International Myeloma Working Group Recommendations for the Diagnosis and Management of Solitary Plasmacytomas

Abstract

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

INTRODUCTION

Plasmacytomas are localized tumors of clonal plasma cells. Solitary plasmacytomas (SPs) are defined as biopsy-proven, single-site clonal plasma cell tumors,^1-3 as opposed to the systemic nature and the more diffuse infiltration of the bone marrow (BM) in multiple myeloma (MM).² This definition requires proven plasma cell clonality and a single tumor site (solitary), without evidence of significant BM infiltration (ie, should be <10% clonal plasma cells) or systemic disease. Most plasmacytomas occur within a bone, typically but not exclusively as a single lytic lesion, and are referred as solitary bone plasmacytoma (SBP). Less common are solitary extramedullary plasmacytomas (SEMP) in which the plasma cell tumors are found in a single nonbony (extraosseous/extramedullary) site.^4-10 Direct invasion or expansion from a bone to an adjacent nonbony (soft tissue) site does not constitute a SEMP; such tumors are called paraskeletal and managed like SBP. About 50%-70% of patients with SBPs and approximately 30% of patients with SEMPs will progress to MM within 5 years after treatment with local radiotherapy.^4,5,11-19

Since the International Myeloma Working Group (IMWG) diagnostic criteria² for MM publication, the widespread use of sensitive imaging modalities for detection and follow-up of solitary lesions and methods for clonality detection have refined diagnostic definitions, treatment, and follow-up of SPs and continue to evolve.

INCIDENCE

SPs are rare, comprising approximately 3%-6% of plasma cell disorders.^20-24 In a SEER analysis (2003-2016) overall age-adjusted incidence rates per 100,000 adults were 0.45 for SBP, 0.12 for SEMP, and 8.47 for MM.²² In a US study (2000-2019), the age-standardized incidence (per 100,000 men and women, respectively) for SBPs were 0.38 and 0.20 and for SEMPs were 0.13 and 0.06. Age-standardized SEMPs incidence declined (especially among women) but not for SBPs during this period.²¹ SP incidence is higher among men (twofold for both SBP and SEMP),^20,22,25-28 and in Black patients and the lowest in Asian/Pacific Islanders. The median age at SP diagnosis is 55-60 years, about a decade younger than in MM.^20,22,25-28

TOPOGRAPHY AND CLINICAL PRESENTATION

Patients with SBP usually present with localized bone pain and/or fracture at the lesion site, less often with neurologic symptoms from spinal cord compression in cases with vertebral involvement. The axial skeleton, particularly sites with active hematopoiesis, is more often involved (thoracic vertebrae more common, pelvis, ribs, upper extremities, skull, femur, sternum); distal appendicular SBPs are uncommon.^{4,14,15,29,30} Patients with SBPs should not have systemic symptoms attributable to the plasma cell clone; if present, further evaluation is needed. Patients with SBP presenting with peripheral neuropathy should be evaluated for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome or, rarely, light-chain amyloidosis^31,32 (Data Supplement, Table S1).

SEMPs typically arise at mucosal sites with high antigenic load, more common in the head and neck region (85%)^26,27,33,34; other sites include the GI tract, lung, thyroid, testis, parotid glands, lymph nodes, and CNS.^35,36 Symptoms should, by definition, only be related to local tumor expansion.

