and other reasons (9.1%). Reasons for treatment discontinuation in the VRd arm consisted of progressive disease (26.2%); AEs (16.4%); death (12.3%), including death from COVID-19 (3.1%); and other reasons (10.8%).

Additional Efficacy and Safety Data

At a 10-6 sensitivity, the overall MRD-negativity rates were 46.2% for the daratumumab plus VRd arm vs 27.3% for the VRd arm (OR, 2.24; 95% CI, 1.48-3.40; P = .0001).

Additionally, 48.7% of patients in the experimental arm achieved sustained MRD negativity at a 10-5 sensitivity for at least 12 months vs 26.3% of patients in the VRd arm (OR, 2.63; 95% CI, 1.73-4.00; P < .0001).

The median PFS was not reached in the daratumumab arm vs 52.6 months in the VRd alone arm (HR, 0.57; 95% CI, 0.41-0.79; P = .0005). The 54-month PFS rates were 68.1% and 49.5%, respectively. Usmani noted that the PFS benefit was generally consistent across prespecified subgroups.

Although Usmani said OS data were not mature and no statistically significant difference was observed between the 2 arms, a trend was observed favoring the daratumumab-based regimen (HR, 0.85; 95% CI, 0.58-1.24). When censoring for deaths due to COVID-19, the trend favoring the experimental regimen improved (HR, 0.69; 95% CI, 0.45-1.05).

Regarding safety, grade 3/4 treatment-emergent AEs (TEAEs) occurred in 92.4% of patients in the daratumumab arm vs 85.6% of patients in the VRd arm. TEAEs led to discontinuation of all study drugs in 7.6% and 15.9% of patients, respectively. Grade 5 non–COVID-19 TEAEs were reported in 10.7% of patients in the experimental arm vs 7.7% of patients in the control arm. The exposure-adjusted grade 5 TEAE rate was 0.39/100 for the daratumumab arm vs 0.31/100 for the control arm.

The most common any-grade TEAEs included blood and lymphatic disorders (daratumumab arm, 82.7%; VRd arm, 64.6%), including neutropenia (55.8%; 39.0%), thrombocytopenia (46.7%; 33.8%), and anemia (37.1%; 31.8%); gastrointestinal disorders (79.7%; 81.5%), including diarrhea (56.9%; 59.0%) and constipation (38.1%; 42.1%); general disorders and administration-site conditions (80.7%; 75.4%), including peripheral edema (42.1%; 39.0%) and fatigue (32.0%; 30.8%); psychiatric disorders (46.2%; 49.2%), including insomnia (32.0%; 32.3%); infections (91.9%; 85.6%), including upper respiratory tract infection (39.6%; 32.8%) and COVID-19 (38.1%; 24.6%); and second primary malignancies (7.6%; 9.2%).

Peripheral sensory neuropathy of any grade occurred in 55.8% of patients in the daratumumab arm vs 61.0% of patients in the VRd arm. The rates of grade 3/4 peripheral sensory neuropathy were 8.1% and 8.2%, respectively.

Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

References

  1. Usmani SZ, Facon T, Hungaria V, et al. Daratumumab SC + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: results of the phase 3 CEPHEUS study. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-63.
  2. Darzalex Faspro-based quadruplet regimen significantly improves minimal residual disease negativity for newly diagnosed multiple myeloma patients for whom transplant is not planned. News release. Johnson & Johnson. September 27, 2024. Accessed September 24, 2024. https://innovativemedicine.jnj.com/darzalex-faspro-based-quadruplet-regimen-significantly-improves-minimal-residual-disease-negativity-for-newly-diagnosed-multiple-myeloma-patients-for-whom-transplant-is-not-planned
  3. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. FDA. July 30, 2024. Accessed September 27, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-multiple
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