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Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma


Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. NCT02757326.

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Fig. 1
Fig. 2

Data availability

The data that support the findings of this study are available on request from the corresponding author. Certain data are not publicly available due to privacy or ethical restrictions.



Adverse event


Twice a day


Chimeric antigen receptor


Common Terminology Criteria for Adverse Events


Dexamethasone, cyclophosphamide, etoposide, and cisplatin


Dose-limiting toxicity


Eastern Cooperative Oncology Group performance status


Immunomodulatory drug


International Myeloma Working Group


Multiple myeloma


Maximal tolerated dose


Newly diagnosed multiple myeloma




Progression-free survival


Proteasome inhibitor




Progressive disease


Relapsed/refractory multiple myeloma


Serious adverse event


Stable disease


Sphingosine kinase


Velcade, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide


Very good partial response


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We thank patients and their families for their support and participation in this study.


This work was supported by NCI R44CA199767 (SBIR award to CS), NCI R01CA197792 (YK), NCI R21CA234701 (YK), NCI P01CA203628 (BO) and Duke Cancer Center Start-up fund (YK). RedHill Biopharma Limited is the IND holder and sponsored the trial including data monitoring and CRO activities.

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Authors and Affiliations



YK: designed the experiments and wrote the manuscript; PS, DF, and SF: performed the correlative studies; CG, GL, ES, AG, SAT, and BNR: accrued patients for the studies; ZL: provided biostatistical support; BL and BO: provided important inputs; LM and VKB-Y: supported the clinical studies; CS: designed the clinical study, wrote and edited the manuscript, and the awardee of the NCI SBIR grant; TP: Medical Director for RedHill Biopharma, the sponsor of the clinical study, wrote and edited the manuscript, and provided input on the protocol and analysis of results.

Corresponding author

Correspondence to Yubin Kang.

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Ethics approval and consent to participate

The study was conducted according to the Declaration of Helsinki and the International Council on Harmonization. The Duke Institutional Review Board (IRB) approved the protocol. All patients provided written informed consent.

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All authors approved the manuscript and the submission.

Competing interests

Yubin Kang received research funding from InCyte Corporation and a consultancy fee from Takeda Oncology USA and Sanofi Genzyme Corp. Charles Smith is the CEO and President, and Lynn Maines is employed by Apogee Biotechnology Corporation. Vered Katz Ben-Yair and Terry Plasse are consultants to RedHill Biopharma Limited. All other authors declare no competing conflicts of interest.

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Kang, Y., Sundaramoorthy, P., Gasparetto, C. et al. Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma. Ann Hematol 102, 369–383 (2023).

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  • Phase I trial
  • Multiple myeloma
  • Opaganib
  • ABC294640
  • Sphingosine kinase inhibitor
  • Maximal tolerated dose
  • Response