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Published online before print December 19, 2006, 10.1148/radiol.2422051980

(Radiology 2006;242:498.)

A more recent version of this article appeared on December 1, 2006
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© RSNA, 2006

Molecular Imaging

Multiple Myeloma: Molecular Imaging with 11C-Methionine PET/CT—Initial Experience1

Anja Dankerl, MD, Peter Liebisch, MD, Gerhard Glatting, PhD, Claudia Friesen, PhD, Norbert M. Blumstein, MD, Darius Kocot, MD, Christiane Wendl, MD, Donald Bunjes, MD and Sven N. Reske, MD

1 From the Departments of Nuclear Medicine (A.D., G.G., C.F., N.M.B., D.K., S.N.R.) and Internal Medicine III (P.L., C.W., D.B.), University of Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany. Received December 7, 2005; revision requested January 19, 2006; revision received February 20; accepted March 10; final version accepted May 1. Address correspondence to S.N.R. (e-mail: sven.reske{at}uniklinik-ulm.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively assess molecular imaging of multiple myeloma (MM) by using the radiolabeled amino acid carbon 11 (11C) methionine and positron emission tomography (PET)/computed tomography (CT).

Materials and Methods: The study was approved by the institutional local ethics committee and the national radiation protection authorities. All patients with MM and control patients gave written informed consent. Nineteen patients with MM (11 women, eight men; age range, 42–64 years) and 10 control patients with hyperparathyroidism without hematologic diseases (six women, four men; age range, 43–75 years) underwent PET/CT 20 minutes after injection of a mean of 1.0 GBq ± 0.2 (standard deviation) 11C-methionine. Presence and extent of CT-assessed tumor manifestations and 11C-methionine bone marrow (BM) uptake were determined on the basis of maximum standardized uptake value (SUVmax). BM imaging patterns, normal BM, and maximal lesion 11C-methionine uptake in patients with MM were compared with those in control patients. In two patients with MM, sulfur 35 (35S) methionine uptake in freshly isolated BM plasma cells was measured. Values for SUVmax of groups were compared by using the Mann-Whitney test on a per-patient basis.

Results: 35S-methionine uptake of plasma cells was five- to sixfold higher than in normal BM cells. 11C-methionine BM uptake in control patients was homogeneous and low. All patients with MM except one with exclusively extramedullary myeloma had 11C-methionine–positive lesions. Maximal lesion and normal BM 11C-methionine mean SUVmax were 10.2 ± 3.5 and 4.3 ± 2.0, respectively, and thus were significantly higher than that of BM in the control group (mean, 1.8 ± 0.3; P < .001). Extramedullary MM was clearly visible in three patients (mean SUVmax, 7.2 ± 2.4). Additional 11C-methionine–positive lesions in normal cancellous bone were found in nearly all patients with MM. In pretreated patients with MM, a moderate fraction of osteolytic lesions had no 11C-methionine uptake.

Conclusion: On the basis of increased methionine uptake in plasma cells, active MM can be imaged with 11C-methionine PET/CT.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Multiple myeloma (MM) is characterized by neoplastic proliferation of plasma cells, and these cells produce nearly always complete monoclonal immunoglobulins or monoclonal immunoglobulin light chains. The unrestricted expansion of a plasma cell clone and the excessive synthesis of monoclonal immunoglobulins result in extensive skeletal destruction, hypercalcemia, anemia, immunosuppression, renal damage, proteinuria, and, sometimes, plasma cell infiltration of various organs or tissues (1). Although the Durie-Salmon staging system was first published more than 30 years ago (1975), it still represents the most widely used staging system for MM. The Durie-Salmon staging system is based on a number of laboratory values, as well as the number of osteolytic bone lesions determined in skeletal surveys, and thus approximatively reflects tumor burden in this disease (2).

Current imaging technology, particularly survey bone marrow (BM) studies with magnetic resonance (MR) imaging and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET), has improved the detection of tumor manifestations and of the extent of these manifestations in patients with MM (3–7). Therefore, attempts have been made to introduce findings from MR imaging and FDG PET into classification systems, such as the Durie-Salmon Plus staging system (2). False-negative results, however, were reported with MR imaging, mostly in the appendicular skeleton and the ribs, as well as with FDG PET in early disease (8). In advanced disease, differentiation of active from inactive myeloma with these techniques may be difficult (8–10).

The purpose of our study was to prospectively assess molecular imaging of MM by using the radiolabeled amino acid carbon 11 (11C) methionine and PET/computed tomography (CT).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Our study was approved by the local ethics committee of our university and the national radiation protection authorities. All patients with MM and control patients gave written informed consent.

