Ga-68 Pentixafor PET/CT in multiple myeloma and its correlation with clinical parameters – institutional pilot study

doi:10.21203/rs.3.rs-5135393/v1

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Ga-68 Pentixafor PET/CT in multiple myeloma and its correlation with clinical parameters – institutional pilot study

https://doi.org/10.21203/rs.3.rs-5135393/v1

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Objective:

This study evaluates the role of Ga-68 Pentixafor PET/CT in staging and follow-up of multiple myeloma (MM) and its correlation with clinical parameters.

Methods:

Thirteen participants (9 males, 4 females; median age 65 years) with MM were recruited in this prospective observational study. Six participants were included for staging evaluation, seven were included for follow-up evaluation and underwent Ga-68 Pentixafor PET/CT. Focal PET-positive bone marrow lesions or diffuse bone marrow uptake (uptake more than liver) was considered a positive scan. Quantitative variables like SUVmax, SUVmean, total bone marrow volume and uptake (TBMV & TBMU) and tumor to background ratio (TBRmax) were obtained. Durie Salmon Plus Staging (DSPS) was used for MM staging by PET/CT and was compared with the International Staging System (ISS). Statistical comparison was performed between PET/CT quantitative variables and laboratory parameters.

Results:

Twelve participants (12/13) had positive Ga-68 Pentixafor PET/CT, among which one was diagnosed to have anaemia of chronic disease. One participant (1/13) who was clinically negative on follow-up had negative Ga-68 Pentixafor PET/CT. The sensitivity, specificity, PPV and NPV of Ga-68 Pentixafor PET/CT in MM (95% CI) was observed to be 100%, 50%, 91.6% and 100%, respectively. The correlation between DSPS and ISS in the patients who came for staging scans was found to be statistically significant (p-value 0.02). In quantitative analysis, either of the quantitative variables in Ga-68 Pentixafor PET/CT was positively correlated with clinical parameters related to tumor burden like CRAB score, Serum Protein Electrophoresis M-protein, beta 2 microglobulin, LDH, percentage of plasma cells infiltrates in bone marrow aspiration, ISS, serum free light chain and negatively correlated with haemoglobin, albumin (p-value < 0.5).

Conclusion:

Ga-68 Pentixafor PET/CT is a promising tracer and the only available non-invasive tool to assess the whole-body disease burden of CXCR4 receptors in staging and follow-up of MM. In addition, it has a vital role in the development of CXCR4-targeted theranostics. Dual tracer imaging using F-18 FDG and Ga-68 Pentixafor PET/CT may help in evaluating tumor heterogeneity in MM and add prognostic value at diagnosis and follow-up.

multiple myeloma

Pentixafor PET

CXCR4 PET

quantitative parameters

Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells in bone marrow producing monoclonal immunoglobulin. It accounts for 1% of all cancers and 10% of all haematological malignancies [1, 2]. The initial presentation of MM includes skeletal involvement, renal disease and immunodeficiency [3]. Assessment of the myeloma tumor burden is vital for prognosis since the 5 years survival rate is around 45% [4]. The commonly used clinical parameters to assess tumor burden are M-protein, serum beta-2 microglobulin, serum and urine-free light chain and percentage of plasma cell infiltrates in the bone marrow. Radiological modalities assess the bone marrow involvement, lytic skeletal lesions and extramedullary disease [5]. The role of F-18 Fluorodeoxyglucose positron emission tomography/ computed tomography (F-18 FDG PET/CT) in the diagnosis, staging, response assessment and management of MM is proven [6, 7]. F-18 FDG PET/CT distinguishes between metabolically active and inactive disease, and evidence of more than three focal lesions in F-18 FDG PET/CT is a negative prognostic value in overall survival [5, 8]. Metabolic tumor burden derived from F-18 FDG PET/CT is also a useful prognostic marker in MM. However, F-18 FDG PET/CT has its limitations like false negative FDG uptake due to loss of hexokinase-2 expression in MM, poor sensitivity in diffuse bone marrow (BM) infiltration, and false positive focal FDG uptake in fractures, inflammation, diffuse FDG uptake in recent chemotherapy, growth factor administration and MM related anaemia [9–13]. Hence, understanding the tumor biology and finding new targets for diagnosis and treatment of MM is the need of the hour.

