-Author name in bold denotes the presenting author
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1992 Differential CD38 Expression on Daratumumab-Naïve Vs. Resistant Multiple Myeloma - a Direct Stochastic Optical Reconstruction Microscopy (dSTORM) Analysis in 53 PatientsClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 652. Multiple Myeloma: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Research, Biological therapies, Antibody Therapy, Clinical Research, Plasma Cell Disorders, Diseases, real-world evidence, Therapies, Lymphoid Malignancies, Biological Processes, Technology and Procedures, omics technologies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Maximilian J Steinhardt, MD1*, Patrick Eiring, PhD2*, Cornelia Vogt3*, Umair Munawar4*, Seungbin Han5*, Larissa Haertle6,7*, Silvia Nerreter3*, Eva Teufel3*, Julia Mersi, MD1*, Xiang Zhou8*, Michael Hudecek, MD, PhD1*, Joaquin Martinez-Lopez, MD, PhD6*, Johannes M Waldschmidt, MD9, Hermann Einsele, MD, PhD1*, Leo Rasche, MD1*, Markus Sauer, PhD2* and K. Martin Kortüm, MD1*

1Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
2Department of Biotechnology and Biophysics, University of Würzburg, Würzburg, Germany
3Department of Internal Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
4Department of Internal Medicine II, University Hospital of Wuerzburg, Wuerzburg, Germany
5Department of Internal Medicine II, University Hospital Würzburg, Wuerzburg, Germany
6Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid, Madrid, Spain
7Department of Internal Medicine II, Department of Internal Medicine II, University Hospital WüRzburg, W, WüRzburg, Germany
8Department of Internal Medicine II, University Hospital Wuerzburg, WüRzburg, Germany
9Department of Internal Medicine II, University of Wuerzburg Medical Center, Wuerzburg, Germany


The anti-CD38 antibody Daratumumab (Dara) has become the new standard of care for the treatment of newly-diagnosed and relapsed/ refractory multiple myeloma (MM). At the same time, Dara resistance remains poorly understood. Potential resistance mechanisms have been proposed and range from intrinsic downregulation in CD38dim MM cells to genetic alterations and splicing variants which may affect CD38 epitope expression (Adamia, ASH 2022). Here, we used super-resolution microscopy for high-precision quantification of CD38 in MM and piloted this approach in a large cohort of 53 MM patients with vs. without Dara resistance.


Direct stochastic optical reconstruction microscopy (dSTORM) is a novel imaging modality based on photoswitching of certain fluorophores coupled to antibodies for molecular representation of surface molecules at unprecedented levels of resolution (<20 nM). To correlate CD38 expression data with clinical outcome, we divided our cohort based on treatment status into two groups: Dara-naïve (n = 31) vs. Dara-resistant (n = 22) patients. Imaging data was complemented by phenotypic assessment using a well-established multi-epitope anti-CD38 antibody (Cytognos), as per standard-of-care.


Mean CD38 receptor density as measured with Dara via dSTORM was significantly higher in Dara-naïve (of 48.81 ± 29.65 receptors/µm²) vs. Dara-resistant patients (15.52 ± 3.9 receptors/µm², p = 0.016). This finding was corroborated by multi-epitope phenotypic analysis which revealed mean CD38 receptor expression levels of 32.09 ± 13.14 receptors/µm² in Dara-naïve vs. 21.65 ± 17.73 receptors/µm² in Dara-resistant patients (p = 0.05). Lower CD38 expression via dSTORM vs. multi-epitope anti-CD38 staining was consistently observed in our cohort and may reflect ongoing blockage of the receptor binding site by Dara in cases with shorter time to last Dara application (median 53 days, range 1-189 days).

As there was no correlation with the interval between Dara application and sampling however, splice-site mutations affecting CD38 receptor accessibility as proposed by Adamia et al. may depict a more relevant mechanism of resistance in our Dara-resistant cohort. In a next step, we therefore investigated alternative epitope binding in Dara-resistant patients. To this end, we investigated antibody binding by dSTORM imaging for isatuximab (Isa), an alternative CD38-directed monoclonal antibody that binds to a location in the C-terminal portion of the CD38 extracellular domain which is entirely different from the Dara epitope. Interestingly, there was a trend for increased detection rate with Isa for mean CD38 receptor expression in Dara-resistant patients (22.2 ± 4.6 receptors/µm²) vs. Dara (15.5 ± 3.9 receptors/µm², p = 0.1) and on par with CD38 receptor expression. No data was available to assess Dara binding in Isa pre-exposed patients.


Innovative microscopy using dSTORM allows for high-resolution epitope quantification at unprecedented granularity. While this finding enables visual proof of differential epitope binding of Dara vs. Isa on CD38 in a clinically feasible setting, correlation studies to determine the clinical relevance of this observation remain ongoing.

Disclosures: Waldschmidt: Takeda: Consultancy; Pfizer: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Research Funding; Pharmamar: Consultancy; Skyline Diagnostics: Consultancy, Research Funding; abc biopply: Consultancy. Einsele: Janssen: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Amgen: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Takeda: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; GlaxoSmithKline: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Sanofi: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Novartis: Honoraria, Other: Consulting or advisory role, Travel support; Bristol Myers Squibb/Celgene: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding. Rasche: BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Skyline Dx: Research Funding; Sanofi: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Amgen: Consultancy; Janssen: Consultancy, Honoraria; Roche: Honoraria. Kortüm: GSK: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Abbvie: Honoraria; Takeda: Honoraria.

*signifies non-member of ASH