Multiple Myeloma
FDG PET/CT for staging, prognosis, and response in plasma-cell disease
Quick Answer
FDG-PET/CT detects focal bone lesions and — uniquely — extramedullary disease in multiple myeloma, provides prognostic information (focal-lesion number and extramedullary spread predict worse outcomes), and assesses response, where normalization of FDG uptake is a sensitive marker of deep response complementing marrow minimal-residual-disease (MRD) testing. It is complementary to whole-body MRI. Note the classic pitfall: the bone scan is negative in myeloma because the lytic lesions provoke little osteoblastic reaction.
Definition
Multiple myeloma is a malignant proliferation of clonal plasma cells in the bone marrow producing a monoclonal immunoglobulin (M-protein). It sits on a continuum from MGUS (monoclonal gammopathy of undetermined significance) → smoldering myeloma → symptomatic multiple myeloma, defined by end-organ damage or validated biomarkers.
Synonyms
Plasma-cell myeloma; Kahler disease. Related plasma-cell disorders: MGUS, smoldering (asymptomatic) myeloma, solitary plasmacytoma, plasma-cell leukemia, and (fibril-forming) AL amyloidosis.
Epidemiology
Myeloma is a disease of older adults (median presentation in the seventh decade), with higher incidence in men and in people of African ancestry. It is consistently preceded by MGUS. It is among the more common hematologic malignancies.
Etiology & Risk Factors
Age, MGUS/smoldering precursor states (defined annual progression risk), African ancestry, family history, prior radiation, and possibly chronic antigenic/inflammatory stimulation. Most cases are otherwise idiopathic.
Pathophysiology
Clonal plasma cells accumulate in the marrow and secrete M-protein, producing the CRAB features: hyperCalcemia, Renal impairment (light-chain cast nephropathy), Anemia (marrow replacement), and Bone disease. Myeloma bone disease is driven by osteoclast activation and osteoblast suppression, yielding purely lytic lesions with little reactive bone formation — the reason the ⁹⁹ᵐTc-MDP bone scan is characteristically negative/insensitive. Extramedullary disease (soft-tissue plasmacytomas) reflects more aggressive, marrow-independent biology.
Genetics & Molecular Biology
Risk stratification uses FISH cytogenetics: high-risk t(4;14), t(14;16), del(17p), and 1q gain/amplification; standard-risk hyperdiploidy and t(11;14) (the latter linked to BCL2/venetoclax sensitivity). These integrate with ISS/R-ISS staging (β2-microglobulin, albumin, LDH, cytogenetics).
Histopathology
Marrow shows sheets/clusters of clonal plasma cells with light-chain restriction (κ or λ) on immunohistochemistry/flow (CD138+, CD38+, often CD56+, cyclin-D1 in t(11;14)). Marrow plasma-cell percentage and clonality are part of the diagnostic criteria.
Clinical Presentation
Bone pain and pathologic fractures, fatigue/anemia, renal impairment, hypercalcemia, and recurrent infections (immunoparesis). Spinal lesions may cause cord compression. Hyperviscosity, neuropathy, and amyloid features occur in subsets.
Laboratory Findings
- SPEP/UPEP with immunofixation (M-spike identity), serum free light chains (κ/λ ratio) — diagnosis, burden, and response.
- β2-microglobulin and albumin (ISS), LDH (R-ISS), calcium, creatinine, hemoglobin.
- Marrow biopsy for plasma-cell percentage, clonality, cytogenetics, and MRD (flow/NGS).
Imaging Findings by Modality
- Whole-body low-dose CT: the modern replacement for skeletal survey — sensitive for lytic lesions.
- Whole-body MRI: most sensitive for diffuse and focal marrow infiltration; part of diagnostic criteria (> 1 focal lesion).
- FDG-PET/CT: focal lesions, extramedullary disease, prognosis, and response/MRD; standardized with IMPeTUs (Deauville-like reference to liver/mediastinum).
- Bone scan (⁹⁹ᵐTc-MDP): not useful — lytic disease with minimal osteoblastic reaction.
Radiopharmaceutical Uptake Mechanisms
FDG reflects the glucose metabolism of active plasma-cell disease. A key caveat: some myeloma has low hexokinase-2 (HK2) expression and is FDG-poor, so a normal FDG-PET does not fully exclude active disease. Bone diphosphonates require osteoblastic activity that myeloma largely lacks (hence the negative bone scan). Research tracers (CXCR4/pentixafor, C-11-methionine) target alternative biology.
Typical PET Tracers
| Tracer | Role |
|---|---|
| ¹⁸F-FDG | Focal lesions, extramedullary disease, prognosis, response/MRD |
| (research) ⁶⁸Ga-pentixafor (CXCR4) | Diffuse marrow disease; potential theranostic pair |
| (research) ¹¹C-methionine | More sensitive marrow-disease detection |
Typical SPECT Tracers
- ⁹⁹ᵐTc-MDP bone scan — classically negative (a teaching point, not a useful test).
- (Historical) Tc-99m-sestamibi marrow imaging.
