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1951 Higher CD56 Expression on Multiple Myeloma Cells Increases CD38 Expression, Reduces Intracellular NAD+ Levels, and Enhances the Efficacy of Daratumumab-Based Treatment Strategies

Program: Oral and Poster Abstracts
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Biological therapies, Antibody Therapy, Translational Research, Plasma Cell Disorders, Diseases, Therapies, Lymphoid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Giulia Giorgetti1,2*, Pamela Becherini2*, Elena Maroto-Martin1,3*, Daniela Fenoglio4,5*, Debora Soncini2*, Claudia Martinuzzi4*, Santina Bruzzone6*, Andrea Benzi6*, Aimable Nahimana7*, Chiara Rosa Maria Uras8*, Anaïs Schavgoulidze1,9*, Jessica Ng Fong1*, Roberto M. Lemoli, MD10,11*, Nikhil C Munshi, MD1,3,12*, Mariateresa Fulciniti, PhD1,3 and Michele Cea4,13*

1Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA
2Clinic of Hematology, Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genova, Italy
3Harvard Medical School, Boston, MA
4IRCCS Ospedale Policlinico San Martino, Genova, Italy
5Centre of Excellence for Biomedical Research and Department of Internal Medicine, University of Genoa, Genova, Italy
6Department of Experimental Medicine (DIMES), University of Genoa, Genova, Italy
7Central Laboratory of Hematology, Department of Medical Laboratory and Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
8Department of Experimental Medicine, Centre of Excellence for Biomedical Research, University of Genoa, Genova, Italy
9Toulouse Cancer Research Center-Oncopole, Toulouse University, INSERM UMR1037, Toulouse, France
10Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy
11IRCCS - San Martino Hospital, Genoa, Italy
12VA Boston Heathcare System, Boston, MA
13Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genova, Italy

NCAM1 (Neural Cell Adhesion Molecule 1), also known as CD56, is a member of the immunoglobulin superfamily and is deregulated in many tumors. In multiple myeloma (MM), high levels of CD56 are observed on MM cells in 70% of patients. This molecule has several functions including tumor growth, adhesion and response to therapy, as suggested by several studies. However, an extensive analysis of the specific landscape underlying its presence and its role as a prognostic biomarker is lacking, especially in MM.

Here, we evaluated CD56 surface levels on tumor cells collected from 136 newly diagnosed MM patients (Policlinic San Martino Hospital, Genoa, Italy) and found that low CD56 expression significantly correlated with extramedullary disease (EMD) (p = .016) while high CD56 levels were associated with a lower risk of disease progression or death (p = .003). When evaluating the surface expression of MM cells, we surprisingly found a positive correlation between CD56 and CD38 levels (p < .0001), which was replicated in a panel of MM cell lines (p = .02).

To gain insight into the biological significance of this, we challenged a panel of MM cell lines with Daratumumab (DARA), a standard-of-care CD38 antibody that kills MM cells through multiple mechanisms including antibody-dependent cellular cytotoxicity (ADCC). Given the correlation between the expression of CD56 and CD38, we hypothesized that higher CD56 expression would lead to enhanced DARA-mediated ADCC. We performed standard 3-hour ADCC assays using NK cells from healthy donors as effector cells and CD56-positive or -negative cell lines. Myeloma cells were stained with calcein-AM and co-cultured with NK cells at indicated effector:target (E:T) ratios. The assay was assessed in the presence or absence of 1μg/mL Daratumumab. We found that MM cell lines with high expression of CD56 were more sensitive to DARA-mediated NK cell killing (p = .004 at ratio 1:1 E:T). Consistently, MM patients with higher levels of CD56 (N = 8) had better overall response rates to DARA-based therapies compared to patients with lower levels (N = 9). CD56 and CD38 are not known to interact, so this correlation may be mediated by the NAD+ biosynthesis pathway.

CD38 is a critical enzyme for breaking down NAD+ in cells. We found that ectopic expression of CD56 led to lower intracellular NAD+ levels (MM1S overexpressing CD56 p = .0875; RPMI 8226 overexpressing CD56 p = .0003) and increased CD38 enzymatic activity (MM1S overexpressing CD56 p = .0035; RPMI 8226 overexpressing CD56 p = .0478), as measured by a cyclase activity assay. As a result, CD56 surface levels affected MM cells' sensitivity to NAD+-lowering agents, including next-generation NAMPT inhibitors. Indeed, MTS assays confirm that CD56-overexpressing MM cells were more vulnerable to these small molecules, whereas CD56 silencing made cells more resistant.

In conclusion, our data suggest CD56 levels as an important determinant of sensitivity to DARA-based therapies. Moreover, our results suggest the next-generation NAMPT inhibitors as an additional therapeutic strategy for CD56-expressing MM patients.

Disclosures: No relevant conflicts of interest to declare.

OffLabel Disclosure: NAMPT inhibitors

*signifies non-member of ASH