Isa-VRD in TIE HRMM

This is a prospective, multicenter, randomized, open-label, Phase IIIb clinical trial. The study aims to evaluate the efficacy and safety of the quadruplet regimen Isatuximab in combination with Bortezomib, Lenalidomide, and Dexamethasone (Isa-VRD) compared to the standard triplet regimen of Bortezomib, Lenalidomide, and Dexamethasone (VRD) in newly diagnosed high-risk multiple myeloma (HRMM) patients who are not candidates for autologous stem cell transplantation.

A total of 117 participants will be enrolled and randomly assigned in a 2:1 ratio to receive either Isa-VRD (78 participants) or VRD (39 participants). The study consists of an induction-consolidation phase (cycles 1-12) followed by a maintenance phase (from cycle 13 onwards until disease progression or unacceptable toxicity).

The primary endpoint is the rate of minimal residual disease (MRD) negativity in the bone marrow assessed by flow cytometry at 12 months of treatment. Key secondary endpoints include MRD negativity rate at 18 months, objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety profile.

Inclusion criteria

• Newly diagnosed Multiple myeloma ，meeting the IMWG 2025 definition of high-risk MM (any one criterion):

(1) Del(17p) (>20% of plasma cells) and/orTP53 mutation or（2）One of these translocations cooccurring with 1q+ and/or del(1p32) , or t(4;14), or t(14;16), or t(14;20) or （3） Monoallelic del(1p32) along with 1q+ or biallelic del(1p32) or（4） High β2M (>5.5 mg/dL) with normal creatinine (<1.2 mg/dL) or（5）Or presents with any other high-risk feature: meeting diagnostic criteria for primary plasma cell leukemia or presence of extramedullary plasmacytoma at baseline;

• Age ≥18 years and ≤80 years;
• Not eligible for autologous hematopoietic stem cell transplantation or has declined transplantation for other reasons.
• ECOG score 0-2
• Expected survival time > 3 months
• Sufficient organ function is defined as follows: absolute neutrophil count ≥ 1.0×10^9/L, platelet count ≥ 50×10^9/L (when the proportion of bone marrow plasma cells is <50%), hemoglobin ≥ 7.5 g/dL; total bilirubin ≤ 1.5 times the upper limit of normal, aspartate aminotransferase and alanine aminotransferase ≤ 2.5 times the upper limit of normal; creatinine clearance rate ≥ 30 mL/min; left ventricular ejection fraction ≥ 50%.
• Fertile female or male subjects must agree to take effective contraceptive measures during the study period and within the specified time after the last administration.
• Voluntarily participated in this study, signed the informed consent form, had good compliance, and was cooperative during the follow-up.

Exclusion criteria

• Prior systemic anti-myeloma therapy;
• Viral infections including HBV, HCV, HIV, etc.;
• Serious cardiovascular and cerebrovascular diseases, such as: within 6 months before screening, myocardial infarction, unstable angina pectoris, severe arrhythmia, New York Heart Function Classification III-IV grade, or left ventricular ejection fraction <50%.
• Severe neurological or mental disorders that affect the ability to give informed consent or comply with the protocol.
• Had an allergic reaction to isatuximab, bortezomib, lenalidomide, dexamethasone or any excipients
• Pregnant or lactating women.
• Participated in other interventional clinical studies, or had received other anti-tumor treatments within the specified time before the first administration of this study.
• The researcher believes that there are any other circumstances unsuitable for participating in this study.