Disease

1. Whole-Body Imaging of Multiple Myeloma:
Diagnostic Criteria
Alípio G. Ormond Filho, MD1; Bruno C. Carneiro, MD1; Daniel Pastore, MD, PhD1; Igor P. Silva,
MD1; Sâmia R. Yamashita, MD1; Flávio D. Consolo, MD1; Vânia T. M. Hungria, MD, PhD2; Alex F.
Sandes, MD, PhD3; Edgar G. Rizzatti, MD, PhD3; Marcelo A. C. Nico, MD1
1Department of Musculoskeletal Radiology, Fleury Medicina e Saúde Higienópolis, São Paulo, SP, Brazil
2Department of Hematology, Clínica São Germano, São Paulo, SP, Brazil
3Department of Hematology and Flow Cytometry, Fleury Medicina e Saúde Higienópolis, São Paulo, SP, Brazil

2. Whole-Body Imaging of Multiple Myeloma: Diagnostic Criteria
Recipient of a Certificate of Merit award for an education exhibit at the 2017 RSNA Annual Meeting (MK258-ED-X).
Address correspondence to Bruno C. Carneiro, MD
Department of Musculoskeletal Radiology, Fleury Medicina e Saúde Higienópolis, Rua Mato Grosso 306, 1º Andar,
Higienópolis, São Paulo, SP, Brazil 01239-040
+55 11 3179-0822, e-mail bruno.carneiro@grupofleury.com.br
Acknowledgments: We acknowledge Xavier Stump, MD, for all of his years teaching the diseases of the musculoskeletal
system to generations of radiologists and always helping our group solve the most difficult cases. We also thank Julio B.
Guimarães, MD, PhD, for helping us with a variety of issues in this work, and Julie C. Dutoit, MD, PhD, for allowing us to
use a figure from her article.

3.  Heterogeneous clonal plasma cell proliferative disease
 Primary infiltration of the bone marrow
 Second most common hematologic malignancy after
lymphoma
 Most frequent malignancy involving the skeleton, with
exception of metastasis
 Different whole-body (WB) imaging modalities indicated in
distinct disease situations
MULTIPLE MYELOMA (MM)

4.  Summary of disease spectrum
 MM criteria scenario
 2014 updated criteria
 Imaging modalities and their applications
 Treatment response evaluation
 Complications
 Conclusion
TABLE of CONTENTS

5. Learning Objectives
1. Describe the disease spectrum of MM
2. Discuss the updated diagnostic criteria and
indications, advantages, and limitations of the WB
imaging modalities
3. Identify and interpret the imaging findings of MM for
diagnosis, follow-up, complications assessment, and
treatment response evaluation

6. DISEASE SPECTRUM – MONOCLONAL GAMMOPATHIES
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)
 Asymptomatic stage
 Low rates of progression to MM
 Present in approximately 3%–4% of the population older than 50 years
SMOLDERING MULTIPLE MYELOMA (SMM)
 Intermediary stage
 Heterogeneous group with different rates of progression to MM
MM
 End-organ damage, CRAB (hypercalcemia, renal failure, anemia, and bone lesions)
symptoms
 Skeletal involvement in 80%–90% of patients
 Complications
Lancet Oncol 2014;15:e538-e548.
Br J Haematol 2011;154:32-75.

7. MM SCENARIO
2003 CRITERIA
 End-organ damage (ie, one or more CRAB features) needed for
diagnosis
 High-risk SMM did not show any benefit from treatment
• Toxic effects
• Early intervention did not extend survival
 WB radiography is reference-standard imaging modality
Lancet Oncol 2014;15:e538-e548.
Hematol J 2003;4(6):379-398.

8. MM SCENARIO
2014 CRITERIA
 Recognition of biomarkers that can be used to identify a subset of
patients at very high risk of progression to active disease (once
referred to as high-risk SMM)
 Major advance in treatment options
• Safer and more effective treatments
• Early intervention can extend survival
 Cross-sectional imaging is reference-standard approach
Lancet Oncol 2014;15:e538-e548.
Hematol J 2003;4(6):379-398.

