Isa-VRD in TIE HRMM

This is a multicenter, prospective, randomized controlled trial designed to compare the quadruplet regimen of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRD) with the standard triplet regimen (VRD) in newly diagnosed, transplant-ineligible patients with high-risk multiple myeloma (HRMM). Primary Hypothesis: The addition of isatuximab to VRD will significantly improve the MRD negativity rate at 12 months compared to VRD alone in HR-NDMM patients. Secondary Hypotheses: Isa-VRD will lead to higher overall response rates (ORR), deeper responses, and improved progression-free survival (PFS) and overall survival (OS). The safety profile of Isa-VRD will be manageable and consistent with the known safety profiles of its individual components.

Sex

All

Minimum age

18 Years

Maximum age

80 Years

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.

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• BACKGROUNDFacon T, Dimopoulos MA, Leleu XP, Beksac M, Pour L, Hajek R, Liu Z, Minarik J, Moreau P, Romejko-Jarosinska J, Spicka I, Vorobyev VI, Besemer B, Ishida T, Janowski W, Kalayoglu-Besisik S, Parmar G, Robak P, Zamagni E, Goldschmidt H, Martin TG, Manier S, Mohty M, Oprea C, Bregeault MF, Mace S, Berthou C, Bregman D, Klippel Z, Orlowski RZ; IMROZ Study Group. Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Oct 31;391(17):1597-1609. doi: 10.1056/NEJMoa2400712. Epub 2024 Jun 3. PMID 38832972
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