*3.5. 68Ga-Pentixafor*

Chemokine receptor 4 (CXCR4) is a pleiotropic, G-protein coupled chemokine receptor expressed on hematopoeitic stem and progenitor cells in the bone marrow niche. CXCR4 can mediate the migration as well as the homing process of these cells in the bone marrow in response to its ligand, stromal cell-derived factor 1 (SDF-1) [58]. In MM, CXCR4 is involved in myeloma cell homing, bone marrow retention, angiogenesis and metastasis, while collective evidence from several studies support the pivotal role of CXCR4 in different stages of MM, disease progression, development of therapeutic resistance and MRD, as well as poor prognosis [59–66].

68Ga-pentixafor is a radiolabeled peptide that shows high affinity for CXCR4. The major advantage of the tracer is its potential use in a thera(g)nostic approach in combination with the 177Lu- or 90Y-labeled agent pentixather in progressive MM patients with CXCR4-positive tumor cells, as confirmed by a 68Ga-pentixafor PET scan. Preliminary results of the CXCR4-directed endoradiotherapy with pentixather in three heavily pretreated MM patients were relatively encouraging with low levels of toxicity, good tolerance of the treatment and high initial response rates [67].

Two studies have investigated the diagnostic performance of 68Ga-pentixafor in comparison to 18F-FDG in patients with advanced MM. The initial results in 14 MM patients showed a slight superiority of the novel tracer over 18F-FDG in the relapsed disease setting, with 10/14 patients showing MM manifestations on 68Ga-pentixafor PET, while 9/14 were positive on 18F-FDG PET [68]. The larger second study included 35 patients undergoing 68Ga-pentixafor PET/CT for evaluation of eligibility for endoradiotherapy. In 19 patients, 18F-FDG PET/CT was also available for correlation. 68Ga-pentixafor PET detected CXCR4-positive disease in 23/35 subjects (66%). Importantly, in the 19 patients in whom a comparison to 18F-FDG PET was available, 8/19 (42%) patients had an equal number of lesions with both tracers, in 4/19 (21%) subjects 68Ga-pentixafor PET detected more lesions, while 18F-FDG PET proved superior in 7/19 (37%) of them [69].

Most recently, the first comparative study of 18F-FDG and 68Ga-pentixafor PET/CT in 30 patients with newly diagnosed MM was published. 68Ga-Pentixafor PET/CT had a significantly higher positive rate than 18F-FDG PET/CT in detection of myeloma lesions (93.3% vs. 53.3%). In quantitative analysis, bone marrow uptake values in 68Ga-Pentixafor were positively correlated with end organ damage, staging, and laboratory biomarkers related to tumor burden including serum β2-microglobulin, serum free light chain, and 24-h urine light chain. In contrary, in 18F-FDG PET/CT, only the SUV mean of total bone marrow was positively correlated with serum free light chain and 24-h urine light chain [70]. These results indicate that 68Ga-pentixafor PET might be a promising biomarker in assessing the tumor burden of newly diagnosed MM patients.