Patient Selection
Nineteen patients with active MM (11 women, eight men) with a mean age of 56 years (range, 42–66 years) and 10 control patients (six women, four men; mean age, 56 years; range, 43–75 years) without hematologic diseases were prospectively enrolled in the study between May 2004 and May 2005 (Table 1). In 14 of 19 patients with MM, myeloma was diagnosed between 1 and 14 weeks before the PET/CT study. Nine of the patients were not treated, whereas five patients were examined during induction chemotherapy. The other five patients with MM were examined at the time of relapse; four of them were untreated between 6 and 28 weeks before the PET/CT study. The other patient received chemotherapy until 4 days before PET/CT examination.


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  		Table 1. Characteristics of Patients with MM and Control Patients

 
Patients with MM received a diagnosis on the basis of the criteria of the International Myeloma Working Group (11). Clinical stage of MM was established according to the criteria of the Durie-Salmon staging system (2). Chromosomal abnormalities were determined with interphase fluorescence in situ hybridization (12). Treatment for patients with a new diagnosis of MM comprised two cycles of high-dose melphalan (140–200 mg/m2 [body surface area]) with autologous stem cell transplantation or one cycle of high-dose melphalan (200 mg/m2 [body surface area]) followed by allogeneic stem cell transplantation after reduced-intensity conditioning with fludarabine, 90 mg/m2 (body surface area); melphalan, 140 mg/m2 (body surface area); and antithymocyte globulin, 30 mg/kg.

One untreated patient was classified as having Durie-Salmon stage 3B disease, and 12 were classified as having stage 3A disease. Two treated patients with MM were classified as having stage 2A disease; three patients, as having stage 3A disease; and one patient, as having stage 3B disease. Results of laboratory tests are summarized in Table 1. On the basis of interphase fluorescence in situ hybridization analysis, 11 patients displayed chromosome 13q deletion, and one patient displayed polyploidy with a relative loss of 13q, a marker of aggressive disease and a dismal prognosis (Table 1). Grade of BM infiltration ranged from absent (approximately 5%) in a patient with extramedullary MM to 100% (Table 1).

The control cohort consisted of patients with primary (n = 7) or secondary (n = 3) hyperparathyroidism. The selection was based on examination with 11C-methionine PET/CT performed between May 2004 and May 2005 and the exclusion of hematologic disease. All control patients had an increased parathyroid hormone level and were referred to the Department of Internal Medicine for imaging of adenoma of the parathyroid gland.

Isolation of CD138+ BM Cells and Cellular Uptake of 35S-Methionine
Sulfur 35 (35S) methionine uptake in CD138-enriched BM plasma cells was determined in patients 2 and 8 with newly diagnosed MM (Table 1). The first two patients with newly diagnosed untreated MM who agreed to undergo this procedure were considered for exploratory analysis because of the painfulness of the procedure of BM aspiration (P.L., with 5 years of experience). CD138+ BM cell isolation and radioactivity measurement were performed by another individual (C.F., with 8 years of experience). Mononuclear cells were isolated by using density gradient centrifugation with a reagent (Ficoll-Paque; Amersham Bioscience, Freiburg, Germany) that had a density of 1.077 g/L. Human BM (10 mL) treated with heparin was diluted with 30 mL of phosphate-buffered saline and 1% fetal calf serum (Biochrom Labs, Terre Haute, Ind). Twenty milliliters of diluted cell suspension was carefully layered over 15 mL of the reagent and centrifuged at 1200g at 20°C in a swinging-bucket rotor without breaking.

After centrifugation, the interphase cells were collected and were washed twice with phosphate-buffered saline and 1% fetal calf serum. Isolated cells (5 x 107) were resuspended in 50 mL of culture medium (RPMI 1640; Gibco, Eggenstein, Germany) that contained 20% fetal calf serum, 10 mmol/L HEPES buffer with pH 7.3, 100 U/mL penicillin (Gibco), 100 µg/mL streptomycin (Gibco), and 2 mmol/L L-glutamine and were incubated with 2.71 GBq of 11C-methionine at 37°C with 5% CO2 for 1 hour. After incubation, cells were washed once with phosphate-buffered saline and 1% fetal calf serum and twice with buffer that contained phosphate-buffered saline, 0.5% bovine serum albumin, and 2 mmol/L ethylenediaminetetraacetic acid (MACS; Miltenyi Biotec, Bergisch Gladbach, Germany). The supernatant was completely removed, and then magnetic labeling of cells was performed (13).

