**2. Case Report**

A 52-year-old male patient with a diagnosis of SMM of IgG-lambda type (initial bone marrow plasma cell infiltration rate 10%) was referred to the nuclear medicine department for staging purposes. The patient underwent both dynamic and static PET/CT (Biograph mCT, S128, Siemens Co., Erlangen, Germany) with 18F-FDG. In particular, after an intravenous bolus administration of 18F-FDG, dynamic PET/CT was performed over the lower abdomen and pelvis for 60 min using a 24-frame protocol (10 frames of 30 s, 5 frames of 60 s, 5 frames of 120 s and 4 frames of 600 s). After the end of the dynamic acquisition, whole body, static imaging from the head to the feet was performed with an image duration of 2 min per bed position for the emission scans. Data analysis of PET/CT consisted of the conventional visual (qualitative) and semi-quantitative (standardized uptake value, SUV) evaluation, as well as the quantitative analysis of the dynamic 18F-FDG PET/CT data, which was based on two-tissue compartment modeling (Figure 1) [25–28] and fractal analysis [29].

**Figure 1.** Schematic representation of the two-tissue compartment model applied for 18F-FDG. K1, k2, k3 and k4 are rate constants (1/min) and describe the directional exchanges between the three compartments. Cplasma represents the vascular compartment, C1 represents the free and non-specifically bound tracer in tissue (non-displaceable compartment) and C2 represents the specifically bound (phosphorylated) tracer in tissue. K1 reflects the carrier-mediated transport of 18F-FDG from plasma to tissue and k2 reflects the transport of the radiopharmaceutical back from tissue to plasma, while k3 represents the phosphorylation rate and k4 the dephosphorylation rate of the glucose analogue.

Baseline PET/CT at SMM diagnosis revealed no pathological findings suggestive of myeloma. Merely, a discretely increased, diffuse tracer uptake in the bone marrow was noticed, which was, however, not higher than liver uptake (Figure 2A). Six months later, a transition from asymptomatic SMM to symptomatic MM was diagnosed, after a pathological fracture of the right humerus—treated with surgery and radiotherapy— accompanied by respective increases of the M-protein (from 3.1 g/dL to 6.1 g/dL), and the lambda light chains in serum (from 135 mg/L to 306 mg/L) and urine (from unmeasurable levels to 20.6 mg/24 h). The patient was re-assessed with dynamic and static PET/CT, which demonstrated no focal hypermetabolic lesions. However, a new, intense, diffuse 18F-FDG uptake in the bone marrow of the axial skeleton was now delineated (Figure 2B). With regard to the semi-quantitative PET/CT parameters, SUVmean and SUVmax of the iliac bone increased by 82% and 91%, respectively, in comparison to the baseline scan. Similar changes were observed in the pharmacokinetic parameters derived from dynamic PET/CT: the regional blood volume (VB) increased by 150%, the tracer influx (Ki) increased by 200%, and fractal dimension (FD) also increased by 16% (Table 1; Figure 3). The patient was treated with bortezomib-based induction therapy, followed by tandem high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT). Two months after therapy, a third PET/CT demonstrated a pronounced remission of the diffuse bone marrow uptake (Figure 2C), accompanied by a marked decrease of the respective semi-quantitative and quantitative parameters to levels similar to or even lower than those of baseline PET/CT (Table 1; Figure 3). These findings were in line with respective changes of the M-protein (decrease to 1.1 g/dL), and the lambda light chains in serum (decrease to 24 mg/L) and urine (decrease to unmeasurable levels). The patient, furthermore, received maintenance therapy with lenalidomide. At last contact, he had not shown any disease progression, having reached a progression-free survival (PFS) of 74 months.

**Table 1.** Semi-quantitative and quantitative parameters of the bone marrow (iliac bone) derived from dynamic PET/CT at the three time points of scanning. The units of parameters fractional blood volume (VB), K1, k3 and influx (Ki) are 1/min. SUVmean, SUVmax and fractal dimension (FD) have no unit.


**Figure 2.** Maximum intensity projection (MIP) 18F-FDG PET/CT images upon SMM diagnosis (**A**), at transition to symptomatic MM (**B**) and after therapeutic intervention (**C**). Baseline PET/CT upon asymptomatic SMM showed no pathological findings. A discretely increased, diffuse tracer uptake in the bone marrow (≤liver uptake) is observed. The foci of increased 18F-FDG uptake in the lower abdomen/pelvis correspond to physiological urinary tracer activity in the ureters, while the focal 18F-FDG accumulation in the right knee joint most likely represents an inflammatory process. Semi-quantitative calculations revealed a SUVmean of the iliac bone of 2.2 (SUVmax 3.3). According to the quantitative, pharmacokinetic analysis, the influx of 18F-FDG in the bone marrow was 0.01 (1/min) (**A**). The first follow-up PET/CT scan at the time of symptomatic myeloma transition (6 months later) revealed an intense, diffuse 18F-FDG uptake in the bone marrow of the axial skeleton without any focal lesions. SUVmean of the iliac bone increased to 4.0 (SUVmax 6.3), while the tracer influx increased to 0.03 (1/min) (**B**). Two months after successful treatment, which involved tandem HDT and ASCT, the patient underwent a second follow-up PET/CT scan. This demonstrated a pronounced remission of the diffuse bone marrow uptake and a reduction of the respective SUV values (SUVmean 1.4, SUVmax 1.6) and influx (0.01 (1/min)) of 18F-FDG. The elongated uptake in the right arm, right thigh and lower leg correspond to muscular activity. Physiological urinary tracer activity is observed in the ureters (**C**).

**Figure 3.** Time activity curves (TACs) depicting 18F-FDG concentration during the 60 min of dynamic PET acquisition upon SMM diagnosis (upper row), at transition to symptomatic myeloma (middle row) and after therapy with tandem HDT and ASCT (lower row). The curves are derived from the bone marrow of the iliac bone (thick blue curve with green dots) and from the common iliac artery (thin blue curve with golden dots). The TAC at baseline imaging shows a relatively stable tracer concentration over time. The transition from asymptomatic SMM to symptomatic MM is accompanied by a change in the respective TAC of the radiotracer, showing a steadily increasing accumulation in the bone marrow compared to the definitely lower tracer concentration upon SMM.After the therapeutic intervention, we notice a decrease of the 18F-FDG concentration in the bone marrow, which is also reflected in the slope of the curve.