Chemokine receptor-4 (CXCR4) is a member of G-protein-coupled chemokine receptor family, expressed on T and B lymphocytes, macrophages, monocytes, neutrophils, eosinophils and hematopoietic stem or progenitor cells. CXCR4 receptor and its ligand CXCL12 or stromal cell-derived factor (SDF-1) play an important role in the recruitment and homing of stem cells, progenitor and immune cells, thus aiding in embryogenesis, neoangiogenesis, haematopoiesis and inflammation. CXCR4 is overexpressed in more than 30 cancer types, promoting tumor growth, progression, invasiveness and metastasis. In MM cells, CXCR4 activation is involved in autocrine stimulation of plasma cell proliferation, migration, adhesion, extravasation and recruitment to the bone marrow. Gallium-68 Pentixafor (Ga-68 Pentixafor) is a novel radiotracer that targets CXCR-4 expressed on inflammatory and cancer cells. Prior preclinical and clinical studies described that Ga-68 Pentixafor PET was superior to F-18 FDG PET in detecting MM lesions and assessing the tumor burden and its potential to be used as a prognostic and theranostic agent [14–20]. Since there were limited studies done using Ga-68 Pentixafor PET/CT in MM, we conducted this prospective study to analyze the diagnostic performance of Ga-68 Pentixafor PET/CT in MM and the correlation of its quantitative bone marrow uptake values with clinical parameters.

Thirteen participants (9 males; 4 females; median age = 65 years) with known or suspected multiple myeloma were recruited in this prospective observational study, which was conducted in the Department of Nuclear Medicine from February 2023 to December 2023. Six participants with suspected MM who came for initial imaging and seven participants with known MM on chemotherapy who came for follow-up evaluation were included. A detailed clinical history and examination were done on all the patients. The clinical parameters related to tumor burdens like CRAB score, haemoglobin, albumin, Serum Protein Electrophoresis M-protein, beta 2 microglobulin, LDH, percentage of plasma cells infiltrates in bone marrow aspiration, International Staging System (ISS) and serum free light chain were recorded. Participants with suspected MM were followed up for their final histopathology results. All the participants underwent Ga-68 Pentixafor PET/CT, and the imaging characteristics and quantitative parameters were measured. The sensitivity, specificity, PPV and NPV of Ga-68 Pentixafor PET/CT in MM, the correlation between quantitative parameters of PET/CT and the clinical parameters related to tumor burden were analyzed. Durie Salmon Plus Staging (DSPS) was used for multiple myeloma staging by PET/CT and was compared with the International Staging System (ISS) (Table 1) [21, 22]. The study design was approved by the Institutional Ethics Committee (IEC) and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. A written consent to participate in the study was obtained from all the participants.

Table 1

Durie Salmon Plus Staging (DSPS) and International Staging System (ISS) for MM:
	Durie Salmon Plus Staging	International Staging System
Stage I	IA* - Normal skeletal survey or a single skeletal lesion ≥ 5 mm	Serum β2 microglobulin < 3.5 mg/l and serum albumin ≥ 3.5 g/dl
Stage I	IB* - < 5 skeletal lesions
Stage II A/B	5–20 skeletal lesions	Neither Stage I nor III
Stage III A/B	> 20 skeletal lesions	Serum β2 microglobulin ≥ 5.5 mg/l
*Subgroup A – serum creatinine < 2.0 mg/dl and no EMD
Subgroup B – serum creatinine > 2.0 mg/dl, and, or presence of EMD

PET/CT imaging:

Ga-68 Pentixafor was synthesized in-house in an automated system (abiding by good manufacturing practice) using an ITG module with disposable single-use cassette kits (ABX) and 25 microgram Pentixafor. Thin-layer chromatography was used to ensure the radiochemical purity (> 98%). Sixty minutes after intravenous injection of 1.8–2.2 MBq (0.049–0.060 mCi) per kilogram body weight of Ga-68 Pentixafor, whole-body PET/CT scans from head to toes were performed on a dedicated PET/CT scanner (Biograph Vision 450 digital PET/CT; Siemens healthcare) [23]. Plain CT was acquired for attenuation correction of PET emission data and fusion with PET images in view of the impaired renal function of the participants. The CT acquisition parameters were as follows: voltage – 120 keV, current – effective mA (200–300 mA using care dose 4D software with scout reference), slice thickness – 5 mm, rotation time – 0.5 s and pitch – 1.2. PET data were reconstructed iteratively using the ordered subset expectation maximization method (Siemens Biograph Vision 450: 3 iterations, 5 subsets, Gaussian filter, image size 440 x 440). After reconstruction, images were transferred to a dedicated workstation (Syngovia client, Siemens healthcare) and quantitative analysis was done using MM Oncology software.