9. Criterion MGUS
(SMCP < 30 g/L)
SM
(SMCP > 30 g/L)
MM*
CBMPC level ≥ 10% (-) (+) (+)
CRAB features (-) (-) (+)
Hypercalcemia, renal
impairment, or anemia
(-) (-) (+)
Bone lesions†
(-) (-) (+)
Myeloma biomarkers (-) (-) (+)
CBMPC level ≥ 60% (-) (-) (+)
MRI lesions‡
(-) (-) (+)
SFLCR ≥ 100 (-) (-) (+)
Note.—CBMPC = clonal bone marrow plasma cell, SFLCR = serum free light chain ratio, SM = smoldering MM, SMCP = serum monoclonal protein level.
*MM defined as CBMPC level of ≥10%, plus one or more CRAB features or one or more biomarkers.
†A single lytic lesion ≥ 5 mm at skeletal survey, WB low-dose (WBLD) CT, or PET/CT is sufficient for a diagnosis of MM.
‡
Two or more lesions ≥ 5 mm at MRI are necessary for a diagnosis of MM.
2014 INTERNATIONAL MYELOMA WORKING GROUP CRITERIA

10. IMAGING MODALITIES
 WB radiography
 WBLD CT
 WB MRI
 PET/CT

11. WB Radiography
 Previously the standard method for detecting bone lesions
 Low accuracy
 Requires 30%–50% bone destruction for detection of a
lesion
 30%–70% false-negative results
 Lower sensitivity in the axial skeleton
 Low accuracy for detection of complications
 No longer indicated unless it is the only option
Haematologica 2015;100(10):1254-1266.

12. a.
c.
b.
FIG. 1: Low Accuracy at WB Radiography
MM in a 71-year-old woman with renal impairment, anemia,
and hypercalcemia. Anteroposterior pelvic radiograph (a), and
coronal (b) and axial (c) T1-weighted fat-saturated gadolinium-
enhanced MR images show that although several aggressive
bone lesions (arrows in b and c), with cortical disruption and
extracortical extension, are seen on the MR images, only the
right iliac lesion (arrow in a) is well characterized on the
radiograph.

13. FIG. 2: Classic MM Lesions
a. b. c.
Classic radiographic findings of MM in three patients. Lateral skull (a), anteroposterior arm (b), and lateral thoracic spine (c) radiographs show several
lytic lesions (solid arrows in a and b) without a sclerotic halo owing to decreased osteoblastic activity, endosteal scalloping (dotted arrows in b),
mottled areas of multiple small lesions (dashed arrow in b), diffuse osteopenia, and vertebral fractures (arrows in c).

14. WBLD CT
 Significantly higher accuracy compared with WB radiography
 Involves better sensitivity, faster acquisition, and less
expense compared with MRI and PET/CT
 Excellent interobserver correlation
 New standard initial procedure in the setting of MM
according to European Myeloma Network
 Not so good for detection of extramedullary lesions
 Not indicated for treatment response evaluation
Haematologica 2015;100(10):1254-1266.
Oncol Lett 2017;13:2490-2494.

15. Tube voltage: 120 kV
Tube current: 40 - 50 mAs
Collimation: 16.0 x 1.5 mm
Pitch: 1
Section thickness: 2 mm
Supine position
Arms beside the body
No need for contrast media
Low-dose radiation, similar to
twice the dose of skeletal survey
Eur J Radiol 2013;82(12):2322– 2327.
Radiation doses:
Chest radiography: 0.1 – 0.3 mSv
PET/CT and body CT: 10–24 mSv
WBLD CT: 4.1 mSv
Skeletal survey: 1.7–2.4 mSv
FIG. 3: WBLD CT Protocol

16. Fig. 4: Focal Lesions at WBLD CT
MM in a 55-year-old man with low back pain, anemia, and a CBMPC
level of 21%. Coronal (a) and sagittal (b) reformatted WBLD CT
images show several osteolytic lesions (arrows) in the axial skeleton.
a. b.

17.  Standard method for detecting bone marrow involvement
 Diffusion-weighted imaging has higher sensitivity
 Greater sensitivity and specificity than PET/CT
 Part of solitary plasmacytoma staging procedures
 Best approach for ruling out focal SMM lesions
 If WBLD CT finding is negative, WB MRI investigation is
necessary
Insights Imaging 2016;7:553-569. Neuroradiol J 2017;30(3):259-268.
Radiology 2016 279(2):345-365.
WB MRI

18.  Has prognostic value
 Not as effective as PET/CT for treatment response
assessment
 Standard procedure for evaluation of painful
complications
 Contrast media not routinely necessary
 Whole-spine MRI and pelvic MRI also are options if WB
MRI is not available
Insights Imaging 2016;7:553-569. Neuroradiol J 2017;30(3):259-268.
Radiology 2016;279(2):345-365.
WB MRI

19. WB MRI Protocol
*WB MRI and whole-spine MRI were performed by using a target volume–adapted
surface reception coil system. STIR = short τ inversion recovery.
†
b = Diffusion-weighted imaging was performed by using b factors of 50 and 800
sec/mm2.
Parameter WB MRI* Whole-Spine MRI*
Coronal sequences T1-weighted, STIR …
Sagittal sequences … T1-weighted, STIR
Axial sequence Diffusion-weighted
†
…
Section thickness
(mm)
5 4
Matrix 512 pixels 512 pixels

20. FIG. 5: WB MRI Protocol
The authors’ WB MRI protocol includes the acquisition of coronal T1-weighted (a), STIR (b), and reconstructed diffusion-weighted inverted
gray-scale (c) MR images, and sagittal T1-weighted (d) and STIR (e) MR images.

