⁶⁸Ga-Pentixafor PET/CT May Fail to Detect Recurrent Multiple Myeloma with Extramedullary Disease

Abstract

Two patients with a history of multiple myeloma experienced a recurrence of the disease.¹⁸F-FDG PET/CT revealed prominent extramedullary disease as well as multi-foci in the bone marrow, both with increased FDG uptake. However, on ⁶⁸Ga-Pentixafor PET/CT, all the myeloma lesions showed significantly lower tracer uptake in comparison with ¹⁸F-FDG PET. This false-negative result of recurrent multiple myeloma with extramedullary disease may be a potential limitation of ⁶⁸Ga-Pentixafor in assessing multiple myeloma.

Figure 1. A 64-year-old man with a history of multiple myeloma (MM) for 8 years, recently presented with a parasternal mass and blindness of the right eye. Serum protein electrophoresis and immunofixation electrophoresis showed positivity for the monoclonal protein (16.2 g/L, IgA-λ). A biopsy of the parasternal mass confirmed plasmacytoma. Considering the recurrence of MM, ¹⁸F-FDG PET/CT was referred. The maximum intensity projection (MIP) of the PET (A) detected multi-foci with intense radioactivity all over the body. The axial fusion images (B,C, bone window) showed most of the FDG-avid foci were located in bone marrow, most prominently in the sternum and pelvis (SUVmax 34.0), accompanied by lytic bone destruction and paramedullary masses. Additionally, the axial fusion images (D,E, soft tissue window) demonstrated extramedullary disease (EMD) with intense FDG uptake in the right kidney and paranasal sinus (SUVmax 22.3), which also involved the right orbit and temporal lobe. Since ⁶⁸Ga-Pentixafor has been reported to be advantageous over ¹⁸F-FDG in assessing MM^1,2, he was included in the clinical trial of ⁶⁸Ga-Pentixafor (NCT03436342). In the MIP (F) and corresponding axial fusion images of ⁶⁸Ga-Pentixafor PET (G–J), the above hypermetabolic foci showed significantly lower tracer uptake as compared with ¹⁸F-FDG PET (bone marrow lesions: SUVmax 16.5; EMD: SUVmax 7.4).

Figure 1. A 64-year-old man with a history of multiple myeloma (MM) for 8 years, recently presented with a parasternal mass and blindness of the right eye. Serum protein electrophoresis and immunofixation electrophoresis showed positivity for the monoclonal protein (16.2 g/L, IgA-λ). A biopsy of the parasternal mass confirmed plasmacytoma. Considering the recurrence of MM, ¹⁸F-FDG PET/CT was referred. The maximum intensity projection (MIP) of the PET (A) detected multi-foci with intense radioactivity all over the body. The axial fusion images (B,C, bone window) showed most of the FDG-avid foci were located in bone marrow, most prominently in the sternum and pelvis (SUVmax 34.0), accompanied by lytic bone destruction and paramedullary masses. Additionally, the axial fusion images (D,E, soft tissue window) demonstrated extramedullary disease (EMD) with intense FDG uptake in the right kidney and paranasal sinus (SUVmax 22.3), which also involved the right orbit and temporal lobe. Since ⁶⁸Ga-Pentixafor has been reported to be advantageous over ¹⁸F-FDG in assessing MM^1,2, he was included in the clinical trial of ⁶⁸Ga-Pentixafor (NCT03436342). In the MIP (F) and corresponding axial fusion images of ⁶⁸Ga-Pentixafor PET (G–J), the above hypermetabolic foci showed significantly lower tracer uptake as compared with ¹⁸F-FDG PET (bone marrow lesions: SUVmax 16.5; EMD: SUVmax 7.4).