Plasma Cell Isolation
CD138 (syndecan-1) is expressed on both normal and malignant plasma cells but not on circulating B cells, T cells, or monocytes. BM plasma cells, cells from the right iliac spine (posterosuperior) of patients 2 and 8 (Table 1), were isolated by one individual (C.F., with 8 years of experience) by using an immunomagnetic cell sorting approach.

Isolated bone marrow cells (5 x 106) were resuspended in 80 µL of buffer, to which 20 µL of CD138 (MACS CD138 MicroBeads; Miltenyi Biotec) was added, mixed well, and incubated for 15 minutes at 4°C. After 15 minutes, 5 µL of the fluorochrome-conjugated CD138 phycoerythrin antibody (Miltenyi Biotec) was added and incubated for an additional 5 minutes at 4°C in the dark to evaluate the efficiency and the quality of magnetic separation by using a flow cytometry system (FACScalibur; Becton Dickinson, Heidelberg, Germany). After incubation, cells were washed twice with 2 mL of buffer, and the cell pellet was resuspended in 1 mL of buffer before magnetic separation.

Therefore, the separation column (MiniMACS; Miltenyi Biotec) was placed in the magnet (MiniMACS; Miltenyi Biotec) and was washed twice with the buffer. After the column was washed, the magnetically labeled cell suspension was pipetted onto the column and was passed through the column, and the effluent was collected as negative fraction (CD138–). The column was washed three times with 500 µL of the buffer. After the column was washed, it was removed from the magnet and was placed on a new collection tube. One milliliter of the buffer was added, and the cells were flushed out by using the plunger that was supplied. The quality of separation (CD138+ and CD138– fractions) was controlled and verified by using the flow cytometry system previously mentioned.

After isolation of CD138+ cells, radioactivity of the CD138+ and the CD138– fractions was measured with a counter (Auto-Gamma Counting System; Packard Instrument, Meriden, Conn) by one individual (C.F., with 5 years of experience).

11C-Methionine PET/CT
11C-methionine was produced according to the method of Comar et al (14). After patients fasted for 5–8 hours, they underwent 11C-methionine PET/CT with an integrated PET/CT scanner (Discovery LS; GE Medical Systems, Waukesha, Wis) after intravenous injection of a mean of 1.0 MBq ± 0.2 (standard deviation) of 11C-methionine (A.D., with 3 years of PET/CT experience, and S.N.R., with 3 years of PET/CT experience and 14 years of PET experience).

PET images (acquisition duration, 3 minutes per bed position) were acquired starting from the distal third of the thighs to the top of the skull 20 minutes after injection (15). Contrast material–enhanced CT (140 kV, 160 mAs, pitch of 1.5) was performed with 125 mL of nonionic contrast material (Ultravist; Schering, Berlin, Germany) administered intravenously as a bolus immediately before PET.

In 14 of 19 patients with MM, CT was performed without contrast agent infusion because of impaired kidney function. In eight of 10 control patients, CT was erformed after contrast agent infusion. PET images were reconstructed with the iterative reconstruction ordered-subset expectation maximum likelihood algorithm of the manufacturer, and attenuation was corrected with the CT data set. Consecutive transverse, coronal, and sagittal PET/CT sections of 4.5-mm thickness were generated.

Image Analysis
The PET images of the PET/CT scans were visually assessed in a consensus reading by two experienced nuclear medicine physicians (A.D. and S.N.R.) who were blinded to clinical data, laboratory values, and results of previous imaging studies. Criteria for the diagnosis of involvement of BM or extramedullary MM were focally increased 11C-methionine uptake in the BM (Fig 1), diffusely increased 11C-methionine in the whole hematopoietic BM with or without expansion of BM into distal parts of long bones (ie, peripheral BM expansion) (Fig 2), or focally increased 11C-methionine uptake in an extramedullary soft-tissue mass (Fig 3).


Figure 1
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  		Figure 1: Transverse maximum intensity projection images in 66-year-old woman with MM. Left top: CT scan. Left bottom: PET/CT scan. Right top: Maximum intensity projection. Right bottom: PET scan. CT scan displays multiple lesions typical for MM in T5, whereas transverse PET scan and maximum intensity projection showed highly increased 11C-methionine uptake (right arrow in maximum intensity projection). Note an additional lesion with increased 11C-methionine uptake in the right humeral shaft (left arrow in maximum intensity projection).

 

Figure 2
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  		Figure 2: Images in 51-year-old female control patient (top row) and 51-year-old male patient with MM (bottom row). Both rows from left to right show maximum intensity projection image; coronal CT, PET, and PET/CT scans; and sagittal CT, PET, and PET/CT scans. Patient with MM shows diffusely increased but homogeneous 11C-methionine uptake in the whole vertebral spine compared with low and homogeneous 11C-methionine uptake in the control patient.