Visual analysis:

Visual assessment of the PET/CT images was done by the consensus in image interpretation of two experienced nuclear medicine physicians. The presence, intensity, distribution and sites of PET-positive BM lesions, lytic skeletal lesions, and paramedullary and extramedullary disease were recorded. Focal PET positive BM lesion was defined as circumscribed focus ≥ 5 mm with Ga-68 Pentixafor uptake more than that of the liver and not caused by fracture. Considering the liver and spleen as reference organs, the intensity of BM uptake was categorized as mild (uptake ≤ liver), moderate (liver < uptake ≤ spleen) and severe (uptake > spleen). A positive scan was defined as the presence of focal PET-positive BM lesions or diffuse BM uptake with moderate or severe intensity. For the visual assessment of the disease extent, the entire skeleton was divided into 13 segments arbitrarily, and a score of 1 was assigned for the involvement of each region (Fig. 1). Extramedullary disease involvement was assigned a score of 1, irrespective of the number of organs involved. Thus, visual assessment had a maximum score of 14.

Quantitative analysis:

Quantitative analysis of the whole-body skeletal tumor burden was performed in the Syngovia workstation using MM Oncology software (Siemens Healthcare). Initially, a volume of interest (VOI) was drawn to include the whole body. The whole-body skeletal tumor burden VOI was automatically generated by MM Oncology software using the maximum semiquantitative uptake value (SUVmax) of the liver as the threshold value for PET and a CT attenuation value of 200 HU or more as a cutoff value for CT. The VOI was then manually corrected to exclude the benign calcifications and fracture sites. In patients with paramedullary or extramedullary disease, VOIs of extraosseous disease were drawn manually and included in the final VOI. Later, the volumetric parameters like SUVmean, SUVmax, total bone marrow volume (TBMV) and total bone marrow uptake (TBMU = SUVmean x TBMV) were generated automatically and were recorded for quantitative analysis. Another quantitative parameter called maximum target to background ratio (TBRmax) was also calculated by dividing SUVmax of the intensely avid skeletal lesion by SUVmax of mediastinal blood pool activity. Figure 2 illustrates the method of volumetric analysis of MM disease extent using VOI.

Statistical analysis:

The data was entered in Microsoft Excel sheet and Statistical Package for Social Sciences (SPSS) version 26.0 software was used to perform statistical analysis. Clinicodemographic data of the patients were analyzed using descriptive statistics such as mean, median, standard deviation, interquartile range, frequency and percentage. Sensitivity, specificity, positive predictive value and negative predictive value were calculated. Chi-square test was used to measure the association of categorical variables. Pearson's correlation coefficient was used to measure the correlation between laboratory, clinical findings and quantitative parameters of Ga-68 Pentixafor PET/CT since the data was in normal distribution. A p-value less than 0.05 was considered statistically significant. Data was represented as tables and charts wherever necessary.

Clinical characteristics:

The study was conducted with 13 participants of Asian origin (9 males and 4 females), which included 6 patients with suspected MM for initial imaging and 7 patients with known MM on chemotherapy for follow-up evaluation. The mean age of the study population was 63.31 ± 8.90 years. The clinical presentation included anaemia (2 patients), weight loss (3 patients), fatigue and back pain (5 patients). The rest of the patients (3 in number) were asymptomatic and came for follow-up evaluation. Among 6 patients with suspected MM for initial imaging, 5 were diagnosed to have MM based on the biochemical and histopathology results, and one patient was diagnosed with anaemia of chronic disease. Thus, 12 out of 13 patients in the study population had MM and were divided into subgroups for staging evaluation (5 patients) and follow-up evaluation (7 patients). The type of M protein observed were IgG in 5 patients, IgA in 3 patients and light chain in 4 patients. The clinical parameters of the study population with MM (12/13) are presented in Table 2. In the subgroup for staging evaluation, 1/5 patients were classified as Stage II and 4/5 patients were classified as Stage III, according to the International Staging System (ISS) for MM [22]. The end organ damage in the staging subgroup was documented as per CRAB criteria [24], which considers one point each for hypercalcemia [1/5 (20%)], renal failure [2/5 (40%)], anaemia [5/5 (100%)] and lytic skeletal lesions [5/5 (100%)].

Table 2

Clinical & Ga-68 Pentixafor PET/CT parameters of the study population with MM
Parameter	Mean	SD
Percentage of plasma cell infiltrates in bone marrow	50.0%	22.0%
Free kappa	328.01	115.06
Free lambda	7970.24	3182.75
Kappa/ lambda ratio	16.95	7.57
Beta 2 microglobulin	22.04	2.57
Serum protein electrophoresis M protein	2.54	1.17
Serum albumin	3.10	0.69
Serum calcium	10.95	2.36
Corrected serum calcium	11.65	2.94
Haemoglobin	8.30	0.69
LDH	194.50	5.19
Serum creatinine	2.40	1.15
CRAB score	3.0	1.15
Skeletal regions involved- extent	7.0	0
SUV max	22.80	3.11
SUV mean	3.0	1.03
Total Bone marrow uptake	3550.57	1008.10
TBRmax	11.10	3.57