Figure 2. A 70-year-old woman with smoldering MM was found to have a solitary plasmacytoma in the frontal bone that was surgically resected one year ago. Recently, she complained of backache and was found with a retroperitoneal mass. Elevation of the monoclonal protein (19.0 g/L) and the presence of IgA-λ in serum immunofixation electrophoresis and infiltration of plasma cells (17.5%) in bone marrow aspiration confirmed the recurrence of MM. ¹⁸F-FDG PET/CT was then performed. The MIP image (A) showed an FDG-avid mass in the abdomen. The axial fusion images (B,C) showed the mass was located in the retroperitoneum with uneven FDG distribution (B, SUVmax 5.7). Furthermore, several bone marrow lesions with increased FDG uptake and lytic bone destruction were found in the occipital bone, C4 vertebra, and right 8th rib (C, SUVmax 4.1). She was also included in the clinical trial and underwent ⁶⁸Ga-Pentixafor PET/CT (D, MIP image; E,F, axial fusion images). However, the retroperitoneal mass and the bone marrow lesions did not demonstrate increased uptake of ⁶⁸Ga-Pentixafor. She then received chemotherapy against MM, and the retroperitoneal mass disappeared after 2 cycles of chemotherapy. ⁶⁸Ga-Pentixafor, a CXCR4-targeted agent, has recently been introduced in MM [1,2,3,4]. Our recent study demonstrated ⁶⁸Ga-Pentixafor had a significantly higher sensitivity than ¹⁸F-FDG in detecting newly diagnosed MM². However, ⁶⁸Ga-Pentixafor was inferior to ¹⁸F-FDG in the current two cases of recurrent MM with extensive EMD. CXCR4 is overexpressed in myeloma cells and is responsible for plasma cells’ homing to the bone marrow niche [5,6]. Development of EMD in MM is associated with CXCR4/CXCL12 downregulation through cell adhesion disruption [7,8,9]. In line with the current cases, Lapa C. et al.’s study found that some EMDs were exclusively identified by ¹⁸F-FDG and were not sensitive to ⁶⁸Ga-Pentixafor [1]. Thus, the significantly lower uptake than ¹⁸F-FDG of recurrent MM with EMD may be a potential limitation of ⁶⁸Ga-Pentixafor in assessing MM.

Figure 2. A 70-year-old woman with smoldering MM was found to have a solitary plasmacytoma in the frontal bone that was surgically resected one year ago. Recently, she complained of backache and was found with a retroperitoneal mass. Elevation of the monoclonal protein (19.0 g/L) and the presence of IgA-λ in serum immunofixation electrophoresis and infiltration of plasma cells (17.5%) in bone marrow aspiration confirmed the recurrence of MM. ¹⁸F-FDG PET/CT was then performed. The MIP image (A) showed an FDG-avid mass in the abdomen. The axial fusion images (B,C) showed the mass was located in the retroperitoneum with uneven FDG distribution (B, SUVmax 5.7). Furthermore, several bone marrow lesions with increased FDG uptake and lytic bone destruction were found in the occipital bone, C4 vertebra, and right 8th rib (C, SUVmax 4.1). She was also included in the clinical trial and underwent ⁶⁸Ga-Pentixafor PET/CT (D, MIP image; E,F, axial fusion images). However, the retroperitoneal mass and the bone marrow lesions did not demonstrate increased uptake of ⁶⁸Ga-Pentixafor. She then received chemotherapy against MM, and the retroperitoneal mass disappeared after 2 cycles of chemotherapy. ⁶⁸Ga-Pentixafor, a CXCR4-targeted agent, has recently been introduced in MM [1,2,3,4]. Our recent study demonstrated ⁶⁸Ga-Pentixafor had a significantly higher sensitivity than ¹⁸F-FDG in detecting newly diagnosed MM². However, ⁶⁸Ga-Pentixafor was inferior to ¹⁸F-FDG in the current two cases of recurrent MM with extensive EMD. CXCR4 is overexpressed in myeloma cells and is responsible for plasma cells’ homing to the bone marrow niche [5,6]. Development of EMD in MM is associated with CXCR4/CXCL12 downregulation through cell adhesion disruption [7,8,9]. In line with the current cases, Lapa C. et al.’s study found that some EMDs were exclusively identified by ¹⁸F-FDG and were not sensitive to ⁶⁸Ga-Pentixafor [1]. Thus, the significantly lower uptake than ¹⁸F-FDG of recurrent MM with EMD may be a potential limitation of ⁶⁸Ga-Pentixafor in assessing MM.