PATHOPHYSIOLOGY OF SPs

The clinical course of SPs is typically more indolent than MM although the biologic basis for these differences remains incompletely understood. The localized aggregation of the clonal cells (v scatter in MM) suggests a critical role of interactions with their microenvironment.³⁷ The localization in bone, for SBPs, versus mucosal surfaces, for SEMPs, suggests differences in their antigen-driven development. Clonal PCs in SPs and MM have similar immunophenotypes, despite subtle differences (eg, lower frequency of CD56 expression in SEMPs)⁴ and carry similar cytogenetic alterations. Interphase fluorescence in situ hybridization (FISH) commonly identifies del(13q; 33%-40%), immunoglobulin heavy chain (IgH) rearrangements (37%-53%), and hyperdiploidy (45%-54%).^38-40 The presence of IgH translocations point to a common origin of SPs and MM.³⁹ In a Mayo Clinic series of 55 patients, high-risk cytogenetic abnormalities [del(17p), t(14; 16), t(4; 14), +1q21(gain or amplification)] were seen in 40% (22/55), with del17p found in 20%(11/55); their presence was associated with short progression time to MM (approximately 8 months).⁴⁰ In an Intergroupe Francophone du Myélome cohort, targeted next generation sequencing (NGS) performed on 47 patients with SBPs identified hyperdiploidy in 64% while 59% harbored MAPK pathway mutations (KRAS, NRAS, and BRAF) and 19% had a TP53 alteration (del17p and/or TP53 mutation). KRAS mutation or TP53 abnormality was associated with inferior progression-free survival. High Ki-67 expression (>20%) also correlated with adverse risk, suggesting that molecular lesions already shape disease evolution at this early stage.⁴¹ Some reports indicate that SEMPs tend to have fewer cytogenetic abnormalities when compared with MM; in a series of 38 patients with SEMPs, there were no patients with t(11; 14), but six (16%) had t(4; 14).³⁸

Patients with SBPs more often have minimal BM involvement and/or detectable monoclonal proteins compared with SEMPs^4,8,42 and exhibit a higher rate of progression to overt MM, which could partly be explained by the above differences.

DIAGNOSTIC CRITERIA

Current Definitions

The diagnosis of SP requires (a) histologic and immunohistochemical confirmation of a monoclonal plasma cell tumor; (b) the absence of additional lesions in the skeleton or outside the skeleton, assessed by advanced functional imaging; (c) the absence of significant (ie, ≥10% clonal plasma cells by immunohistochemistry [IHC]) BM involvement; and (d) the absence of myeloma defining events.²

The term solitary plasmacytoma with minimal marrow involvement encompasses patients in whom clonal plasma cells are present in the BM, but the clonal plasma infiltration by IHC is <10%. The two different conditions (without and with minimal marrow involvement) carry different risks of progression to MM and should be reported separately (Fig 1).

FIG 1.

Graphical overview of the approach to diagnosis and treatment of SPs. ^aMinimal marrow involvement: <10% in IHC and/or clonal cells/clone detected in NGF/NGS. ^bNo marrow involvement: no clonal cells in IHC and no clonal cells/clone detected in NGF/NGS. ^cFor patients with two lesions, it is reasonable to consider local therapy for both lesions and observe closely, in particular if belonging to the same anatomic area; however, we do not recommend this approach if one or both lesions are large (ie, > 5 cm), and we recommend greater caution if the lesions belong to completely different areas/mixed osseous/extra osseous. CT, computed tomography; DWI, diffusion-weighted imaging; IHC, immunohistochemistry; MRI, magnetic resonance imaging; NGF, next generation flow cytometry; NGS, next generation sequencing; PET, positron emission tomography; SP, solitary plasmacytoma; WB, whole-body.

Histologic Diagnosis

Both SBPs and SEMPs are characterized by the presence of mature plasma cells, expressing CD138 and/or CD38, with light chain restriction. Clonality is usually assessed with IHC or PCR-based methods.^43,44

The histologic diagnosis of SEMPs may be challenging,⁴⁵ requiring an experienced hematopathologist. Malignant plasma cells in SEMP may exhibit a plasmablastic morphology, but compared with the extramedullary MM involvement, CD56 expression is less frequent, and proliferation rate is lower. A histologic three-grade classification developed for SEMP is not widely used.⁴⁶ A SEMP variant, with predominantly IgA expression, manifests in head and neck lymph nodes, in younger patients with immune dysregulation.⁴⁷

In some SEMP cases, an accompanying neoplastic B-cell population raises the possibility of an extranodal marginal zone or lymphoplasmacytic lymphoma (Table 1). Plasma cells immunophenotype can help because B-cell lymphomas with plasmacytic differentiation contain clonal plasma cells more like their normal counterparts. Localized amyloid deposits are common and do not necessarily indicate systemic AL amyloidosis but warrant further evaluation to exclude systemic involvement.^48-56 Notably, the clonal cells may be missed within the amorphous material, and careful evaluation is needed to confirm clonality.

TABLE 1.

