CM336 Plus Daratumumab and Lenalidomide in Transplant-Ineligible Newly Diagnosed Multiple Myeloma

Inclusion criteria

• Able to understand and voluntarily sign a written informed consent form (ICF).
• Age 18 to 75 years.
• Newly diagnosed symptomatic multiple myeloma according to International Myeloma Working Group (IMWG) criteria. Patients who have received no more than one cycle of anti-myeloma therapy before enrollment are eligible.
• Not planned to undergo autologous stem cell transplantation as first-line treatment and meeting at least one of the following criteria, including but not limited to:

• Age ≥65 years;
• Eastern Cooperative Oncology Group (ECOG) performance status of 3-4;
• Considered unable to tolerate autologous stem cell transplantation based on investigator assessment.
• Measurable disease, defined by at least one of the following:

• Serum M-protein ≥10 g/L by serum protein electrophoresis (SPEP); for IgA or IgD myeloma, quantitative IgA or IgD levels may be used instead;
• Urine M-protein ≥200 mg/24 hours;
• If neither serum nor urine M-protein meets the above criteria, involved serum free light chain (FLC) ≥100 mg/L with an abnormal serum FLC ratio (normal range: 0.26-1.65).
• Adequate hepatic function, defined as:

• Total bilirubin <1.5 × upper limit of normal (ULN), except for participants with Gilbert syndrome, who must have total bilirubin <3 × ULN;
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN.
• Adequate renal function, defined as creatinine clearance ≥30 mL/min calculated using the Cockcroft-Gault formula.
• Hematologic parameters within 7 days prior to screening meeting the following criteria:

• White blood cell (WBC) count ≥1.5 × 10^9/L;
• Absolute neutrophil count (ANC) ≥1.0 × 10^9/L;
• Hemoglobin ≥70 g/L;
• Platelet count ≥75 × 10^9/L if bone marrow plasma cells are <50%, or ≥50 × 10^9/L if bone marrow plasma cells are ≥50%.
• Participants receiving hematopoietic growth factor support, including erythropoietin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or thrombopoietic agents (e.g., eltrombopag, thrombopoietin, or interleukin-11), must have an interval of at least 2 weeks between the last administration of growth factor support and screening assessment.
• Participants receiving blood product transfusions must meet the following requirements:

• At least 2 weeks between the last red blood cell (RBC) transfusion and hemoglobin assessment at screening;
• At least 1 week between the last platelet transfusion and platelet assessment at screening.
• Able and willing to receive protocol-recommended prophylactic anticoagulation therapy.
• Female participants of childbearing potential must:

• Have a negative serum pregnancy test at screening; and
• Agree to use effective contraception from the date of signing informed consent throughout study treatment and for at least 3 months after the last dose of study treatment.

Male participants, including those who have undergone vasectomy, must agree to use condoms during sexual intercourse with women of childbearing potential and must not plan to father a child from the date of signing informed consent throughout study treatment and for at least 3 months after the last dose of study treatment.

Exclusion criteria

• Diagnosis of smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), Waldenström macroglobulinemia, POEMS syndrome, amyloidosis, or primary or secondary plasma cell leukemia.
• Central nervous system (CNS) involvement or clinical evidence of leptomeningeal involvement.
• Known intolerance, hypersensitivity, allergy, or contraindication to daratumumab, lenalidomide, or CM336.
• Severe and/or uncontrolled cardiovascular disease, including:

• Unstable angina;
• Symptomatic congestive heart failure;
• Myocardial infarction within 6 months prior to enrollment;
• Severe and uncontrolled cardiac arrhythmias;
• Any other cardiovascular or cerebrovascular condition deemed by the investigator to make participation inappropriate.
• Active infection, including:

• Human immunodeficiency virus (HIV) infection;
• Active hepatitis B infection (HBV DNA positive);
• Active hepatitis C infection (HCV RNA positive);
• Active or latent syphilis infection (Treponema pallidum antibody positive);
• Active pulmonary tuberculosis, as evidenced by chest imaging or other relevant examinations within 3 months before screening or during the screening period;
• Concurrent malignancy or any serious concomitant disease that, in the investigator's judgment, could compromise participant safety or interfere with completion of the study.
• Pregnant or breastfeeding women.
• Expected life expectancy of less than 6 months.
• Any active gastrointestinal disorder that may impair the participant's ability to swallow oral medication or may interfere with absorption of study treatment.
• Major surgery within 2 weeks prior to enrollment (e.g., surgery requiring general anesthesia), incomplete recovery from prior surgery, or planned major surgery during study participation. Kyphoplasty and vertebroplasty are not considered major surgery. Participants undergoing procedures under local anesthesia may be eligible.
• Receipt of a live attenuated vaccine within 4 weeks before the first dose of study treatment.
• Any active severe psychiatric disorder, medical condition, symptom, or other circumstance that, in the investigator's judgment, may interfere with treatment, protocol compliance, or the ability to provide informed consent.
• Inability or unwillingness to provide written informed consent.