Ga-68 Pentixafor PET/CT visual findings:

Based on the visual assessment criteria mentioned earlier, Ga-68 Pentixafor PET/CT was positive in 12/13 patients – 6/6 patients with suspected MM for initial imaging and 6/7 patients with known MM on chemotherapy for follow-up evaluation. The intensity of Ga-68 Pentixafor uptake was moderate in 6 patients and severe in 6 patients. Paramedullary disease was observed in 2 patients. One patient showed extramedullary disease with involvement of the skeleton, lymph nodes, pleura, rectum, liver, spleen and adrenals. The number of participants with involvement of 1,2,3,8,9,13,14 skeletal regions include 2,1,1,4,2,1,1 respectively. According to DSPS, twelve patients with positive Ga-68 Pentixafor PET/CT were categorized into Stage IB (2/12), IIA (2/12), IIIA (2/12) and IIIB (6/12). Based on the biochemical and histopathology results, 5/6 patients in the suspected MM group were diagnosed as MM, and 6/7 patients with known MM on chemotherapy had active disease. Thus, sensitivity, specificity, positive predictive value and negative predictive value of Ga-68 Pentixafor PET/CT in the assessment of MM (with 95% confidence interval) were observed to be 100%, 50%, 91.6% and 100%, respectively (Table 3). The representative cases are illustrated in Figs. 2–5.

Table 3

Sensitivity, specificity, PPV, NPV of Ga-68 Pentixafor PET/CT in Multiple myeloma
			Clinical diagnosis		Total
			Positive	Negative
Ga-68 Pentixafor PET/CT	Positive	Count	11	1^$	12
		%	91.7%	8.3%	100.0%
	Negative	Count	0	1	1
		%	0.0%	100.0%	100.0%
Total		Count	11	2	13
		%	84.6%	15.4%	100.0%
Sensitivity = 100%
Specificity = 50%
PPV = 91.6%
NPV = 100%
$ - Clinical diagnosis – Anaemia of Chronic disease

Ga-68 Pentixafor PET/CT quantitative findings:

The mean SUVmax, SUVmean, TBMU and TBRmax of the study population with MM (12/13) are described in Table 2. A detailed summary of the clinical and Ga-68 Pentixafor PET/CT findings of the 5 patients in the subgroup for staging evaluation of MM is shown in Table 4. The correlation between DSPS and ISS for MM was found to be statistically significant in the subgroup for staging evaluation of MM (Chi-square value − 5.00; p-value = 0.02). However, the correlation of skeletal regions involved and ISS for MM was observed to be statistically not significant in this subgroup (Chi-square test − 5.00; p value = 0.17). Pearson's correlation analysis was performed between the clinical findings and quantitative parameters of Ga-68 Pentixafor PET/CT. A moderate positive correlation was observed between TBMU and CRAB score (p-value 0.04); TBRmax and M protein (p-value 0.02); SUVmax and beta 2 microglobulin (p-value 0.03); TBRmax and beta 2 microglobulin (p-value 0.03); TBMU and percentage of plasma cell infiltrates in bone marrow aspiration (p-value 0.003); TBRmax and percentage of plasma cell infiltrates in bone marrow aspiration (p-value 0.03); TBMU and free lambda (p-value 0.002). A strong positive correlation was observed between TBMU and beta 2 microglobulins (p-value 0.01), SUVmean and LDH (p-value 0.01). A moderate negative correlation was observed between SUVmax and Hemoglobin (p-value 0.01); SUVmean and Hemoglobin (p-value 0.04); TBMU and Hemoglobin (p-value 0.005); TBRmax and Hemoglobin (p-value 0.04); TBMU and serum albumin (p-value 0.02). Pearson correlation analysis of clinical parameters and quantitative parameters in Ga-68 Pentixafor PET/CT are given in Table 5. Further, a statistically significant positive correlation was observed between each stage of ISS and TBMU of Ga-68-Pentixa for PET/CT imaging (p-value 0.02).