Therapy Indications
- Symptomatic myeloma: multi-drug induction (proteasome inhibitor + immunomodulatory drug + anti-CD38 antibody + steroid), often followed by autologous stem-cell transplant and maintenance (lenalidomide ± others).
- Relapsed/refractory: BCMA-directed CAR-T cells, bispecific antibodies (BCMA/GPRC5D), and additional novel agents.
- Supportive: bone-modifying agents (bisphosphonate/denosumab), radiotherapy for painful/cord-threatening lesions, and infection prophylaxis.
Theranostics
No radioligand therapy is standard in myeloma, but CXCR4 (pentixafor imaging → pentixather therapy) and BCMA-directed radioligands are under investigation — a plausible future image-and-treat pathway analogous to other radiotheranostics. Currently, the nuclear-medicine role is diagnostic, prognostic, and response-defining.
Differential Diagnosis
- MGUS / smoldering myeloma (no CRAB / below biomarker thresholds) vs symptomatic disease.
- Metastatic lytic disease (e.g. renal, thyroid, lung) and lymphoma.
- Reactive/post-therapy marrow (G-CSF, anemia) causing diffuse FDG uptake that mimics or masks disease.
Reporting Checklist
- Report focal-lesion count, extramedullary/paramedullary disease, and diffuse marrow pattern.
- Use IMPeTUs (Deauville-like) for standardized reference-organ comparison and response.
- Correlate with whole-body MRI (complementary) and marrow MRD.
- Flag post-therapy/G-CSF marrow uptake and the FDG-low myeloma caveat.
Prognosis
Staged by ISS/R-ISS (β2-microglobulin, albumin, LDH, high-risk cytogenetics). On imaging, a higher number of focal FDG lesions and extramedullary disease independently predict worse outcomes, and FDG normalization after therapy (imaging MRD) is favorable, especially combined with marrow MRD negativity. Outcomes have improved markedly with modern combination and immune therapies.
Board Pearls
FDG-PET/CT is the modality of choice for extramedullary disease (which MRI and skeletal survey miss) and is prognostic — focal-lesion number and extramedullary spread predict worse outcomes; post-treatment FDG normalization is a sensitive deep-response marker complementing marrow MRD.
The bone scan is characteristically negative in myeloma — the lytic lesions provoke minimal osteoblastic reaction — so use low-dose whole-body CT, MRI, and FDG-PET, not ⁹⁹ᵐTc-MDP.
FDG-PET and whole-body MRI are complementary, not interchangeable — each detects disease the other can miss. Two pitfalls: diffuse marrow uptake after chemotherapy/G-CSF mimics or masks disease, and some myeloma is FDG-low (low HK2), so a normal scan does not fully exclude active disease.
Related Pages
- Tracer: FDG (preparation, physiologic distribution).
- Related: Cardiac amyloidosis (AL amyloid overlaps the plasma-cell-dyscrasia spectrum).
- Pitfalls: Pearls, pitfalls & normal variants.
Figure / Diagram Suggestions
- The MGUS → smoldering → myeloma progression continuum with defining criteria.
- A modality-complementarity plate (CT vs MRI vs FDG-PET; what each detects).
- IMPeTUs / Deauville-like reference schematic for myeloma response.
Common Pitfalls
- Diffuse marrow infiltration can be missed on FDG-PET when uptake only mildly exceeds the reference organs — whole-body MRI is more sensitive for the purely diffuse pattern.
- Skull and skull-base lesions are easily obscured by intense physiologic brain FDG — scrutinize the calvarium and correlate with CT/MRI.
- Recent corticosteroids or recent chemotherapy suppress FDG uptake and can render active disease falsely negative — record steroid/chemo timing before calling a lesion resolved.
- Degenerative joints, fractures, and post-vertebroplasty/surgical change take up FDG and can be mistaken for focal myeloma lesions.
Self-Check (Board-Style)
Q1. A myeloma patient's ⁹⁹ᵐTc-MDP bone scan is unremarkable despite known lytic lesions. Why?
Answer: Myeloma lesions are purely lytic with minimal osteoblastic reaction, so diphosphonate bone scans are characteristically insensitive — use low-dose CT, MRI, or FDG-PET instead.
Q2. Which imaging finding uniquely favors FDG-PET over whole-body MRI in myeloma?
Answer: Extramedullary disease — FDG-PET is the modality of choice for detecting soft-tissue plasmacytomas that MRI and skeletal survey can miss (and it carries prognostic weight).
Q3. A post-induction FDG-PET is negative but the patient's myeloma was known to be low-avid at baseline. How do you interpret a "negative" scan?
Answer: With caution — some myeloma is FDG-low (low hexokinase-2), so a normal scan does not fully exclude active disease. Correlate with MRI and marrow MRD.
Q4. Two weeks after G-CSF, diffuse marrow FDG uptake is seen. Disease or artifact?
Answer: Likely reactive marrow stimulation mimicking/masking disease — account for recent chemotherapy/G-CSF timing before interpreting diffuse marrow uptake.
Evidence & sources
https://nuc.med/multiple-myeloma/ Report an issue