Phase III Randomized Open‑Label Study of Cevostamab Combination Therapy Versus Standard of Care in Relapsed/Refractory Multiple Myeloma After 1‑3 Prior Lines

The primary objective is to compare the efficacy of Cevostamab combined with pomalidomide and dexamethasone versus standard of care in previously treated multiple myeloma, using the co‑primary endpoints of MRD‑negative complete response rate and progression‑free survival. Secondary objectives are to evaluate: the very good partial response or better rate and overall survival; health‑related quality of life, measured as time to confirmed deterioration in the disease‑symptoms scale of the EORTC QLQ‑MY20; a comprehensive set of efficacy outcomes including overall response rate, complete response, time to first response, time to best response, duration of response, progression‑free survival, second progression‑free survival, overall MRD‑negative complete response rate, overall MRD‑negative rate, and sustained MRD‑negative complete response; safety of the Cevostamab‑pomalidomide‑dexamethasone regimen; additional health‑related quality‑of‑life assessment; and the immunogenicity of cevostamab.

The trial enrolled 251 individuals diagnosed with Multiple Myeloma who met predefined eligibility criteria. Eligible participants were adults spanning the adult and elderly age categories, with both female and male patients represented, and inclusion of vulnerable subjects was permitted. Enrollment required an Eastern Cooperative Oncology Group (ECOG Performance Status) of 0 or 1 at screening (or a score of 2 attributable solely to myeloma‑related symptoms), a minimum life expectancy of 12 weeks, and confirmation of disease per International Myeloma Working Group diagnostic standards with measurable disease parameters. Candidates must have received one to three prior treatment lines, including regimens containing an anti‑CD38 agent and lenalidomide, and, depending on region, a proteasome inhibitor. Participants were required to consent to scheduled study procedures such as bone marrow biopsies and to adhere to standard clinical care without specific dietary or physical activity restrictions.

The study is a Phase III, randomized (1:1), open‑label, multicenter trial comparing Multiple Myeloma patients receiving cevostamab in combination with pomalidomide and dexamethasone (CevosPd) versus a standard‑of‑care regimen selected by the investigator; the trial enrolment period spans from May 2026 to June 2029 and each participant remains on study until disease progression, unacceptable toxicity, withdrawal of consent, death, or the scheduled end‑of‑study visit. After providing informed consent, participants attend a screening visit for eligibility assessments, including bone‑marrow biopsy, ECOG performance‑status evaluation, and laboratory verification of measurable disease. Eligible subjects are randomized at the baseline visit and begin treatment cycles administered every 28 days, with study visits scheduled at the start of each cycle for safety labs, adverse‑event monitoring, and drug administration, as well as disease‑assessment visits (e.g., bone‑marrow aspirate at month 9 for MRD‑negative complete response) and quality‑of‑life questionnaires at predefined intervals. An end‑of‑study visit occurs after the last scheduled assessment or earlier if discontinuation criteria are met. Early termination may be triggered by confirmed disease progression, grade ≥ 3 treatment‑related adverse events, protocol non‑compliance, or patient decision to discontinue. The overall participant involvement therefore extends for up to several years, encompassing active treatment, follow‑up assessments, and the final study closure.

Cevostamab is supplied as a concentrate for solution for infusion and administered intravenously. The investigational regimen uses a defined infusion schedule; each infusion is performed in a clinical setting under observation. Dose calculations are based on body weight or surface area as specified in the protocol, and the infusion rate follows manufacturer recommendations. Administration records are maintained for each dose to ensure compliance.

Pomalidomide is provided as oral capsules. The drug is taken once daily on a cyclic schedule (e.g., 21 days on, 7 days off) as defined in the study protocol. Patients receive printed dosing instructions and are instructed to take the medication at the same time each day. Pill counts and patient diaries are used to monitor adherence.

Dexamethasone is available in both oral tablets and intravenous solution. The oral formulation is taken daily according to the protocol, while the intravenous formulation may be administered on the day of infusion to manage acute reactions. Dosing frequency (e.g., daily or on infusion days) follows the study schedule, and administration is documented in the trial record.

Elotuzumab (Empliciti) is supplied as a powder for concentrate for solution for infusion (300 mg or 400 mg). It is administered intravenously at the dose and interval specified in the standard‑of‑care arm, typically weekly for the first two cycles and then every two weeks. Infusion times and any pre‑medication are recorded to ensure protocol compliance.

Carfilzomib is presented as an intravenous solution. The drug is given by infusion on a schedule consistent with approved regimens (e.g., twice weekly for a defined number of days per cycle). Infusion parameters, including duration and any dose adjustments, are captured in the case report form.

Daratumumab is administered subcutaneously as a single‑dose injection. The injection is performed on the day designated by the protocol, with observation for immediate adverse events. Injection site and dose are logged for each administration.

Efficacy will be evaluated using predefined clinical and laboratory parameters. The primary endpoints are the Minimal Residual Disease-negative complete response (CR) rate assessed at 9 months from a bone‑marrow aspirate using next‑generation sequencing, and Progression‑Free Survival measured from randomization to the earliest occurrence of disease progression, as determined by independent review committee (IRC) assessment according to International Myeloma Working Group (IMWG) criteria, or death from any cause. Participants who have not progressed and remain alive will be censored at the date of the last disease evaluation.

Secondary efficacy assessments include the proportion of participants achieving very good partial response (VGPR) or better, overall survival, time to confirmed deterioration in disease‑symptom and quality‑of‑life scales (EORTC QLQ‑MY20 and EORTC QLQ‑C30), overall response rate, CR rate, time to first response, time to best response, duration of response, investigator‑assessed PFS, PFS2, overall MRD‑negative CR rate, overall MRD‑negative rate, and sustained MRD‑negative CR rates at 6, 12, and 24 months. Patient‑reported outcomes will be captured using the NCI PRO‑CTCAE, FACT‑G GP5, and the disease‑symptom and global health status/quality‑of‑life scales of the EORTC questionnaires. Safety‑related laboratory tests, vital signs, and anti‑drug antibody (ADA) monitoring will be performed at baseline and at scheduled study visits throughout treatment and follow‑up. All assessments will be recorded according to the protocol‑specified visit schedule and analyzed using appropriate statistical methods for time‑to‑event and categorical outcomes.