Table 4

Detailed summary of the clinical and Ga-68 Pentixafor PET/CT findings of the 5 patients in the subgroup for staging evaluation of MM
No.	Age (years)/ Sex	Clinical diagnosis	% of plasma cells infiltrate in bone marrow aspiration	Free kappa (3.30–19.40 mg/dl)	Free lambda (5.70–26.30 mg/L)	Kappa/ Lambda ratio (0.37–3.1 for renal impairment)	Beta 2 microglobulin (0.97–2.64 mg/dl)	Serum protein electrophoresis 'M' protein (g/dl)	Serum Albumin (3.2–4.6 g/dl)	Seum Calcium (8.6–10.2 mg/dl)	Hemoglobin (11.5–16.5 g/dl)	LDH (125–220 U/L)	Serum creatinine (0.5–1.2 mg/dl)	CRAB score (1–4)	International staging system (ISS)	Ga-68 Pentixafor PET/CT findings
No.	Age (years)/ Sex	Clinical diagnosis	% of plasma cells infiltrate in bone marrow aspiration	Free kappa (3.30–19.40 mg/dl)	Free lambda (5.70–26.30 mg/L)	Kappa/ Lambda ratio (0.37–3.1 for renal impairment)	Beta 2 microglobulin (0.97–2.64 mg/dl)	Serum protein electrophoresis 'M' protein (g/dl)	Serum Albumin (3.2–4.6 g/dl)	Seum Calcium (8.6–10.2 mg/dl)	Hemoglobin (11.5–16.5 g/dl)	LDH (125–220 U/L)	Serum creatinine (0.5–1.2 mg/dl)	CRAB score (1–4)	International staging system (ISS)	Intensity of Ga-68 Pentixafor uptake- mild / moderate / severe	Number of lesions	No. of skeletal regions involved	SUV max	SUV mean of intense avid lesion	TBMU	TBRmax	Durie Salmon Plus staging
1	74/ F	MM	60%	23.88	4843.7	0.005	14.2	0.44	3	7.9	6.6	252	2.1	3	III	severe	> 20	13	10	5.52	3179	3.5	IIIB
2	73/ M	MM	50%	55.16	15922.74	0.003	24.27	0.66	2.5	13	7.7	190	3.4	4	III	severe	> 20	9	20.1	2.1	4423.62	8	IIIB
3	53/ M	MM	16%	3.01	2047.62	0.001	6.8	1.33	3.2	7.8	7.4	268	1.6	2	III	severe	> 20	14	34.2	14.65	4040.39	13.7	IIIB
4	60/ M	MM	18%	1919.43	20.36	94.27	4.82	3.11	3	9	7.8	173	1.2	2	II	severe	< 5 (3)	2	6.7	3.5	72.29	2.9	IB
5	70/ F	MM	44%	600.86	17.75	33.9	19.81	4.43	3.7	8.9	8.9	199	1.4	2	III	severe	> 20	9	25.5	3.9	2677.53	14.2	IIIB

Table 5

Pearson correlation analysis of clinical parameters and quantitative parameters in Ga-68 Pentixafor PET/CT
Clinical parameters		SUVmax	SUVmean	TBMU	TBRmax
CRAB score	r	-0.19	-0.45	0.55	-0.30
CRAB score	p-value	0.59	0.19	0.04	0.39
Haemoglobin	r	-0.57	-0.48	-0.63	-0.45
Haemoglobin	p-value	0.01	0.04	0.005	0.04
Albumin	r	0.47	0.45	-0.42	0.60
Albumin	p-value	0.12	0.40	0.02	0.30
M protein	r	0.02	-0.14	-0.24	0.44
M protein	p-value	0.95	0.62	0.46	0.02
Beta 2 microglobulin	r	0.57	-0.08	0.95	0.57
Beta 2 microglobulin	p-value	0.03	0.76	0.001	0.03
LDH	r	0.17	0.91	-0.24	0.03
LDH	p-value	0.63	0.001	0.48	0.92
% of plasma cell infiltrates in bone marrow aspiration	r	0.31	0.19	0.63	0.47
% of plasma cell infiltrates in bone marrow aspiration	p-value	0.18	0.41	0.003	0.03
Free kappa	r	-0.15	-0.16	-0.36	-0.11
Free kappa	p-value	0.55	0.50	0.13	0.66
Free lambda	r	0.18	-0.12	0.58	0.07
Free lambda	p-value	0.46	0.61	0.002	0.76

Currently, F-18 FDG PET/CT plays an important role in the diagnosis and prognosis of MM, however, false negativity may be encountered in the assessment of bone marrow infiltration [6, 12, 25, 26]. A recent review of the IMWG consensus recommendations on imaging in disorders involving monoclonal plasma cells noted that since bone marrow infiltration in MM may be heterogenous, it is necessary to use sensitive and novel imaging techniques to distinguish between diffuse and focal plasma cell infiltration to quantify the disease accurately [27]. Furthermore, the bone marrow heterogeneity in MM may cause discrepancies in the results obtained from trephine biopsy and whole-body MRI in terms of estimation of disease burden and extent [28].

Hence, the advent of newer radiopharmaceuticals in MM to overcome the limitations of F-18 FDG, as well as to be used as a theranostic agent is the need of the hour. The expression of chemokine receptor CXCR4 is seen in more than 70% of solid tumors and is significantly high in multiple haematological malignancies like lymphoma, MM and leukaemia [29, 30]. Ga-68 Pentixafor PET studies in MM has been of interest after the demonstration of CXCR4 expression in MM by clinical PET imaging [14, 15].

