In patients with transplant-ineligible or -deferred newly diagnosed multiple myeloma, adding Darzalex (daratumumab) to Velcade (bortezomib), Revlimid (lenalidomide) and dexamethasone (VRd) demonstrated improved minimal-residual disease (MRD) responses.
These findings were based on an analysis of MRD outcomes from the phase 3 CEPHEUS trial, presented at the 2024 ASH Annual Meeting.
In addition, the combination led to improved progression-free survival (PFS), regardless of MRD negative or positive status.
Glossary
Minimal-residual disease (MRD): microscopic traces of cancer that remain in the body after receiving treatment. MRD-negativity means there are no detectable traces of cancer in the body.
Progression-free survival (PFS): time patients live without their cancer worsening or spreading.
Complete response (CR): patients fully responded to treatment, meaning they no longer show signs or symptoms of cancer.
Partial response (PR): patients respond to treatment but not completely, meaning their tumors shrunk after receiving treatment.
End point: the main goal of a study measured at the end to see if the treatment worked.
Subcutaneous: treatment given beneath the skin.
ECOG performance status: a measurement of how independently patients can complete daily tasks. A score of 0 means patients can perform tasks fully independently and a score of 4 means they cannot perform tasks independently.
“These data support the use of [Darzalex] in combination with VRd as a normal standard of care in patients with newly diagnosed multiple myeloma who are transplant ineligible or when transplant is deferred,” Dr. Sonja Zweegman from the Department of Hematology at Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Netherlands, said during a presentation of the data.
After a median follow-up of 58.7 months, at a 10-5 sensitivity, the overall MRD-negativity rate was 60.9% for patients treated with Darzalex plus VRd (197 patients) versus 39.4% for those given VRd alone (198 patients). At a 10-6 sensitivity, the overall MRD-negativity rates were 46.2% for patients in the daratumumab plus VRd group versus 27.3% for the VRd group.
“It can be appreciated … that adding [Darzalex] to VRd led to a 50% increase in MRD negativity,” Zweegman said.
The 54-month PFS rates were 68.1% and 49.5%, respectively, reducing the risk for disease progression or death by 43%. Zweegman noted that the MRD negativity rates were generally consistent across prespecified subgroups.
When evaluating cumulative MRD negative complete response (CR) rates from the sensitivity level 10-5, patients reached MRD negativity faster, with higher rates at all time points. “And the difference of the MRD negativity rates between the [two treatment groups] is increasing up to three years,” Zweegman added.
This same effect was seen at the sensitivity level 10-6, which is even more related to PFS, she noted. “And importantly… [Darzalex] almost doubles the MRD negative CR rates that sustained for more than 12, 24 and 36 months.”
As sensitivity level 10-6, MRD-negative patients experienced superior PFS, compared with MRD-positive patients in both treatment groups. Further, the 54-month PFS rates for MRD-negative patients treated with Darzalex plus VRd or VRd alone were 86.2% and 79.0%, respectively. In MRD-positive patients, these rates were 51% and 36.5%.
“So [Darzalex] provides PFS benefit regardless of the MRD negativity CR status,” Zweegman said.
Additional Study Findings
The CR or better rate was 81.2% in the Darzalex group versus 61.6% in the VRd group. In the Darzalex plus VRd group, 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 group, these respective rates were 44.4%, 17.2%, 25.3% and 6.1%.
Regarding safety, grade 3 or 4 (severe or life-threatening) treatment-emergent side effects occurred in 92.4% of patients in the Darzalex group versus 85.6% of patients in the VRd group. Treatment-emergent side effects led to discontinuation of all study drugs in 7.6% and 15.9% of patients, respectively.
The most common any-grade treatment-emergent side effects included blood and lymphatic disorders (Darzalex group, 82.7%; VRd group, 64.6%), including neutropenia (55.8%; 39.0%), thrombocytopenia (46.7%; 33.8%) and anemia (37.1%; 31.8%). Gastrointestinal disorders occurred (79.7%; 81.5%), including diarrhea (56.9%; 59%) and constipation (38.1%; 42.1%); general disorders and administration-site conditions (80.7%; 75.4%), including peripheral edema (42.1%; 39%) and fatigue (32%; 30.8%). Psychiatric disorders occurred (46.2%; 49.2%), including insomnia (32%; 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%).
More About MRD-Negativity in Multiple Myeloma
“We all know that MRD negativity is associated with longer survival, and it's a strong prognostic for clinical end points in multiple myeloma and a key goal of multiple myeloma therapy,” Zweegman explained. “And therefore, MRD negativity was supported by the [FDA Oncologic Drugs Advisory Committee] as an early end point for accelerated approval in multiple myeloma.”
The phase 3 CEPHEUS trial was the first phase 3 study of Darzalex with MRD as a primary end point. In the trial, investigators demonstrated that the addition of subcutaneous Darzalex with VRd in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma led to superior rates of overall and sustained MRD negativity, as well as more CR, and it significantly improved PFS.
At the 2024 ASH Annual Meeting, Zweegman reported on an expanded analysis of MRD outcomes from the CEPHEUS trial.
In the trial, investigators randomly assigned patients evenly to receive Darzalex at 1,800 milligrams (mg) once per week, then once every three weeks, plus 1.3 mg per square meter of Velcade; 25 mg of Revlimid and 20 mg of dexamethasone; or VRd alone at the same dosing schedule. Starting in cycle 9, patients in the experimental group received 1,800 mg of Darzalex once every 4 weeks plus 25 mg of Revlimid and 40 mg of dexamethasone; patients in the control group 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; and CR or better rate.
Patients were required to have an ECOG performance status (PS) of 0 to 2 and a frailty score of 0 or 1.
Reference
“Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide and Dexamethasone (VRd) Versus Alone in Patients with Transplant-Ineligible Newly Diagnosed Multiple Myeloma or for Whom Transplant Is Not Planned As Initial Therapy: Analysis of Minimal Residual Disease in the Cepheus Trial” by Dr. Sonja Zweegman, et al. Presented at: 2024 ASH Annual Meeting; December 7-10, 2024; San Diego, California.
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