Identifying CD38+ cells in patients with multiple myeloma: first-in-human imaging using copper-64-labeled daratumumab

Abstract

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG. Here, we report the results of a phase 1 trial designed to (1) assess the safety and feasibility of 64Cu-daratumumab PET/CT and (2) preliminarily evaluate and characterize the ability of 64Cu-daratumumab to accurately detect or exclude MM lesions. A total of 12 daratumumab-naive patients were imaged. Prior to the injection of 15 mCi/5 mg of 64Cu-daratumumab, patients were treated with 0 (n = 3), 10 (n = 3), 45 (n = 3), or 95 mg (n = 3) of unlabeled daratumumab to assess its effect on image quality. No significant adverse events were observed from either unlabeled daratumumab or 64Cu-daratumumab. Of the dose levels tested, 45 mg unlabeled daratumumab was the most optimal in terms of removing background signal without saturating target sites. 64Cu-daratumumab PET/CT provided safe whole-body imaging of MM. A trial comparing the sensitivity and specificity of 64Cu-daratumumab PET/CT with that of FDG PET/CT is planned. This trial was registered at www.clinicaltrials.gov as #NCT03311828.

Conflict of interest statement

Conflict-of-interest disclosure: A.K. is a consultant for Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, Karyopharm Therapeutics, and Regeneron Pharmaceuticals; is on the scientific advisory board for Sutro Biopharma; serves on the speakers bureau for Amgen, Bristol Myers Squibb, and Takeda; and has stock ownership in Bristol Myers Squibb. J.P. is a consultant for Gilead. M.R. is on the speakers bureau for Janssen Pharmaceuticals. The remaining authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

64Cu-daratumumab biodistribution in subjects imaged without preinfusion of unlabeled daratumumab. (A) Maximum intensity projections showing diffuse 64Cu-daratumumab uptake in the liver, spleen, spine, and pelvis among the 3 patients. Magnification of the cervical (B) and pelvic (C) regions showing reduced radiotracer uptake (red squares) in regions corresponding to the sites in which patient 1 and patient 3 received palliative radiation. pts, patients.

Figure 2.

64Cu-daratumumab uptake as a result of increasing doses of unlabeled daratumumab. (A) PET/CT scan of 1 representative patient from each cohort treated with 64Cu-daratumumab and increasing concentrations of preinfused unlabeled antibody (0, 10, 45, and 95 mg) showing higher liver and spleen uptake in patients who did not receive any unlabeled daratumumab (0 mg) compared with the 10-, 45-, and 95-mg cohort of patients. Increased BM uptake was instead observed in the 10- and 45-mg cohort compared with both the 0- and the 95-mg cohorts. Coronal and axial images through these PET scans are also shown for visualizing relative organ uptake between the cohorts. Color bar is shared between all coronal and axial images. (B) Bar graphs showing the SUVmean values for each cohort in the organs of interest. The BM uptake of the plasmacytoma patient in the 45-mg cohort was not included in the graph. Two-way analysis of variance Tukey multiple comparison test was used to calculate the significance in liver and spleen uptake among treatment cohorts. (C) Dot plots showing radiotracer concentration in the whole blood of the different cohorts at early (1 to 3 hours) and late time points (25 to 27 hours). One-way analysis of variance Tukey multicomparison test was conducted. MIP, maximum intensity projection.

Figure 3.

Accumulation of64Cu-daratumumab in patients preadministered 45 mg of unlabeled daratumumab. (A) Maximum intensity projections on day 1 and day 2 showing significant BM uptake in the 2 patients with systemic MM. (B) Calvarial, vertebral, and pelvic uptake of 64Cu-daratumumab shown in coronal views of the PET/CT fused image. Color bars for the fused PET/CT images are shared between patient 7 and patient 8. (C-D) The patient with a solitary plasmacytoma had comparatively low levels of radiotracer in the marrow and enhanced activity in the circulation, as evident from the day 1 scan. Heterogeneous and elevated uptake of radiotracer in all 3 regions is seen in the first 2 patients when compared with the patient with solitary plasmacytoma.

Figure 4.

Comparison of64Cu-daratumumab with18F-FDG. (A-B) Maximum intensity projections comparing the uptake of 64Cu-daratumumab with 18F-FDG. Similar skeletal uptake in the right humerus for both tracers was observed (red rectangles) in patient 1 (A), while 64Cu-daratumumab, but not 18F-FDG uptake in the femur and fibula (SUVmax 3.3), was observed in patient 7 (B). (C) Sagittal cross-section through scans comparing 64Cu-daratumumab and 18F-FDG uptake in 2 regions (sternum and pelvis, red arrows) found positive for MM infiltration by biopsy. (D) Heterogeneous pelvis uptake of 64Cu-daratumumab in the region that was found positive for MM by biopsy (red arrow), but negative by 18F-FDG. (E) Biopsy acquired (red arrow) from patient 2 with right clavicular uptake on 18F-FDG but not on 64Cu-daratumumab, which was negative for MM infiltration upon biopsy. (F) Sagittal cross-section through scans comparing 64Cu-daratumumab and 18F-FDG uptake in another patient showing elevated 18F-FDG and no 64Cu-daratumumab uptake in the pleural-based mass, a region indicated to be myeloma-negative by biopsy. (G) Prominent calvarial uptake (yellow arrows) around bone lesions was seen in the 64Cu-daratumumab PET images of patient 1, which is typically obscured by the brain uptake of 18F-FDG. Color bars are shared between the 18F-FDG PET and 64Cu-DOTA–daratumumab PET images when 1 color bar is grouped with a pair of images.