In the present study, the diagnostic performance of Ga-68 Pentixafor PET/CT in MM and the correlation of its quantitative bone marrow uptake values with clinical parameters was analyzed. Ga-68 Pentixafor PET/CT was positive in all 6 patients with suspected MM with an uptake of severe intensity. However, one patient was histopathologically negative for multiple myeloma on further evaluation. Four of five patients with confirmed MM staged as IIIB by DSPS belonged to stage III as per the clinical staging of ISS, and this correlation between DSPS and ISS for MM was found to be statistically significant in the subgroup for staging evaluation of MM. This finding is in concurrence with the results of a comparative study between Ga-68-Pentixafor PET/CT and F-18-FDG PET/CT in staging multiple myeloma, which showed that though both the tracers had the same stage as demonstrated by ISS in nearly half of the patients, Ga-68-Pentixafor, upstaged a greater number of patients than F-18-FDG PET imaging [18]. Additionally, on comparison of the Ga-68-Pentixafor uptake values of each ISS stage by Pan et al., a significant difference with a trend of increasing uptake values towards a higher stage was observed [14]. Similarly, in the present study, a significant positive correlation was observed between each ISS stage and TBMU of the Ga-68-Pentixa for PET imaging study. However, the correlation of skeletal regions involved and ISS for MM was observed to be statistically not significant in this subgroup.

In quantitative analysis, the present study observed a positive correlation between Ga-68-Pentixafor uptake values in total bone marrow (TBMU, TBRmax, SUVmax, SUVmean) and laboratory biomarkers relating to tumor burdens such as CRAB score, beta 2 microglobulin, serum-free lambda, M protein and LDH. These findings are in concurrence with the study of Pan et al. [14] which demonstrated similar positive correlations of Ga-68-Pentixafor uptake values in total bone marrow and end-organ damage, staging as well as laboratory biomarkers. However, in contrast to the present study wherein a moderate positive correlation was observed between TBRmax and M protein, Pan et al. [14] observed no significant correlation between M protein and Ga-68-Pentixafor uptake values, attributing it to the fact that M protein is not a good marker for tumor burden in light chain myeloma [31].

A significant positive correlation was also identified between TBMU and TBRmax with plasma cell percentage in bone marrow aspiration, unlike the findings of Pan et al. [14], wherein plasma cell percentage in bone marrow aspiration did not correlate well with Ga-68-Pentixafor uptake values. In concordance with the present study, a comparative study between Ga-68-Pentixafor PET/CT and F-18-FDG PET/CT for staging in multiple myeloma [18] demonstrated that the median plasma cell percentage in bone marrow had a positive correlation with Ga-68-Pentixafor findings and TBRmax values. They further observed that the same was not significant with F-18-FDG findings. A negative correlation was observed between Ga-68-Pentixafor uptake values in total bone marrow (TBMU, TBRmax, SUVmax, SUVmean) and haemoglobin, like the observation by Pan et al [14]. Further, TBMU negatively correlated with serum albumin.

In the follow-up evaluation subgroup, all six of seven patients with biochemical and histopathological active disease showed uptake of moderate to severe intensity in Ga-68-Pentixa for PET/CT imaging. The prognostic value of F-18-FDG PET/CT in patients with MM at diagnosis and relapse has been well established [6, 25], and the lack of FDG uptake in the focal lesions post-therapy has been associated with better survival outcomes.[32]. The Utility of CXCR4 expression in MM cells as a prognostic tool has also been evaluated; however, there is currently minimal data regarding the prognostic significance of Ga-68-Pentixafor PET/CT. In an interesting study by Lapa et al. [33], the authors reported that time to progression and OS tended to be longer in Ga-68-Pentixafor PET-negative subjects.

In addition, a study assessing the prognostic significance of Ga-68‑Pentixafor PET/CT in multiple myeloma recurrence showed that MM patients with positive scan results for both FDG and CXCR4 had a worse prognosis than those with negative results for both scans, thereby supporting the hypothesis that MM patients with negative PET scans have a higher chance of a longer survival than those with metabolically active, CXCR4-expressing lesions, regardless of clinical and laboratory findings [19].

