Isa-VRdlite for of Frail and/or Much Older Patients With High Risk Newly Diagnosed Multiple Myeloma Base on Circulating Plasma Cells

• Isatuximab (Drug): Newly diagnosed transplant-ineligible multiple myeloma patients (high-risk defined by GA score and circulating plasma cells (CPCs) ≥0.07%) will receive isatuximab plus reduced-intensity VRD (VRDlite) induction therapy, as detailed below: Isatuximab (Isa) 10 mg/kg per administration. Cycle 1: administered on Days 1, 8, 15 and 22. From Cycle 2 onwards: once every two weeks (Days 1 and 15). Dose reduction of isatuximab is prohibited throughout treatment until disease progression, intolerable toxicity, or completion of scheduled therapy. Reduced-intensity VRD (VRDlite) Bortezomib (V): 1.3 mg/m², subcutaneous injection, Days 1, 8, 15, 22 per cycle. This administration route reduces the incidence of peripheral neuropathy. Lenalidomide (R): 15 mg once daily orally, Days 1-21 per cycle. Dose should be further individualized and reduced for patients with renal insufficiency according to eGFR
• VRD (Drug): Newly diagnosed transplant-ineligible multiple myeloma patients (high-risk defined by GA score and circulating plasma cells (CPCs) ≥0.07%) will receive isatuximab plus reduced-intensity VRD (VRDlite) induction therapy, as detailed below: Isatuximab (Isa) 10 mg/kg per administration. Cycle 1: administered on Days 1, 8, 15 and 22. From Cycle 2 onwards: once every two weeks (Days 1 and 15). Dose reduction of isatuximab is prohibited throughout treatment until disease progression, intolerable toxicity, or completion of scheduled therapy. Reduced-intensity VRD (VRDlite) Bortezomib (V): 1.3 mg/m², subcutaneous injection, Days 1, 8, 15, 22 per cycle. This administration route reduces the incidence of peripheral neuropathy. Lenalidomide (R): 15 mg once daily orally, Days 1-21 per cycle. Dose should be further individualized and reduced for patients with renal insufficiency according to eGFR Dexamethasone (D): 20 mg once daily, orally or intravenously

Primary outcomes

• Overall response rate [12months]: defined as the proportion of patients achieving stringent complete response \[sCR\], complete response \[CR\], very good partial response \[VGPR\] or partial response \[PR\]
• 12-cycle clearance rate of circulating plasma cells (CPCs). [12months]: 12-cycle clearance rate of circulating plasma cells (CPCs).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Aged ≥ 18 years with newly diagnosed symptomatic multiple myeloma who have not received any prior anti-myeloma therapy.
* Confirmed positive circulating abnormal plasma cells (CPCs) in peripheral blood via flow cytometry (CPCs ≥ 0.07%).
* Deemed ineligible for autologous hematopoietic stem cell transplantation due to advanced age, poor physical performance, or underlying comorbidities precluding transplant tolerance.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3.
* Estimated life expectancy of at least 6 months.
* Adequate baseline function of major vital organs to tolerate treatment; no absolute contraindications on complete blood count, liver and renal function, cardiac enzymes or coagulation profile.
* Voluntarily participate in this study, provide written informed consent, and be available for regular follow-up visits.

Exclusion Criteria:

* Diagnosis of primary plasma cell leukemia, solitary plasmacytoma, smoldering multiple myeloma or secondary multiple myeloma.

  * Prior exposure to any anti-myeloma agents, radiotherapy, or stem cell transplantation.
  * Concurrent other malignant tumors (except for in situ carcinoma cured for more than 5 years).
  * Severe active infection, active autoimmune disease, or severe cardiovascular and cerebrovascular diseases (NYHA class III-IV heart failure, recent myocardial infarction or cerebral infarction).
  * Known hypersensitivity to isatuximab, bortezomib, lenalidomide, dexamethasone, or any excipients of the study drugs.
  * Pregnant or breastfeeding females.
  * Unwilling or unable to complete follow-up, or patients with incomplete clinical data.