21. Interpretation of Bone Marrow Diffusion-weighted Imaging Findings
YELLOW MARROW
 Reduced water content and
extracellular matrix
 Large amount of big hydrophobic lipid
cells
 Low blood supply
 High restriction to water movement
 Very low apparent diffusion coefficient
(ADC) values
RadioGraphics 2014;34(5):1163-1677. Quant Imaging Med Surg 2015;5:740-
RED MARROW
 More water content and extracellular
matrix
 Less lipid and more hematopoietic
cells
 Higher blood supply
 Less restriction to water movement
 Higher ADC values
• Mimics lesions or diffuse pattern
• Decreases lesion conspicuity
Radiology 2016;279(2:345-365.
MM lesions have higher ADC values than bone marrow lesions

22. Fat marrow or
Late after treatment
MGUS
10-25%
plasma cells
SMM / MM
25-50%
plasma cells
SMM / MM
>50%
plasma cells
MM
Red marrow Post-treatment
WATER
FAT
Signal
intensity
DWI
ADC
Fat cell Necrosis / edematous plasma cell
water
plasma cell
hematopoietic cell
Adapted and reprinted, with permission, from Insights Imaging 2016;7:553-569.

23. Bone Marrow Diffusion-weighted Imaging Interpretation
 Inverted gray-scale analysis increases lesion conspicuity
 Excellent tumor-to-background contrast; however,
nonspecific
• Increased signal intensity of benign bone tumors, red
marrow, edema, fractures, infection, and degenerative
disease; low specificity
• Interpretation with conventional MRI sequences and CT, if
necessary, adds specificity
Radiology 2016;279(2):345-365.

24. FIG. 7: Patterns of Involvement at MRI
1. Apparently normal bone marrow
2. Diffuse pattern
3. Focal lesions 4. Focal and diffuse
5. “Salt and Pepper”
Eur J Radiol 2005;55(2005):56-63.

25. a. 0,850 x 10-3 mm2/s
d.
c.
b.
Findings in 62-year-old man with back pain, anemia, and a palpable left clavicular nodule. (a, b) Coronal reformatted colored (a) and inverted gray-scale (b) diffusion-weighted
images, and axial diffusion-weighted image (c) and ADC map (d) show small lesions in the right femur (arrows in a and b). The largest lesions (arrowheads in a and b) were in
the left clavicle and left sacral wings and demonstrated cortical disruption and extramedullary extension, with high signal intensity (arrowhead in c) at diffusion-weighted
imaging and low signal intensity (region of interest 1 in d) at ADC mapping. Left clavicle biopsy revealed a plasmacytoma, confirming the diagnosis of MM.
FIG. 8: Focal Lesions at WB MRI

26. a. b.
c.
FIG. 9: Higher Accuracy at Diffusion-weighted imaging
Findings in a 68-year-old man with mild anemia, hypercalcemia, and a CBMPC level of 33%. (a)
Coronal T1-weighted MR image shows only discrete heterogeneity of the clavicular bone marrow
(arrows) without any focal lesion. (b, c) However, the inverted gray-scale diffusion-weighted images
show focal lesions on both clavicles (solid arrows in b), the sternum (dotted arrows), and the
posterior elements of the spine (arrowheads in c) that were undetectable with other sequences,
confirming the diagnosis of MM. A few weeks later, the patient developed renal impairment.

27. a.
b.
c.
d.
FIG. 10: Focal Lesions and Right Rib Fractures
Findings in a 59-year-old woman who had acute low-energy trauma, anemia, and an SFLCR of 108. (a–d) Coronal STIR (a), sagittal T1-weighted (b), and axial
diffusion-weighted (c and d) WB MR images show right low rib fractures (arrows in a), lesions in the T8 and T9 vertebral bodies (arrows in b and c), and left iliac
bone lesions (arrow in d). A CBMPC level of 12.8% confirmed the diagnosis of MM. Serum creatinine and calcium levels were normal.

