CM313 Monotherapy in Patients with Relapsed/Refractory Multiple Myeloma or Marginal Zone Lymphoma: A Multicenter, Phase 1 Dose-Escalation and Dose-Expansion Trial
CM313 Monotherapy in Patients with Relapsed/Refractory Multiple Myeloma or Marginal Zone Lymphoma: A Multicenter Phase 1 Dose-Escalation and Expansion Trial
Academic Background
Multiple Myeloma (MM) is a common hematologic malignancy, accounting for approximately one-tenth of all hematologic malignancies. Although the use of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has significantly prolonged patient survival, relapse is almost inevitable. For patients refractory to IMiDs and PIs, the prognosis is poor, highlighting the urgent need to develop new targeted therapies. CD38 is a type II transmembrane glycoprotein highly expressed in hematologic malignancies but low in normal tissues, making CD38-targeting antibodies a novel therapeutic option for relapsed/refractory multiple myeloma (RRMM). Currently, two anti-CD38 monoclonal antibodies—daratumumab and isatuximab—have been approved for the treatment of RRMM.
CM313 is a novel humanized monoclonal antibody with a unique complementarity-determining region sequence that enables high-affinity binding to CD38-positive cells. Preclinical studies have shown that CM313 exhibits comparable in vitro killing activity and antitumor efficacy to daratumumab, with no significant off-target toxicity. Additionally, CM313 has demonstrated encouraging efficacy and safety in patients with immune thrombocytopenia. This paper reports the results of the first-in-human Phase 1 clinical trial of CM313 monotherapy in patients with RRMM and marginal zone lymphoma (MZL).
Source of the Paper
This paper was co-authored by Huixing Zhou, Zhongxia Huang, Baijun Fang, and other hematology experts from multiple hospitals in China, including Beijing Chao-Yang Hospital, Henan Cancer Hospital, and Peking University Third Hospital. The paper was published in 2025 in the American Journal of Hematology with the DOI 10.1002/ajh.27573.
Research Process
1. Study Design and Patient Recruitment
This was a multicenter, open-label Phase 1 clinical trial consisting of a dose-escalation phase and a dose-expansion phase (NCT04818372). The study enrolled 41 RRMM patients and 3 MZL patients. Inclusion criteria for RRMM patients included: confirmed diagnosis of MM according to the International Myeloma Working Group guidelines, measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2, and prior treatment with IMiDs and PIs. Exclusion criteria included primary refractory MM, amyloidosis, plasma cell leukemia, and POEMS syndrome.
2. Dose Escalation and Expansion
In the dose-escalation phase, patients received nine escalating doses of CM313 intravenously (0.006, 0.06, 0.3, 1.0, 2.0, 4.0, 8.0, 16, and 24 mg/kg), with dose-limiting toxicities (DLTs) observed every 21 days, followed by weekly (QW) injections for 7 doses, biweekly (Q2W) injections for 8 doses, and then every four weeks (Q4W) until disease progression or unacceptable toxicity. In the dose-expansion phase, CM313 was administered at doses of 4.0 and 16 mg/kg weekly for 8 doses, followed by biweekly injections for 8 doses, and then every four weeks until disease progression or unacceptable toxicity.
3. Primary and Secondary Endpoints
The primary endpoints included safety and tolerability in the dose-escalation phase and overall response rate (ORR) in the dose-expansion phase. Secondary endpoints included clinical benefit rate (CBR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics, and immunogenicity.
Research Results
1. Safety
No dose-limiting toxicities were reported in the dose-escalation phase, and the maximum tolerated dose was not reached. Infusion-related reactions (IRRs) were reported in 59.1% of patients, mostly grade 1 or 2, with only one patient in the 1.0 mg/kg cohort experiencing a grade 3 reaction. IRRs primarily occurred during the first infusion, with a median duration of 1.5 hours. The most common treatment-emergent adverse events (TEAEs) were decreased white blood cell count (47.7%) and decreased lymphocyte count (43.2%). Twenty-five patients reported grade ≥ 3 TEAEs, and 19 patients reported grade ≥ 3 drug-related TEAEs. Ten patients reported serious adverse events (SAEs), and six patients reported drug-related SAEs. No TEAEs led to permanent treatment discontinuation.
2. Efficacy
At a median follow-up of 19.4 months, the ORR in RRMM patients was 36.6% (15⁄41), with an ORR of 44.4% (8⁄18) in the 16 mg/kg cohort. The CBR was 46.3% (19⁄41) in all RRMM patients and 50.0% (9⁄18) in the 16 mg/kg cohort. The median TTR was 0.9 months, and the median DOR was 16.4 months. The median PFS was 4.3 months in all RRMM patients and 4.6 months in the 16 mg/kg cohort. The median OS was not reached, with 12-month and 24-month OS rates of 80.5% and 60.5%, respectively.
3. Pharmacokinetics and Pharmacodynamics
CM313 exposure increased in a greater-than-dose-proportional manner, with nonlinear and time-dependent elimination. Receptor occupancy (CD3+ T cells, CD14+ monocytes, and CD19+ B cells) reached 60%-100% at 2 hours after a single dose and remained high during treatment. Peripheral blood NK cell counts (total NK cells and CD38+ NK cells) decreased by 80%-100% compared to baseline in all dose groups.
Conclusions and Significance
CM313 monotherapy demonstrated favorable tolerability and significant clinical efficacy in RRMM patients. IRRs and other TEAEs were generally manageable, and RRMM patients achieved rapid, deep, and durable responses. The pharmacokinetic and pharmacodynamic profiles of CM313 support its further development in RRMM treatment. Currently, a multicenter Phase 1⁄2 study is underway to evaluate the efficacy and safety of subcutaneous CM313 in RRMM patients (NCT06126237).
Research Highlights
- Innovation: CM313 is a novel anti-CD38 monoclonal antibody with a unique complementarity-determining region sequence, demonstrating antitumor activity comparable to daratumumab.
- Safety: CM313 exhibited favorable tolerability in RRMM patients, with IRRs and other TEAEs being generally manageable.
- Efficacy: RRMM patients achieved rapid, deep, and durable responses, with ORR and CBR comparable to existing anti-CD38 monoclonal antibodies.
- Pharmacokinetic Advantages: CM313 exposure increased in a greater-than-dose-proportional manner, and receptor occupancy remained high during treatment.
Additional Valuable Information
Detailed data from this study are available from the corresponding author upon request. Further research will provide more mature OS data and explore the potential of CM313 in other hematologic malignancies.