 

Figure 3
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  		Figure 3: Images in 42-year-old man with diagnosis of extramedullary MM. A, Coronal maximum intensity projection image. B, Transverse CT (top) and PET/CT (bottom) scans. C, PET scan shows left cervical mass (arrow) with high 11C-methionine uptake indicative of a lymph node infiltrated with tumor. D, Coronal CT scan. E, PET scan. F, PET/CT scan shows bulky abdominal tumor (arrow) with intense 11C-methionine uptake. Nonenhanced CT was performed because of impaired renal function.

 
Normal 11C-methionine BM uptake was determined in the BM space of T11 or an adjacent visually normal vertebra when T11 was involved from MM. The maximum standardized uptake value (SUVmax) for 11C-methionine was determined in respective BM areas by using a circular 1-cm-diameter region of interest. SUVmax is defined as the measured maximal activity concentration divided by the injected radioactivity normalized to body weight (16). SUVmax in the lesion with highest 11C-methionine uptake in patients with MM was determined. According to the published classification in the study by Durie et al (2), patients with MM were categorized into three cohorts on the basis of the number of lesions they had. In group 1, patients had fewer than five lesions; in group 2, patients had 5–20 lesions; and in group 3, patients had more than 20 lesions.

The CT images of the PET/CT scans were evaluated as described by Angtuaco et al (5) in a consensus reading by two board-certified radiologists (N.M.B. and D.K., with 13 and 10 years of experience, respectively) who were blinded to clinical and laboratory data and results of previous imaging studies. The number of CT-defined lesions was determined, and the patients were classified into previously mentioned cohorts (5). In a separate session, the two radiologists and the two board-certified nuclear medicine physicians classified all lesions defined by using CT as either 11C-methionine positive—when the uptake of 11C-methionine was higher than that in normal BM—or 11C-methionine negative—when there was virtually no 11C-methionine uptake in the lesion (Fig 4).


Figure 4
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  		Figure 4a: (a) Coronal maximum intensity projection PET scan in 59-year-old woman with relapsing MM and disseminated spotty bone lesions with intense 11C-methionine uptake. (b) Transverse PET (top), CT (middle), and PET/CT (bottom) scans of the pelvis in the same patient as in a. Some lesions have intense 11C-methionine uptake, whereas others have virtually none. (c) Coronal maximum intensity projection PET scan in 64-year-old woman with recurrent MM and multiple lesions with increased 11C-methionine uptake. (d) Transverse PET (top), CT (middle), and PET/CT (bottom) scans of the right ilium in the same patient as in c. Images show highly increased focal 11C-methionine uptake and normal bone structure, which suggest presence of new metabolically active lesions that were developing earlier than structural osteolytic bone changes.

 

Figure 4
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  		Figure 4b: (a) Coronal maximum intensity projection PET scan in 59-year-old woman with relapsing MM and disseminated spotty bone lesions with intense 11C-methionine uptake. (b) Transverse PET (top), CT (middle), and PET/CT (bottom) scans of the pelvis in the same patient as in a. Some lesions have intense 11C-methionine uptake, whereas others have virtually none. (c) Coronal maximum intensity projection PET scan in 64-year-old woman with recurrent MM and multiple lesions with increased 11C-methionine uptake. (d) Transverse PET (top), CT (middle), and PET/CT (bottom) scans of the right ilium in the same patient as in c. Images show highly increased focal 11C-methionine uptake and normal bone structure, which suggest presence of new metabolically active lesions that were developing earlier than structural osteolytic bone changes.

 

Figure 4
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  		Figure 4c: (a) Coronal maximum intensity projection PET scan in 59-year-old woman with relapsing MM and disseminated spotty bone lesions with intense 11C-methionine uptake. (b) Transverse PET (top), CT (middle), and PET/CT (bottom) scans of the pelvis in the same patient as in a. Some lesions have intense 11C-methionine uptake, whereas others have virtually none. (c) Coronal maximum intensity projection PET scan in 64-year-old woman with recurrent MM and multiple lesions with increased 11C-methionine uptake. (d) Transverse PET (top), CT (middle), and PET/CT (bottom) scans of the right ilium in the same patient as in c. Images show highly increased focal 11C-methionine uptake and normal bone structure, which suggest presence of new metabolically active lesions that were developing earlier than structural osteolytic bone changes.