Ga-68 Pentixafor PET studies in MM has been of interest in recent times to overcome the limitations of F-18 FDG PET/CT. In the present study, Ga-68 Pentixafor PET/CT was found to have a significant role in the diagnosis and follow up of MM. A positive correlation between DSPS staging and ISS staging was identified. In addition, quantitative analysis showed a positive correlation between Ga-68 Pentixafor uptake values in total bone marrow (TBMU, TBRmax, SUVmax, SUVmean) and laboratory biomarkers relating to tumor burden, including plasma cell percentage in bone marrow aspiration. In the follow-up evaluation subgroup, biochemical and histopathological active disease showed uptake of moderate to severe intensity in Ga-68-Pentixafor PET/CT imaging. Hence, the limitations of F-18-FDG PET/CT may be addressed with complementary Ga-68-Pentixafor PET/CT for a more accurate risk stratification. Future studies may be directed towards the use of Ga-68-Pentixafor PET/CT imaging as a non-invasive alternative to assess the overall survival and prognosis of patients with MM and CXCR4 targeted radiopharmaceuticals in theranostics.

The limitations of the study include a small sample size, as it was an institutional pilot study. Further, the study did not take into consideration Ga-68-Pentixafor uptake by non-malignant activated inflammatory cells in the bone marrow with upregulated CXCR4 expression. Hence, the uptake values measured may not purely represent CXCR4 expression by myeloma cells but a combination of both malignant and activated inflammatory cells in the bone marrow.

