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Abstract Introduction: With over 30,000 new cases annually, multiple myeloma (MM) is the second most common blood cancer in the United States. The development of new myeloma drugs and immunotherapies in the past 2-3 decades has significantly improved outcomes; however, further progress is severely limited by the proclivity of neoplastic bone marrow plasma cells to acquire drug resistance in the course of treatment. Elucidating the molecular underpinnings of resistance is thus an important research task poised to uncover new molecular targets. We believe that CLPTM1L (Cleft Lip and Palate Transmembrane 1-Like protein) is a potential target in multiple myeloma. CLPTM1L is an endoplasmic reticulum (ER) stress-inducible, transmembrane, oncofetal protein. Its increased plasma membrane expression has been implicated in chemoresistance and poor survival of patients with solid tumors, such as pancreatic and ovarian cancer. Importantly, CLPTM1L is expressed on the plasma membrane of myeloma cells and thus lends itself to immunotherapy using antibody or CAR T cell-based strategies, particularly those targeting chemotherapy-resistant cancers. Methods: Pan-cancer analysis of CLPTM1L expression was performed with the help of the Human Protein Atlas. Western blotting and flow cytometry were employed to measure CLPTM1L levels in myeloma cells and demonstrate its expression on the plasma membrane, respectively. The online ClusPro protein-protein docking tool was used to evaluate the interaction of CLPTM1L with HSPA5 (aka GRP78), AKT1 and PI3K. Thapsigargin (0–2 μM, 16 hours) was used to induce ER stress in OPM2 myeloma. siRNA was used to knock down CLPTM1L in OPM2 and RPMI8226 myeloma, followed by measurement of cell growth and survival, immunoblot analysis of AKT activation and regulators of programmed cell death, and determination of sensitivity (IC50) to bortezomib. Co-immunoprecipitation was used to confirm the CLPTM1L-HSPA5 interaction predicted by ClusPro. Results: Interrogation of the Human Protein Atlas demonstrated that CLPTM1L is highly expressed in myeloma cells compared to a large panel of non-cancer cell lines. This was confirmed at the bench using western blotting and flow cytometry. Molecular docking analysis of CLPTM1L using ClusPro revealed a potential physical interaction with GRP78, PI3K, and AKT1, with ClusPro scores of -1296.4, -1413.5, and -1100.8, respectively. Co-immunoprecipitation confirmed the CLPTM1L-HSPA5 (GRP78) interaction in OPM2 myeloma cells. siRNA-mediated knockdown of CLPTM1L in OPM2 and RPMI8226 led to down regulation of pAKT (T308) and upregulation of pro-apoptotic proteins such as cleaved caspase-3, BID and cleaved PARP. In sync with that, the anti-apoptotic proteins, BCL2 and BCLXL, were downregulated. Knock down of CLPTM1L in OPM2 enhanced the sensitivity to the proteasome inhibitor, bortezomib, resulting in a drop in IC50 from 12 nM to 7 nM. Treatment of OPM2 using the ER stress inducer, thapsigargin, led to upregulation of CLPTM1L together with increased levels of the ER stress markers, calnexin and CHOP. Conclusion: CLPTM1L is an ER stress-inducible candidate myeloma gene that regulates cell growth / survival through AKT signaling. Its inhibition sensitizes myeloma cells to proteasome inhibitors. Ongoing studies in our group are aimed at elucidating this mechanism in greater depth. Given that CLPTM1L is expressed on the plasma membrane of primary, patient-derived myeloma cells, it may constitute an attractive molecular target for novel immune therapies of myeloma.