 

Figure 4
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  		Figure 4d: (a) Coronal maximum intensity projection PET scan in 59-year-old woman with relapsing MM and disseminated spotty bone lesions with intense 11C-methionine uptake. (b) Transverse PET (top), CT (middle), and PET/CT (bottom) scans of the pelvis in the same patient as in a. Some lesions have intense 11C-methionine uptake, whereas others have virtually none. (c) Coronal maximum intensity projection PET scan in 64-year-old woman with recurrent MM and multiple lesions with increased 11C-methionine uptake. (d) Transverse PET (top), CT (middle), and PET/CT (bottom) scans of the right ilium in the same patient as in c. Images show highly increased focal 11C-methionine uptake and normal bone structure, which suggest presence of new metabolically active lesions that were developing earlier than structural osteolytic bone changes.

 
Follow-up
Remission state was determined during follow-up after 11C-methionine PET/CT in all patients with MM until November 2005 by two physicians (A.D. and P.L.). The medical records of all the patients in the study were reviewed. Immunofixation was used to detect monoclonal proteins in serum or urine. Negative immunofixation (urine and serum) is required to define complete remission in secretory MM (17).

Statistical Analysis
Data are presented as mean and standard deviation or as median and range. The values for SUVmax between groups were compared by using the Mann-Whitney test. The nonparametric Mann-Whitney test was used because a test for normality was not possible given the small number of patients. Differences with two-tailed P < .05 were considered statistically significant. Statistical analysis was performed by using software (Prism, version 4.03 for Windows; GraphPad Software, San Diego, Calif).

The receiver operating characteristic analysis was performed by calculating the sensitivity and specificity for a sample of threshold values of the SUVmax. A binormal receiver operating characteristic curve was fitted to the SUVmax values with a maximum likelihood estimation (18). The diagnostic accuracy of correctly identifying patients with MM and control patients was evaluated by calculating the area under the receiver operating characteristic curve and the 95% confidence interval by using software (ROCKIT; C. E. Metz, University of Chicago, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
35S-Methionine Uptake in CD138+ BM Cells of Patients with MM in Vitro
The CD138+ MM cells had a five- to sixfold increased 35S-methionine uptake in vitro as compared with that of CD138– mononuclear BM cells in two patients with MM (Fig 5). This compared favorably with a five- to sixfold increased 11C-methionine uptake in MM lesions in the same patients in vivo that was measured with PET/CT.


Figure 5
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  		Figure 5: Increased 35S-methionine uptake in CD138+ MM cells. Autoradiograph of sodium dodecyl sulfate–polyacrylamide gel electrophoresis of proteins of CD138+ MM cells incubated with 35S-methionine (lane 3). Incorporation of 35S-methionine into multiple cellular proteins was observed, with roughly 20% 35S-methionine incorporation into immunoglobulin fraction (arrow). Protein electrophoresis of CD138+ MM cells (lane 2) and of blood serum (lane 1) for comparison were performed with Coomassie brilliant blue R-250 stain. alb = albumin, {alpha}1 = {alpha}1-globulin, {alpha}2 = {alpha}2-globulin, ß = ß-globulin, {gamma} = {gamma}-globulin, 1e6 = 1 x 10–6.

 
Imaging Findings: 11C-Methionine PET
The BM 11C-methionine uptake was homogeneously low in all 10 control patients (Fig 2). The mean SUVmax of BM in the control group as assessed in BM of T11 was 1.8 ± 0.3 and was significantly lower than that of visually normal BM of untreated patients with MM (mean, 4.3 ± 2.0; P = .001) or that of treated patients with MM (mean, 4.6 ± 2.9; P = .008).

In contrast, 13 untreated patients with MM had multiple focal BM lesions. The maximal lesion uptake SUVmax of each patient with MM displayed a clearly higher 11C-methionine uptake as compared with that of the control group (mean, 10.2 ± 3.5 vs 2.8 ± 0.5; P < .001) (Fig 6).


Figure 6
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  		Figure 6: Top: SUVmax of 11C-methionine BM uptake in T11. Middle: Maximal lesion uptake in untreated patients with MM (UT), treated patients with MM (T), and control patients (C). Bottom: Receiver operating characteristic curve for maximal lesion uptake indicates nearly perfect separation of patients with MM from control patients. Az = area under the receiver operating characteristic curve, CI = 95% confidence interval.

 
On the basis of the maximal lesion uptake in BM or T11 in patients with MM versus control patients, receiver operating characteristic analysis allowed a clear separation of patients with MM and control patients (Fig 6). The corresponding mean areas under the curves were 0.99 ± 0.01 and 0.90 ± 0.06, respectively (Fig 6).

The number of skeletal lesions with focally increased 11C-methionine uptake ranged from zero in a patient with extramedullary disease to more than 100 (Table 2). In regard to the number of lesions in 14 patients with MM and a primary diagnosis, one had extramedullary myeloma and no bone lesions, five were in group 1, two were in group 2, and six were in group 3 (Table 2). In five patients with MM at relapse, one was in group 1, two were in group 2, and two were in group 3. One patient with newly diagnosed MM had exclusively extramedullary tumor manifestations but no BM involvement.