Differential Diagnosis of Clonal Extramedullary Infiltrates With Plasmacytic/Plasmablastic Differentiation

Characteristic Feature	SEMP	LPL	EMZL	EMM	PBL
Clinical features	Localized disease, frequently upper respiratory tract No or minimal BM involvement	Systemic disease with BM infiltration and IgM paraprotein in most cases, IgM MGUS as precursor Indolent clinical course, symptoms because of IgM not uncommon	Frequently localized disease at typical extranodal locations BM involvement rare, excellent prognosis	Usually in advanced/terminal stage MM, occasionally isolated extramedullary relapse after treatment Poor prognosis	Aggressive disease (B-symptoms frequent) in HIV infection, iatrogenic immunosuppression, elderly immunocompetent patients. Frequently extranodal (oral cavity, GI tract), 50% nodal in immunocompetent patients
Cytology	Mostly mature PCs in monotonous sheets	Lymphocytes and lymphoplasmacytic cells, variable amounts of PCs	Small lymphocytes, centrocytoid or monocytoid cells, variable amounts of PCs	Sheets of PCs, anaplastic or plasmablastic features can be observed	Monomorphic proliferation of large cells with prominent nucleoli, usually lack of mature PCs
Immunophenotype	PC markers MUM1 + , CD38 + , CD138+ CD79a ± , LC restriction; CD19 and CD45-; CD56-/+ (weak), lack of CD20, PAX5, cyclin D1, MYC or p53 overexpression EBV + in up to 15%	CD20 + , CD5-/+, CD23-/+  PCs express CD19 and CD45; lack CD56, cyclin D1, and CD117 EBV negative	CD20 + , CD5-/+, CD43-/+  PCs express CD19 and CD45; lack CD56, cyclin D1, and CD117 EBV negative	PC markers MUM1 +, CD38 + , CD138 + , LC restriction; CD19 and CD45-; CD56 ± ; MYC and/or p53 overexpression common, high MIB-1 EBV usually negative	PC markers MUM1 +, CD38 + , CD138 +, LC restriction; frequently CD19 and CD45-; CD56±; MYC and/or p53 overexpression common, high MIB-1 EBV + in 50%-75%
Genetics	IGH translocations with absence of t(11; 14), MM-type trisomies Mutational spectrum unknown	MYD88 L265P in > 90%, CXCR4mut in 30%-40% Lack of MM-type translocations	EMZL-type translocations depending on location TNFAIP3 mutations Lack of MM-type translocations	Primary genetic alterations of MM, enrichment of high-risk cytogenetics, and secondary alterations including del(17p), 1q gains, MYC translocations, and TP53 mutations	MYC translocation in 50%, lack of MM-type translocations Mutations in RAS-RAF, JAK-STAT, and NOTCH pathways

NOTE. Adapted from Fend et al.⁴⁵

Abbreviations: BM, bone marrow; EBV, Epstein-Barr virus; EMM, extramedullary multiple myeloma; EMZL, extranodal marginal zone B-cell lymphoma; IGH: immunoglobulin heavy chain; LC, light chain; LPL, lymphoplasmacytic lymphoma; MM, multiple myeloma; PBL, plasmablastic lymphoma; PC, plasma cell; SEMP, solitary extramedullary plasmacytoma.

Plasmablastic lymphoma, commonly involves the oral cavity or mucosal surfaces, exhibits plasmablastic morphology, typically in immunocompromised individuals, and is frequently associated with Epstein-Barr virus (EBV). Morphologic and immunohistochemical studies cannot always differentiate between plasmablastic lymphoma and SEMP; markedly increased proliferation rate, necrosis, and association with EBV infection, as well as aggressive clinical presentation, suggest plasmablastic lymphoma rather than SEMP; a rare EBV-positive SP has also been described.⁵⁷

Differential diagnosis of SPs includes both nonmalignant and malignant tumors such as fibrous dysplasia, enchondromas,^58-60 POEMS and adenopathy and extensive skin patch overlying a plasmacytoma (AESOP)^32,61-64 syndromes, Castleman disease, and metastatic solid malignancies. The differential diagnosis also includes nonmalignant conditions (reactive plasmacytosis, plasma cell granuloma,⁶⁵ and IgG4 disease,⁶⁶ Table 2). Careful evaluation is needed in patients with a monoclonal gammopathy, when histology reveals the possibility of a metastatic tumor. In most cases, the diagnosis is straightforward; however, if the material is limited and polyclonal plasma cells are present, additional confirmatory studies are needed.

TABLE 2.

