CD33 Is Expressed in a Significant Subset of Multiple Myeloma Patients in the US and May Represent a Viable Therapeutic Target

Background: CD33 (sialic acid binding Ig-like lectin 3; SIGLEC3) is a type I transmembrane receptor glycoprotein that may function as a sialic acid-dependent cell adhesion molecule. CD33 is generally viewed as a marker of myeloid lineage, and its expression on lymphoid lineage cells is thought to be aberrant and rare, reported to be present in only 1% - 8% of non-myeloid samples, with estimated similarly low expression in multiple myeloma plasmocytes specifically. Some data indicate that CD33 may be expressed on multiple myeloma (MM) plasmocytes in a much larger proportion of MM patients than previously thought, and that when expressed it may confer worse prognosis. However, these data were obtained from established MM cell lines and small series of patient samples. For the first time, we have attempted to obtain data on CD33 expression on MM plasmocytes from patient samples in a large US library.

Methods: Data from the IA9 release of the MMRF CoMMpass study was downloaded from the MMRF Researcher Gateway. The per patient visit clinical table was filtered to include only patient visits with numerical calls in the "CD33_detected" field, which indicates whether CD33 was detected on the surface of MM plasmocytes by flow cytometry. Data in the per patient visit clinical table was further filtered to include only "Baseline" and "Confirm Progression" visits. Any patient with a baseline visit was considered in the analysis of baseline, newly-diagnosed MM patients. Only patients with both a baseline and at least one confirm progression visit were considered in the analysis of patients with CD33 data at two or more timepoints. For each visit, the percent CD33+ plasma cell calls (CD33_PC_Percent) were assigned a bin as follows: <20%, 20-39%, 40-59%, 60-79%, 80-100% CD33 positive plasma cells. High expression of CD33+ was defined as CD33 detected in ≥40% of MM plasmocytes whereas very high expression was defined as CD33 detected in ≥60% of MM plasmocytes.

Results: The IA9 CoMMpass release includes 995 samples that have corresponding CD33 data, representing 865 unique patients. Samples were collected at baseline for newly-diagnosed MM patients (n=865) and at relapse when patients had progression events (n=59 patients, 66 samples). Among newly-diagnosed MM patients at baseline 25% (n=219) of patient tumors expressed CD33 based on flow cytometry analysis, whereas 75% (n=646) did not. Among patients with CD33+ MM, the proportion of CD33+ plasmocytes detected were as follows: <20% cells: 11.0% of samples (n=24); 20%-39% of cells: 27.4% of samples (n=60); 40%-59% of cells: 20.5% of samples (n=45); 60%-79% of cells: 10.5% of samples (n=23); 80-100% of cells: 30.6% of samples (n=67). At baseline, 61.6% (n=135) of patients exhibited a high percentage of CD33+ plasmocytes (≥40% of MM plasmocytes expressing CD33) and 41% (n=90) of patients exhibited a very high percentage of CD33+ plasmocytes (≥60% of MM plasmocytes expressing CD33).

Similarly to newly diagnosed patients, among the 59 patients that had samples available at baseline and at least one progression visit, 27.1% (n=16) were CD33+ at relapse. Plasmocytes from 62.7% (n=37) were CD33- at both baseline and progression, 20.3% (n=12) were CD33+ at both baseline and progression, 10.2% (n=6) were CD33+ at baseline and CD33- at progression, and 6.8% (n=4) were CD33- at baseline and CD33+ at progression. Among the 12 patients that were CD33+ at both baseline and progression, 58.3% (n=7) had very high CD33 at both timepoints. Of the other 5 patients, 25% (n=3) exhibited an increase in the percent of CD33+ plasmocytes, going from low to high (n=1), low to very high (n=1), and high to very high (n=1), whereas 16.7% (n=2) of patients exhibited a decrease in the percent of CD33+ plasmocytes, going from very high to high (n=1) or very high to low (n=1) at baseline versus relapse.

Conclusions: These findings indicate that a substantial proportion of MM patients express CD33 on their myeloma plasmocytes, including relapsed patients. Therefore, CD33 may represent a viable target in multiple myeloma. Relevance of this pattern of CD33 expression may be further enhanced by the presence of a number of CD33 targeting agents already in clinical trials in acute myeloid leukemia, which could allow for a rapid translation into the clinical settings in multiple myeloma. One trial in relapsed and refractory multiple myeloma with a CD33 targeting radiolabeled monoclonal antibody is underway.