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  		Table 2. Findings of 11C-Methionine PET/CT according to Classification of MM and Pretreatment Status

 
Peripheral BM expansion was present in 11 of 13 untreated and four of six treated patients with MM (Table 2). Fifteen of 19 patients with MM displayed osteopenia as found at CT. Mono- or multifocal asymptomatic 11C-methionine–positive lesions were found in 12 patients with MM (Table 2).

Imaging Findings: CT
Bone and BM space were normal and without pathologic findings at CT in all control patients. In contrast, all patients with MM except for the patient with exclusive extramedullary disease had osteolytic lesions: Among the 13 untreated patients with MM, three patients were in group 1, six were in group 2, and four were in group 3. Among the six treated patients, one was in group 1, one was in group 2, and three were in group 3. One patient of the six had extramedullary myeloma and no bone lesions (Table 2).

Imaging Findings: 11C-Methionine PET/CT Fusion Imaging
All 19 patients with MM had pathologic findings at 11C-methionine imaging. A countable number of lesions were observed in 14 patients with MM (11 untreated, three treated). In the remaining five patients with MM, there were numerous osteolytic lesions: Two patients had lesions that were predominantly 11C-methionine positive. Two patients had predominantly 11C-methionine–negative lesions. One patient showed a balanced pattern of 11C-methionine–positive uptake and 11C-methionine–negative uptake.

In nine of 13 untreated patients with newly diagnosed MM and 83 osteolytic lesions, 55 (66%) of the lesions were 11C-methionine positive and 28 (34%) were 11C-methionine negative. In addition, 45 lesions displayed only 11C-methionine uptake but no CT abnormality (Table 3). In contrast, in four of 13 untreated patients with MM at relapse, 29 (34%) of 86 osteolytic lesions were 11C-methionine positive and 57 (66%) were 11C-methionine negative (Fig 4). Twenty lesions were identified by using 11C-methionine uptake, whereas no lesions were identified at CT of the respective skeletal location.


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  		Table 3. Abundance and Pattern of MM Lesions according to Diagnosis and Treatment Status in 19 Patients

 
Extramedullary MM
Extramedullary lesions, diagnosed by using CT or MR imaging, were present in three patients with MM. In two of these patients, additional 11C-methionine–positive extramedullary lesions were detectable. The mean SUVmax in extramedullary lesions was 7.2 ± 2.4. The additionally detected extramedullary MM lesions were identified also on the CT scans retrospectively when the results of 11C-methionine PET were made available to CT readers.

Follow-up
Median follow-up in all patients with MM was 11 months (range, 1–14 months). In the cohort of patients with MM (n = 14) imaged with 11C-methionine PET at the time of diagnosis, two patients did not receive therapy and were followed up with watchful waiting, two patients had complete remission, two patients had near-complete remission, four patients had partial remission, two had progressive disease, and two patients were lost to follow-up. In the group of patients with MM (n = 5) imaged with 11C-methionine PET at the time of relapse, one patient had near-complete remission (immunofixation positive), three patients had progressive disease (one of these patients died of MM), and one patient was undergoing a preparative regimen for autologous stem cell transplantation.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
This is, to our knowledge, the first report that describes 11C-methionine PET/CT for imaging of MM. Rapid uptake and metabolic incorporation of radiolabeled amino acids into newly synthesized immunoglobulins is well known (19). Accordingly, we observed a five- to sixfold higher uptake of 35S-methionine into myeloma cells as compared with other hematopoietic cells in two patients with newly diagnosed MM. Therefore, 11C-methionine incorporation into immunoglobulins of the malignant plasma cell clone in vivo can be assumed. Because immunoglobulins, radiolabeled in vivo through metabolic incorporation of a radiolabeled amino acid, are secreted only after a lag phase of 2–4 hours (19), 11C-methionine confers a radioactive tag on the malignant plasma cell clone. The radioactive tag can be easily measured and precisely localized with PET/CT within a time window of several hours. On the other hand, 11C-methionine uptake in the BM of control patients was homogeneous and was roughly half of the 11C-methionine uptake in visually normal BM of patients with MM.

In all patients with MM except one with exclusive extramedullary disease and one with monofocal medullary MM, we detected disseminated multifocal 11C-methionine–positive BM lesions; this finding suggests widespread dissemination of MM in hematopoietic BM. This pattern was in clear contrast to the pattern with homogeneous 11C-methionine uptake in control patients.

