Recommendations for the diagnosis of extramedullary multiple myeloma

Clinical Questions When should imaging be recommended for suspected extramedullary multiple myeloma (EMM), and which imaging modality is preferred? In which clinical scenarios is tissue biopsy necessary for suspected EMM, and what diagnostic tests should be performed on biopsy specimens? How is EMM diagnosed when it involves special sites, such as the central nervous system (CNS) or pleura? Recommendations Recommendations for the diagnosis of extramedullary multiple myeloma - Number Recommendations Quality level of evidence Strength of recommendations 1 All newly diagnosed and relapsed MM patients require imaging screening for EMM, particularly in cases with markedly elevated lactate dehydrogenase levels, 17p deletion, or concurrent EMM at initial diagnosis. Moderate Strong 2 MRI constitutes the imaging modality of choice for spinal and CNS involvement; otherwise, whole-body 18F-FDG PET/CT is recommended. Moderate Strong 3 Tissue biopsy with immunohistochemistry is recommended to confirm the diagnosis of EMM. Biopsy is mandatory when lesions are located in sites not typically involved in EMM, areas of predilection for secondary malignancies, or when macrofocal MM is clinically suspected. Moderate Strong 4 FISH and gene sequencing could be performed on biopsy specimens when feasible. Moderate Weak 5 For EMM involving special sites (e.g., the CNS or pleura), diagnostic protocols should incorporate CSF/pleural effusion cytology and flow cytometry. Moderate Strong Grading criteria for the quality of evidence and strength of recommendations can be found in Supplementary Table 1, https://links.lww.com/CM9/C643. CNS: Central nervous system; CSF: Cerebrospinal fluid; EMM: Extramedullary multiple myeloma; FDG: Fluoro-D-glucose; FISH: Fluorescence in situ hybridization; MM: Multiple myelom; MRI: Magnetic resonance imaging; PET/CT: Positron emission tomography/computed tomography. Recommendation Explanation EMM manifests in two distinct patterns: Extramedullary bone-related (EMB) lesions arise from skeletal lesions and predominantly involve the spine and ribs. The incidence ranges from 7.00–34.4% in newly diagnosed MM and from 6.00–34.2% in relapsed/refractory MM. Extramedullary extraosseous (EME) lesions develop in soft tissues/organs via hematogenous spread. The incidence in newly diagnosed MM is 1.7–4.8%, with skin/soft tissue involvement in 23.0–36.9% of cases. In patients with relapsed/refractory MM, the incidence increases to 3.4–14.2%, most frequently affecting the liver (15.1–34.0%), pleura (6.0–16.3%), and CNS (3.0–14.1%). Diagnostic criteria for EMM A confirmed diagnosis of EMM requires meeting all three of the following criteria: A confirmed MM diagnosis per the International Myeloma Working Group criteria. Imaging evidence of extramedullary lesions at bony or extraskeletal sites. Histopathological confirmation of plasmacytoma through lesion biopsy or exclusion of alternative diagnoses when biopsy is unavailable. Imaging considerations Imaging screening for EMM is recommended for all newly diagnosed and relapsed multiple myelom (MM) patients, particularly those with a marked increase in lactate dehydrogenase levels, 17p deletion, or concurrent EMM at diagnosis. A prospective study of 134 newly diagnosed MM patients revealed that 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and magnetic resonance imaging (MRI) had comparable detection rates for spinal involvement (91% vs. 95%), with discordant findings in only 11 cases.[1] PET/CT identified EME in 10% of the patients, which is a higher rate than previously reported. Additionally, PET/CT-confirmed EME at diagnosis independently predicted poor progression-free survival and overall survival. In the Total Therapy 3 trial (n = 270), baseline 18F-FDG PET/CT and spine/pelvis MRI detected significantly more lesions than conventional X-ray-based metastatic bone surveys did. PET/CT identified EME in 6% of the patients, with those who exhibited baseline EME showing markedly reduced 30-month overall survival compared with that of their non-EME counterparts (50% vs. 87%, P = 0.002).[2] In addition to baseline EME, other parameters provided by PET/CT, such as the number of focal lesions (>3 at diagnosis or >10 at relapse)[2] and the maximum standard uptake value (SUVmax) (>4.2), are also significant adverse prognostic factors in MM patients. These studies confirm that PET/CT and MRI provide comparable results for evaluating spinal lesions. However, MRI has a distinct advantage in patients suspected of having spinal cord or nerve root compression, as it allows precise assessment of the lesion location and the extent and degree of epidural space involvement. Additionally, MRI is more suitable for evaluating CNS lesions. Conversely, PET/CT offers superior sensitivity in diagnosing EME and provides valuable prognostic insights. Tissue biopsy for EMM diagnosis Tissue biopsy with immunohistochemistry is mandatory for confirming EMM, especially for lesions in atypical anatomical locations, areas prone to secondary malignancies, or when macrofocal MM is suspected. Immunophenotypic profiles: EMM is characterized by strong CD38/CD138/CD81 and monoclonal light chain restriction expression with dim/negative CD19/CD27/CD56/CD117 expression. To differentiate EMM from other malignancies, including lymphoma and metastatic carcinoma, the recommended markers for an immunohistochemistry panel include CD19, CD20, CD38, CD56, CD138, CD3, κ, λ and Pan-Cytokeratin (PanCK). Genomic profiles: fluorescence in situ hybridization (FISH) and comprehensive next-generation sequencing of biopsy specimens have revealed key molecular features, including 1q gain/amplification, TP53 mutations and MAPK pathway alterations.[3,4] MAPK pathway mutations drive inherent or acquired resistance to treatments, which explains their high prevalence in patients with EMM.[4] Integrating molecular profiling helps stratify disease risks and guide precision therapeutic strategies. However, the recommendation strength is limited because of insufficient existing data. Diagnosis of EMM at special anatomical sites For CNS or pleural EMM, additional diagnostic tools include cytological analysis of the cerebrospinal fluid (CSF) and pleural effusion combined with flow cytometry. Immunocytochemistry can be used for cytological preparations to characterize tumors of unknown origin, while flow cytometry can accurately differentiate clonal plasma cells from polyclonal plasma cells found under reactive conditions. For suspected leptomeningeal EMM, combining these techniques confirms the diagnosis in approximately 90% of cases.[5] For parenchymal brain lesions, stereotactic brain biopsy remains the preferred diagnostic method.