28. c.
b.
a.
FIG. 11: Appendicular Skeleton lesions
0,73 x 10-3 mm2/s
d.
Findings in a 57-year-old asymptomatic woman with laboratorial anemia (hemoglobin level, 7.6 g/dL [76 g/L]) and an SFLCR of 1138. (a) Coronal reformatted
WBLD CT image shows several ill-defined focal bone lesions (arrows) in both femurs that are visible in the soft-tissue window only. (b–d) At further
investigation, findings on the coronal T1-weighted (b) and axial diffusion-weighted (c) and ADC (d) images confirmed the presence of several focal bone marrow
lesions (arrows in b and c, line in d). A CBMPC level of 34% confirmed the diagnosis of MM.

29. d.
FIG. 12: Costal MM Pseudolesion
a.
b. c.
Findings in a 57-year-old woman with low back pain,
mild anemia, and a CBMPC level of 10%. (a) Sagittal
99mTc scintigram shows focal increased uptake in the
ninth left costal arch (arrow). (b, c) Axial (b) and sagittal
(c) reformatted WBLD CT images depict a focal
osteolytic bone lesion (arrow) with sclerotic margins at
the same location as in a. (d) There is no depiction of
the lesion on the axial WB diffusion-weighted MR
image. Abdominal CT data (not shown) showed that
the lesion was stable for 8 years, excluding MM and
confirming the benignity of this lesion and the
diagnosis of SMM. Scintigraphy has poor accuracy and
should not be used for MM screening.

30. b.
1,87x 10-3 mm2/s
c.
d.
MM in a 39-year-old man with lower limb paresthesia and weakness. (a) Coronal T1-weighted pelvic MR image obtained before treatment shows a large left iliac
bone lesion (arrow). (b, c) Coronal T1-weighted MR image (b) and axial ADC map (c) obtained after induction therapy and autologous stem cell transplantation
show a good treatment response, with decreased lesion size and partial fatty bone marrow repopulation (arrow in b) and an increased ADC value (round region of
interest and line in c). (d) Axial diffusion-weighted image shows peripheral neuropathy (arrows) due to amyloidosis with paresthesia and muscle denervation in
the anterior and lateral compartments of the legs.
FIG. 13: Posttreatment Response at MRI
a.

31.  Best tool for posttreatment evaluation
 Has prognostic relevance
 Good option for disease diagnosis
 High sensitivity for detection of bone lesions and
extramedullary involvement
 Sufficient for excluding focal lesions if WB MRI is not available
 Diffuse FDG uptake does not meet the criteria
Lancet Oncol 2017;18:e206-e217.
PET/CT

32. a. f
.
FIG. 14: Focal Lesions at PET/CT
b.
c.
(a–c) MM in a 68-year-old man with anemia, renal
impairment, hypercalcemia, and a CBMPC level of
45.8%. (a) Coronal maximum intensity projection
PET image shows several hepatic and bone lesions
(arrows) with increased uptake. (b, c) Axial fused
PET/CT images show the hepatic lesions (arrows in
b) with greater conspicuity and a large iliac bone
lesion (arrow in c) with extramedullary extension.
(d) Axial fused PET/CT image obtained in another
patient with MM shows lytic bone lesions (arrows)
with FDG uptake.
d.

33. a.
b.
e.
f
.
FIG. 15: Posttreatment Response at PET/CT
MM in a 61-year-old man. (a–c) Axial CT (a) and PET (b) images and coronal PET image (c) obtained before induction therapy show a
MM lesion (arrow in a and b) in the right sacral wing . (d–f) Coronal PET (d) and axial CT (e) and PET (f) images show a treatment
response in most lesions. After chemotherapy, although the right sacral wing lesion (arrow in e and f) remained stable at CT (e), it
exhibited virtually no metabolic activity at PET (f).

34.  Infections are the main cause of death
 Vertebral fractures may be neoplastic or osteoporotic
 MRI can differentiate between these
 Spinal cord or nerve root compression
 Fractures or extramedullary tumor extension
 Osteonecrosis: usually treatment related
 Meningeal myelomatosis
 Neuropathy
 Venous thrombosis and/or thromboembolism
COMPLICATIONS

35. FIG. 16: Insufficiency Fracture
Sagittal STIR (a) and T1-weighted (b) MR images show
an L4 vertebral body insufficiency fracture (arrow) in a
patient with MM. Note: Patients with MM do not
always have pathologic neoplastic fractures.
b.
a.
Findings in a patient with pain caused by MM progression. Sagittal
pretreatment STIR (a) and 1-year-posttreatment (b) MR images
show posterior element (long solid arrows in b) and vertebral
body (short solid arrows in b) lesions. Note the epidural mass
(dotted arrow in b) causing spinal stenosis. Neural compression is
an MM-related emergency that should be addressed with
radiation therapy within 24 hours.
b.
a.
FIG. 17: Cauda Equina Compression

36. b. c.
a.
FIG. 18: Neoplastic Fractures and Spinal Cord Compression
Findings in a 72-year-old woman with MM-related severe back pain. Sagittal STIR (a) and T1-weighted fat-saturated gadolinium-enhanced
(b) MR images depict several vertebral body involvement lesions (thin straight arrows), extramedullary epidural implants (arrowheads in a)
with spinal cord compression, a prevertebral mass (thick arrow), and a pathologic vertebral fracture (curved arrow in a and c).