Multifocal increase of 11C-methionine in osteolytic lesions was very similar to multifocal BM infiltration depicted with MR imaging (9,20–22) or with FDG PET (3,4,7,8). Diffusely increased 11C-methionine uptake in virtually the whole hematopoietic BM was observed in this series in some patients with MM and might correspond to the published diffusely increased FDG uptake pattern and disseminated myelomatous infiltration into hematopoietic BM shown by using MR imaging (3,4,20,23).

Peripheral BM expansion was observed in 15 patients with MM, and mono- or multifocal asymptomatic lesions in the peripheral long bones were observed in 12 patients with MM. Relapsing MM may originate from incompletely eradicated MM lesions. We therefore believe that locating active MM lesions with 11C-methionine may be helpful not only for classification of the stage of the lesions and for provision of an estimate of MM mass but also for initiation of local radiation therapy in a given clinical context.

In untreated patients with MM, there was a trend toward predominance of 11C-methionine–positive osteolytic lesions in patients with a primary diagnosis of MM and toward predominance of 11C-methionine–negative osteolytic lesions in patients with a relapse of disease. Because of the possibility that these differences were related to the small number of patients with MM examined in the present series, these differences were not statistically significant and need to be studied prospectively. A lack of metabolic 11C-methionine uptake in CT-proved osteolytic lesions suggests macroscopically undetectable myeloma or scar tissue. Absent lesion uptake of FDG was interpreted as indicative of macroscopically inactive disease in treated myeloma (3,6).

There were a substantial number of focal 11C-methionine–positive lesions without any structural changes visible with CT in both patients with MM at diagnosis and patients with MM at relapse. It is tempting to speculate that these 11C-methionine–positive lesions without structural changes of cancellous bone might represent early manifestations of MM in which lytic changes of cancellous bone have not developed yet.

Extramedullary MM had a high 11C-methionine uptake and was sensitively detected and localized with 11C-methionine PET/CT. One of the three patients with extramedullary MM died during follow-up because of progression of disease. Similarly, Durie et al (3) reported high FDG uptake in myelomatous soft-tissue lesions. The authors reported an aggressive course and a dismal prognosis for patients with MM who had FDG-positive extramedullary MM lesions (3).

The median 11-month follow-up of this study is certainly too short for estimation of outcome of the patients with MM who were examined. Relapse was observed in seven of 10 pretreated patients with MM after 11-month follow-up despite intensive radiation therapy and chemotherapy, and one patient died of MM. These findings strongly argue for the presence of viable myeloma at the time of 11C-methionine PET/CT examination, although histologic confirmation of 11C-methionine–positive lesions was not available. The lack of histologic confirmation of both PET-positive lesions, indicative of active MM, and PET-negative lesions, indicative of scar tissue, is a clear limitation of the study.

Histologic confirmation of manifestations of disseminated multifocal malignant disease, however, is impossible in a clinical context. Nevertheless, presence of MM was unambiguously confirmed histologically in all patients. Also, availability of BM histologic findings in the control patients would be desirable. Because of the invasive and potentially harmful procedure of obtaining BM without a clinical benefit for respective patients, BM biopsies could not be performed in control patients and could be performed in only two patients with MM who were willing to undergo the procedure. Very small lesions of MM might be missed because of the limited spatial resolution of the PET scanner. Because asymptomatic MM is left untreated, we believe that identification of lesions very early during disease development is of minor clinical concern.

In summary, we observed a five- to sixfold increased 35S-methionine uptake of myeloma cells as compared with that of nontumorous BM cells in patients with active MM and increased focal 11C-methionine uptake in most osteolytic lesions. 11C-methionine–positive focal lesions in skeletal areas with normal cancellous bone might be indicative of early detection of new lesions. In pretreated patients with MM, only a fraction of skeletal lesions harbor metabolically active MM. Extramedullary myeloma was detected. We therefore believe that metabolic imaging with 11C-methionine PET/CT may provide an estimate of tumor burden, may complement classification of the stage of myeloma, and may help locate active medullary and extramedullary manifestations of myeloma, particularly in clinically silent and unexpected localizations.