Sources of funding - Nil

Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet. 2009;374:324–39. https://doi.org/10.1016/S0140-6736(09)60221-X.
Jemal A, Clegg LX, Ward E, Ries LAG, Wu X, Jamison PM et al. Annual report to the nation on the status of cancer, 1975–2001, with a special feature regarding survival. Cancer. 2004; 101: 3–27. https://doi.org/10.1002/cncr.20288
Hanrahan CJ, Christensen CR, Crim JR. Current concepts in the evaluation of multiple myeloma with MR imaging and FDG PET/CT. Radiographics. 2010;30:127–42. https://doi.org/10.1148/rg.301095066.
Lutje S, de Rooy JWJ, Croockewit S, Koedam E, Oyen WJG, Raymakers RA. Role of radiography, MRI and FDG-PET/CT in diagnosing, staging and therapeutical evaluation of patients with multiple myeloma. Ann Hematol. 2009;88:1161–68. https://doi.org/10.1007/s00277-009-0829-0.
Walker RC, Brown TL, Jones-Jackson LB, De Blanche L, Bartel T. Imaging of multiple myeloma and related plasma cell dyscrasias. J Nucl Med. 2012;53:1091–101. https://doi.org/10.2967/jnumed.111.098830.
Bartel TB, Haessler J, Brown TLY, Shaughnessy JD, van Rhee F, Anaissie E, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114:2068–76. https://doi.org/10.1182/blood-2009-03-213280.
Dimitrakopoulou-Strauss A, Hoffmann M, Bergner R, Uppenkamp M, Haberkorn U, Strauss LG. Prediction of progression-free survival in patients with multiple myeloma following anthracycline-based chemotherapy based on dynamic FDG-PET. Clin Nucl Med. 2009;34:576–84. https://doi.org/10.1097/RLU.0b013e3181b06bc5.
Cavo M, Terpos E, Nanni C, Moreau P, Lentzsch S, Zweegman S, et al. Role of (18)F-FDG PET/CTin the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group. Lancet Oncol. 2017;18:e206–17. https://doi.org/10.1016/s1470-2045(17)30189-4.
Zamagni E, Nanni C, Patriarca F, Englaro E, Castellucci P, Geatti O, et al. A prospective comparison of F-18-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica. 2007;92:50–5.
Spinnato P, Bazzocchi A, Brioli A, Nanni C, Zamagni E, Albisinni U, et al. Contrast enhanced MRI and (1)(8)F-FDG PET-CT in the assessment of multiple myeloma: a comparison of results in different phases of the disease. Eur J Radiol. 2012;81:4013–8. https://doi.org/10.1016/j.ejrad.2012.06.028.
Nanni C, Zamagni E, Farsad M, Castellucci P, Tosi P, Cangini D, et al. Role of F-18-FDG PET/CT in the assessment of bone involvement in newly diagnosed multiple myeloma: preliminary results. Eur J Nucl Med Mol Imaging. 2006;33:525–31. https://doi.org/10.1007/s00259-005-0004-3.
Rasche L, Angtuaco E, McDonald JE, Buros A, Stein C, Pawlyn C, et al. Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood. 2017;130:30–4. https://doi.org/10.1182/blood-2017-03-774422.
Nanni C, Zamagni E, Versari A, Chauvie S, Bianchi A, Rensi M, et al. Image interpretation criteria for FDG PET/CT in multiple myeloma: a new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma criteria for PET USe). Eur J Nucl Med Mol Imaging. 2016;43:414–21. https://doi.org/10.1007/s00259-015-3200-9.
Pan Q, Cao X, Luo Y, Li J, Feng J, Li F. Chemokine receptor-4 targeted PET/CT with (68) Ga-Pentixafor in assessment of newly diagnosed multiple myeloma: comparison to (18)F-FDG PET/CT. Eur J Nucl Med Mol Imaging. 2020;47(3):537–46.
Lapa C, Schreder M, Schirbel A, Samnick S, Kortum KM, Herrmann K, et al. [(68) Ga] Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - Comparison to [(18)F] FDG and laboratory values. Theranostics. 2017;7(1):205–12.
Kircher M, Herhaus P, Schottelius M, Buck AK, Werner RA, Wester HJ, et al. CXCR4-directed theranostics in oncology and inflammation. Ann Nucl Med. 2018;32(8):503–11.
Lapa C, Herrmann K, Schirbel A, Hanscheid H, Luckerath K, Schottelius M, et al. CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed Multiple Myeloma. Theranostics. 2017;7(6):1589–97.
Shekhawat AS, Singh B, Malhotra P, Watts A, Basher R, Kaur H, et al. Imaging CXCR4 receptors expression for staging multiple myeloma by using Ga-68-Pentixafor PET/CT: comparison with F-18-FDG PET/CT. Br J Radiol. 2022. 10.1259/bjr.20211272.
Kuyumcu S, Isik EG, Tiryaki TO, Has-Simsek D, Sanli Y, Buyukkaya F, Özkan ZG, Kalayoglu-Besisik S, Unal SN. Prognostic significance of Ga-68-Pentixafor PET/CT in multiple myeloma recurrence: A comparison to F-18-FDG PET/CT and laboratory results. Ann Nucl Med. 2021;35(10):1147–56. 10.1007/s12149-021-01652-1.
Pan Q, Cao X, Luo Y, Li J, Feng J, Li F. Chemokine receptor-4 targeted PET/CT with 68 Ga-Pentixafor in assessment of newly diagnosed multiple myeloma: comparison to 18 F-FDG PET/CT. Eur J Nucl Med Mol Imaging. 2020;47:537–46.
Durie BG. The role of anatomic and functional staging in myeloma: description of Durie/Salmon plus staging system. Eur J Cancer. 2006;42(11):1539–43. 10.1016/j.ejca.2005.11.037.
Greipp PR, Miguel JS, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412–20.
Fendler WP, et al. Ga-68-PSMA PET/CT: Joint EANM and SNMMI procedure guideline for Prostate Cancer Imaging: Version 1.0. Eur J Nucl Med Mol Imaging. 2017;44(6):1014–24. 10.1007/s00259-017-3670-z.
Durie BG, Salmon SE. A clinical staging system for multiple myeloma correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36(3):842–54.
van Lammeren-Venema D, Regelink JC, Riphagen II, Zweegman S, Hoekstra OS, Zijlstra JM. F-18-fluoro-deoxyglucose positron emission tomography in assessment of myeloma-related bone disease: a systematic review. Cancer. 2012;118(8):1971–81.
Elena Z, Cristina N, Francesca P, Emanuela E, Paolo C, Onelio G, et al. A prospective comparison of F-18-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica. 2007;92(1):50–5.
Hillengass J, Usmani S, Rajkumar SV, Durie BG, Mateos M-V, Lonial S, et al. International Myeloma Working Group Consensus Recommendations on imaging in monoclonal plasma cell disorders. Lancet Oncol. 2019;20(6). 10.1016/s1470-2045(19)30309-2.
Latifoltojar A, Boyd K, Riddell A, Kaiser M, Messiou C. Characterising spatial heterogeneity of multiple myeloma in high resolution by whole body magnetic resonance imaging: Towards macro-phenotype Driven Patient Management. Magn Reson Imaging. 2021;75:60–4. 10.1016/j.mri.2020.10.005.
Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4(7):540–50.
Kuyumcu S, Yilmaz E, Buyukkaya F, Ozkan ZG, Unal SN. Imaging of chemokine receptor CXCR4 in mycosis fungoides using Ga-68-Pentixafor PET/CT. Clin Nucl Med. 2018;43(8):606.
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2008;23(1):3–9. 10.1038/leu.2008.291.
Varettoni M, Corso A, Pica G, Mangiacavalli S, Pascutto C, Lazzarino M. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: A longitudinal study on 1003 consecutive patients. Ann Oncol. 2010;21(2):325–30. 10.1093/annonc/mdp329.
Lappa C, Schreder M, Schirbel A, Samnick S, Kortüm KM, Herrmann K, et al. [Ga-68] pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [F-18] FDG and laboratory values. Theranostics. 2017;7(1):205–12. 10.7150/thno.16576.

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Ga-68 Pentixafor PET/CT in multiple myeloma and its correlation with clinical parameters – institutional pilot study

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