Multiple myeloma (MM) is the second most common blood cancer. A novel FDA-approved antibody-based drug daratumumab (DARA) has shown to improve therapeutic efficacy when combined with common triplet regimens. DARA targets CD38, a protein that is highly expressed on the surface of MM cells; it kills MM cells by triggering antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, high-risk MM patients who too often experience relapsed or refractory disease received little benefit from DARA. As a monotherapy, the response rate to DARA remains low. Thus, understanding how MM cells resist to DARA could help us to improve the therapeutic efficacy and surv...

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Multiple myeloma (MM) is the second most common blood cancer. A novel FDA-approved antibody-based drug daratumumab (DARA) has shown to improve therapeutic efficacy when combined with common triplet regimens. DARA targets CD38, a protein that is highly expressed on the surface of MM cells; it kills MM cells by triggering antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, high-risk MM patients who too often experience relapsed or refractory disease received little benefit from DARA. As a monotherapy, the response rate to DARA remains low. Thus, understanding how MM cells resist to DARA could help us to improve the therapeutic efficacy and survival in MM patients. Using the largest public database for MM patients, we examined tumor gene expression and patients' best clinical response, and we identified a candidate NHE6 that may be involved in MM DARA resistance. We found that NHE6 is highly expressed in MM cells and its high expression is correlated with patients' poorer prognosis, high-risk genetic features, and MM stage progression. Moreover, MM cells with high NHE6 level was less responsive to DARA. NHE6 is a membrane transporter of early endosomes, whose movement is crucial for engulfment of antibody-antigen into the cells. Thus, we hypothesize that NHE6 may contribute to DARA resistance by promoting CD38 internalization into MM cells, leading to sequestering of CD38-DARA complex on MM cell surface for ADCC and CDC. We will investigate the role and mechanism by which MM cell NHE6 induces DARA resistance (aim 1) and develop NHE6 as a new target to improve DARA efficacy in mouse models and patients (aim 2). Knowledge gained from our study will elucidate an innovative insight on how MM cell escapes from DARA treatment. Given that DARA is an emerging compound used as standard care for MM patients, we believe that our new strategy of targeting NHE6 could significantly improve DARA-based MM therapy.

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