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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: BM = bone marrow • FDG = fluorine 18 fluorodeoxyglucose • MM = multiple myeloma • SUVmax = maximum standardized uptake value

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, S.N.R.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, A.D., C.F., N.M.B., D.K., S.N.R.; clinical studies, A.D., N.M.B., D.K., C.W., D.B., S.N.R.; experimental studies, P.L., C.F., S.N.R.; statistical analysis, G.G., S.N.R.; and manuscript editing, A.D., P.L., G.G., C.F., N.M.B., S.N.R.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

  1. Munshi NC, Anderson KC. Plasma cell neoplasms. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005.
  2. Durie BG, Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors of the International Myeloma Foundation. Hematol J 2003;4:379–398.[CrossRef][Medline]
  3. Durie BG, Waxman AD, D'Agnolo A, Williams CM. Whole-body 18F-FDG PET identifies high-risk myeloma. J Nucl Med 2002;43:1457–1463.[Abstract/Free Full Text]
  4. Schirrmeister H, Buck AK, Bergmann L, Reske SN, Bommer M. Positron emission tomography (PET) for staging of solitary plasmacytoma. Cancer Biother Radiopharm 2003;18:841–845.[CrossRef][Medline]
  5. Angtuaco EJ, Fassas AB, Walker R, Sethi R, Barlogie B. Multiple myeloma: clinical review and diagnostic imaging. Radiology 2004;231:11–23.[Abstract/Free Full Text]
  6. Schirrmeister H, Bommer M, Buck AK, et al. Initial results in the assessment of multiple myeloma using 18F-FDG PET. Eur J Nucl Med Mol Imaging 2002;29:361–366.[CrossRef][Medline]
  7. Orchard K, Barrington S, Buscombe J, Hilson A, Prentice HG, Metha A. Fluoro-deoxyglucose positron emission tomography imaging for the detection of occult disease in multiple myeloma. Br J Haematol 2002;117:133–135.[CrossRef][Medline]
  8. Bredella MA, Steinbach L, Caputo G, Segall G, Hawkins R. Value of FDG PET in the assessment of patients with multiple myeloma. AJR Am J Roentgenol 2005;184:1199–1204.[Abstract/Free Full Text]
  9. Moulopoulos LA, Dimopoulos MA, Smith TL, et al. Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma. J Clin Oncol 1995;13:251–256.[Abstract/Free Full Text]
  10. Lecouvet FE, Malghem J, Michaux L, et al. Skeletal survey in advanced multiple myeloma: radiographic versus MR imaging survey. Br J Haematol 1999;106:35–39.[CrossRef][Medline]
  11. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749–757.[CrossRef][Medline]
  12. Liebisch P, Viardot A, Bassermann N, et al. Value of comparative genomic hybridization (CGH) and fluorescence in-situ hybridization (FISH) for molecular diagnostics in multiple myeloma. Br J Haematol 2003;122:193–201.[CrossRef][Medline]
  13. Jego G, Bataille R, Pellat-Deceunynck C. Interleukin-6 is a growth factor for nonmalignant human plasmablasts. Blood 2001;97:1817–1822.[Abstract/Free Full Text]
  14. Comar D, Catron JC, Maziere M, Marazano C. Labelling and metabolism of methionine-methyl-11C. Eur J Nucl Med 1976;1:11–14.[Medline]
  15. Schmid DT, John H, Zweifel R, et al. Fluorocholine PET/CT in patients with prostate cancer: initial experience. Radiology 2005;235:623–628.[Abstract/Free Full Text]
  16. Kwee SA, Coel MN, Lim J, Ko JP. Prostate cancer localization with 18fluorine fluorocholine positron emission tomography. J Urol 2005;173:252–255.[CrossRef][Medline]
  17. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Br J Haematol 1998;102:1115–1123.[CrossRef][Medline]
  18. Metz CE. ROC methodology in radiologic imaging. Invest Radiol 1986;21:720–733.[Medline]
  19. Hammerton K, Cooper DA, Duckett M, Penny R. Biosynthesis of immunoglobulin in human immunoproliferative diseases. I. Kinetics of synthesis and secretion of immunoglobulin and protein by bone marrow cells in myeloma. J Immunol 1978;121:409–417.
  20. Baur-Melnyk A, Buhmann S, Durr HR, Reiser M. Role of MRI for the diagnosis and prognosis of multiple myeloma. Eur J Radiol 2005;55:56–63.[CrossRef][Medline]
  21. Baur A, Stabler A, Nagel D, et al. Magnetic resonance imaging as a supplement for the clinical staging system of Durie and Salmon? Cancer 2002;95:1334–1345.
  22. Mahnken AH, Wildberger JE, Gehbauer G, et al. Multidetector CT of the spine in multiple myeloma: comparison with MR imaging and radiography. AJR Am J Roentgenol 2002;178:1429–1436.[Abstract/Free Full Text]
  23. Rahmouni A, Montazel JL, Divine M, et al. Bone marrow with diffuse tumor infiltration in patients with lymphoproliferative diseases: dynamic gadolinium-enhanced MR imaging. Radiology 2003;229:710–717.[Abstract/Free Full Text]




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