CM336 Plus Isa-VR in Newly Diagnosed Primary Plasma Cell Leukemia

A Prospective, Single-Arm, Single-Center, Phase II Study Evaluating the Safety and Efficacy of CM336 in Combination With Isatuximab, Lenalidomide, and Bortezomib in Newly Diagnosed Primary Plasma Cell Leukemia

The goal of this clinical trial is to learn whether CM336, a BCMA/CD3 bispecific antibody, can improve treatment outcomes when combined with isatuximab, lenalidomide, and bortezomib in adults with newly diagnosed primary plasma cell leukemia (pPCL). The study will also evaluate the safety of this treatment combination.

The main questions it aims to answer are:

How many participants achieve minimal residual disease (MRD) negativity after 9 treatment cycles? What side effects occur during treatment with CM336 combined with isatuximab, lenalidomide, and bortezomib? How many participants respond to treatment, and how long do those responses last? How long do participants remain free from disease progression, and how long do they survive after starting treatment? All participants will receive the study treatment. There is no comparison group in this study.

Participants will:

Receive CM336 by subcutaneous injection together with isatuximab, lenalidomide, and bortezomib in 28-day treatment cycles.

Undergo regular blood tests, bone marrow examinations, and disease assessments to monitor treatment response and safety.

Have stem cells collected after the first 3 treatment cycles if appropriate. Continue treatment for up to 18 cycles, followed by maintenance treatment with isatuximab and lenalidomide until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision.

Be monitored throughout the study for side effects.

Inclusion Criteria:

1. Able to understand and voluntarily sign a written informed consent form (ICF).

2. Age 18 to 75 years.

3. Newly diagnosed primary plasma cell leukemia (pPCL) according to International Myeloma Working Group (IMWG) criteria, defined as either:

   • ≥5% circulating plasma cells on peripheral blood smear; or
   • Absolute circulating plasma cell count >2 × 10⁹/L.

   Patients who have received no more than one prior cycle of anti-myeloma therapy before enrollment are eligible, provided they have not received monoclonal antibodies or immunotherapy agents.

4. Measurable disease, defined by at least one of the following:

   • Serum M-protein ≥10 g/L as measured 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).

5. 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.

6. Adequate renal function, defined as creatinine clearance ≥30 mL/min, calculated using the Cockcroft-Gault formula.

7. Adequate hematologic function within 7 days prior to enrollment, defined as:

   • White blood cell (WBC) count ≥1.5 × 10⁹/L;
   • Absolute neutrophil count (ANC) ≥1.0 × 10⁹/L;
   • Hemoglobin ≥70 g/L;
   • Platelet count ≥50 × 10⁹/L;

   Alternatively, eligibility may be determined by the investigator based on clinical judgment.

8. Participants receiving hematopoietic growth factor support, including erythropoietin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or thrombopoietic agents, must have a washout period of at least 2 weeks between the last administration of growth factor support and screening assessments.

9. 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 count assessment at screening.

10. Able and willing to receive protocol-recommended prophylactic anticoagulation therapy.

11. Female participants of childbearing potential must have a negative serum pregnancy test at screening and agree to use effective contraception from the time of signing the informed consent form, 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 time of signing informed consent through 3 months after the last dose of study treatment.

Exclusion Criteria:

1. Diagnosis of smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), Waldenström macroglobulinemia, POEMS syndrome, amyloidosis, or secondary plasma cell leukemia.

2. Central nervous system (CNS) involvement or clinical evidence of leptomeningeal involvement.

3. Known intolerance, hypersensitivity, allergy, or contraindication to CM336, isatuximab, bortezomib or lenalidomide.

4. 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.

5. 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 (positive Treponema pallidum antibody test); Active pulmonary tuberculosis, as evidenced by chest imaging or other relevant assessments within 3 months prior to screening or during the screening period; Any other infection considered by the investigator to make participation inappropriate.

6. Concurrent active malignancy or any serious concomitant disease that, in the investigator's judgment, could compromise participant safety or interfere with study participation.

7. Pregnant or breastfeeding women.

8. Estimated life expectancy of less than 6 months.

9. Active gastrointestinal disorders that may impair the participant's ability to swallow oral medication or may interfere with the absorption of study treatment.

10. 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.

11. Receipt of a live attenuated vaccine within 4 weeks before the first dose of study treatment.

12. 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.

13. Inability or unwillingness to provide written informed consent.