Search

TPS8070 Background: Multiple myeloma (MM) remains an incurable disease. Although new treatment paradigms have increased survival, most patients relapse and treatment in later lines remains a challenge. Prognosis for patients refractory to immunomodulatory drugs, proteasome inhibitors and anti-CD38 antibodies is extremely poor, with an estimated survival of < 1 year (Gandhi et al. 2019). Therefore, patients with relapsed/refractory (R/R) disease represent a high unmet need, and new targets and treatment modalities are needed. Cevostamab is an IgG1-based T-cell-dependent bispecific antibody engineered to target the most membrane-proximal domain of fragment crystallizable receptor-like 5 (FcRH5) on myeloma cells, and cluster of differentiation 3 (CD3) on T cells. This dual binding results in efficient immunological synapse formation and T-cell-mediated killing of myeloma cells. In the ongoing first-in-human Phase I GO39775 study, intravenous (IV) administration of cevostamab monotherapy continues to show clinically meaningful activity and durable responses in patients with heavily pre-treated R/R MM (Trudel et al. ASH 2021), and uses Cycle (C) 1 step-up dosing for the mitigation of cytokine release syndrome (CRS). Subcutaneous (SC) delivery of antibody therapies has been shown to be effective and well tolerated and offers several advantages over IV administration in regards to improved healthcare utilization, including ease of administration, reduced treatment burden and reduced hospitalization. The slower absorption rate observed with SC versus IV antibody therapies may also support the potential for SC cevostamab to provide a further improved CRS profile (Bartlett et al. ASH 2021). CAMMA 3 (GO43227; ISRCTN26168155) is an open-label, multicenter, Phase Ib dose-escalation and dose-expansion trial evaluating the safety, tolerability, pharmacokinetics (PK) and preliminary activity of SC cevostamab monotherapy in patients with R/R MM. Methods: For inclusion, patients must be aged ≥18 years and must have R/R MM for which no established therapies are available or appropriate. Cevostamab is administered by SC injection in 28-day cycles, with step-up dosing in C1, q2w dosing in C2–6, and q4w dosing in C7–13. Patients may receive up to 13 cycles unless there is disease progression or unacceptable toxicity. Patients who respond to cevostamab but develop recurrent or progressive disease after 13 cycles may be eligible for cevostamab re-treatment. Primary objectives are to evaluate the safety and tolerability (including the maximum tolerated dose and dose-limiting toxicities) of SC cevostamab and to identify a recommended Phase II dose. Secondary objectives include assessment of PK, activity, and immunogenicity, and identification of biomarkers associated with response and resistance. Clinical trial information: 26168155.

Additional file 2: Supplementary figures.

Additional file 1: Supplementary methods and results.

Additional file 1: Supplementary Appendix. Specifically used regimens in Asia

Colorectal cancer (CRC) is one of the most common cancer types, however, newer drug development has reached a plateau at present. Bortezomib (PS-341, Velcade®) is a proteasome inhibitor and approved in the treatment of hematologic malignancies including multiple myeloma. A few trials of bortezomib alone or combination chemotherapy for CRC patients have been reported, however, the results were not so satisfactory, and it might be due to the lack of understanding on the action mechanism. In this report, we suggest the possibility of using bortezomib as a proteasome inhibitor in human colon cancer cells. Although bortezomib has been known to induce apoptosis and cell cycle arrest in various human cancer cells, the inhibitory mechanism of it was not clear. First, bortezomib induced G2-M arrest. Its treatment causes an increase of intracellular reactive oxygen species (ROS) levels and activation of ATM-CHK1 pathway, but not ATR. Also, activation of that pathway led to inactivation of cdc2. Moreover, treatment with NAC, ROS scavenger, inhibited phosphorylation of ATM and subsequent to decrease of cell number at G2-M phase in response to bortezomib indicating that the increased level of ROS after exposure to bortezomib is a result of ATM phosphorylation. In addition, knockdown of endogenous ATM by RNA interference induced the decreased sensitivity to bortezomib. Therefore, these results suggest that bortezomib induces G2-M arrest through ROS-inducible ATM phosphorylation and shows antitumor activity in human colon cancer cells, implying a potential possibility of further investigations in the treatment of CRC patients. Acknowledgement: This study was supported by grants from the Korea Health 21 R&D Project, Ministry of Health and Welfare and Family Affairs, Korea (A062254).