37. Suspicion of MM
1
WBLDCT2
Lytic lesion(s)
(+) (-)
MM
SM?
WBMRI
3
Complications
• Pain
• Fracture
• Neural compression
• Meningeal myelomatosis SM
SM
3-6 months follow-up MRI
MM
(-)
Single or doubtful lesions
4
Smaller lesions < 5mm
Diffuse Pattern
Salt-and-pepper
2 or more focal
lesions ≥ 5 mm
Post-treatment evaluation
1CBMPC ≥ 10% is mandatory. 2PET/CT also is an option. 3Whole-spine and pelvic MRI is indicated if WB MRI is not available. 4Biopsy may be an option.
MRI
PET/CT

38. Conclusions
 WB radiography is a poor option unless it is the only choice.
 WBLD CT is the initial standard imaging procedure.
 WB MRI is the most sensitive imaging modality for detecting
“early” MM and excluding SMM bone lesions.
 Standard MRI is the method of choice for evaluation of painful
complications.
 PET/CT is the best tool for assessment of treatment response.

39. Conclusions
 2014 International Myeloma Working Group updated criteria
• Major role of radiologists in diagnosis
• Greater importance of imaging, with different WB techniques
indicated in distinct disease scenarios
 Radiologists must know the disease criteria, advantages and
limitations of each imaging modality, and recommendations for
early follow-up and treatment response evaluation.

40. Suggested Readings
• Baur-Melnyk A, Buhmann S, Dürr HR, Reiser M. Role of MRI for the diagnosis and prognosis of
multiple myeloma. Eur J Radiol 2005;55(1):56–63.
• Bhojwani N, Szpakowski P, Partovi S. Diffusion-weighted imaging in musculoskeletal radiology-
clinical applications and future directions. Quant Imaging Med Surg 2015;5(5):740–753.
• Bird JM, Owen RG, D'Sa S, et al. Guidelines for the diagnosis and management of multiple myeloma
2011. Br J Haematol 2011;154(1):32–75.
• Cavo M, Terpos E, Nanni C, et al. Role of 18F-FDG PET/CT in 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(4):e206–e217.
• Dimopoulos MA, Hillengass J, Usmani S, et al. Role of magnetic resonance imaging in the
management of patients with multiple myeloma: a consensus statement. J Clin Oncol
2015;33(6):657–664.

41. Suggested Readings
• 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(6):379–398. [Published correction appears in Hematol J 2004;5(3):285.]
https://doi.org/10.1038/sj.thj.6200312.
• Dutoit JC, Verstraete KL. MRI in multiple myeloma: a pictorial review of diagnostic and
post-treatment findings. Insights Imaging 2016;7:553–569.
• Ippolito D, Besostri V, Bonaffini PA, Rossini F, Di Lelio A, Sironi S. Diagnostic value of
whole-body low-dose computed tomography (WBLDCT) in bone lesions detection in
patients with multiple myeloma (MM). Eur J Radiol 2013;82(12):2322–2327.
• Lambert L, Ourednicek P, Meckova Z, Gavelli G, Straub J, Spicka I. Whole-body low-
dose computed tomography in multiple myeloma staging: superior diagnostic
performance in the detection of bone lesions, vertebral compression fractures, rib
fractures and extraskeletal findings compared to radiography with similar radiation
exposure. Oncol Lett 2017;13(4):2490–2494.

42. Suggested Readings
• Lasocki A, Gaillard F, Harrison SJ. Multiple myeloma of the spine. Neuroradiol J
2017;30(3):259–268.
• Lecouvet FE. Whole-Body MR Imaging: Musculoskeletal Applications. Radiology
2016;279(2):345–365.
• Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma
Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol
2014;15:e538–e548.
• Subhawong TK, Jacobs MA, Fayad LM. Diffusion-weighted MR imaging for characterizing
musculoskeletal lesions. RadioGraphics 2014;34(5):1163–1177.
• Terpos E, Kleber M, Engelhardt M, et al. European Myeloma Network guidelines for the
management of multiple myeloma-related complications. Haematologica
2015;100(10):1254–1266.