Differential Diagnosis of SPs From Other Malignant and Nonmalignant Conditions

Nonmalignant Tumor	Histologic, Clinical, and Radiographic Characteristic
Monostotic (involving only one bone) fibrous dysplasia	Benign solitary lesion, present in children and young adults, can appear as a well-defined, ground glass lesion with cortical thinning; MRI findings are nonspecific; CT can better delineate morphologic osseous changes of bone58-60
Reactive plasmacytosis	Usually associated with proliferation of small lymphocytes and other immune cells. Plasma cells in reactive processes express CD19 with CD45; they lack expression of CD56, CD117, and cyclin D1, and show no light chain restriction. Clinical history is important
Plasma cell granuloma	Are characterized by polyclonal plasma cells within a background proliferation of spindle cells associated with a variably dense polymorphic infiltrate of mononuclear inflammatory cells65; often (but not always) located in the lung
IgG4 disease	Histologic findings highly suggestive of IgG4-related disease include dense polyclonal lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis, increased (>40%) IgG4/IgG plasma cell ratio and IgG4+ plasma cells counts66

Malignant Tumors	Histologic, Clinical, and Radiographic Characteristic
POEMS syndrome	A SBP may be associated with POEMS syndrome POEMS is characterized by the presence of neuropathy and a monoclonal gammopathy (in >98% with λ light chain restriction), along with other systemic features and elevated vascular endothelial growth factor levels31 The bone lesions in POEMS usually have some sclerotic components or may be entirely sclerotic Both CT or PET/CT (especially bone windows) and MRI are important for their evaluation Specific diagnostic criteria are available (Data Supplement, Table A1)
AESOP syndrome	Very rare paraneoplastic syndrome seen in patients with a SP which can also coincide with or precede POEMS syndrome32,61-64
Amyloidoma	Localized masses of amyloid deposition Imaging cannot reliably differentiate amyloidomas from other bone tumors or plasmacytoma48-56

Abbreviations: AESOP, adenopathy and extensive skin patch overlying a plasmacytoma; CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; SBP, solitary bone plasmacytoma.

IMAGING

Advanced whole-body (WB) functional imaging is critical to exclude the presence of additional lesions and for follow-up after treatment (Table 3; Fig 2).

TABLE 3.

Proposed Work-Up for the Initial Evaluation and Follow-Up Assessments of Patients With SP

Assessment at the Time of Diagnosis	Follow-Up Assessment
Complete history and physical examination Special focus on the presence of systemic symptoms, neurologic signs and symptoms, and skin changes	Every 3-6 months
A biopsy of the suspected lesion, obtained using either CT, US, or MRI guidance	Not indicated
Advanced functional imaging with  WB diffusion-weighted imaging WB-MRI (DWI) or 18F-fluorodeoxyglucose (18F-FDG) PET/CT combined with axial MRI (first option) For SBP only, if WB-MRI and PET/CT are unavailable, WB CT for bone lesion combined with axial MRI (second best) For SEMPs only, if WB-MRI and PET/CT are unavailable, WBCT or high-resolution CT with IV contrast (second best)	Response assessment requires advanced functional imaging (PET/CT or WB-MRI-[DWI]) performed 6-9 months after radiotherapy, interpreted according to MY-RADS and IMPETUS criteria, respectively In patients with imaging complete remission, annual functional reimaging is suggested for the first 5 years, or earlier if clinically indicated For residual tumor masses with partial response, re-evaluation every 6 months can be considered, until complete response or stable residual disease; switching imaging modality can be considered as cross-check
Unilateral BM aspiration and biopsy with sensitive flow cytometry is recommended if available (no data for peripheral blood circulating tumor cells) Cytogenetics with FISH or NGS is highly recommended (in both the plasmacytoma specimen and BM if feasible)	Routine BM biopsy and/or aspiration is not recommended, unless clinically indicated
Complete blood count and differential with examination of the peripheral blood smear	Every 3-6 months
Full chemistry screen panel	Every 3-6 months
Complete assessment for the presence and typing of monoclonal immunoglobulin  SPEP with immunofixation and quantitation of immunoglobulins and a serum FLC assay.—provide type of FLC assay (data for Freelite only—no data for N-latex)  Mass spectrometry for the assessment of very small amounts of monoclonal immunoglobulin, if available (uncertain prognostic impact yet)  24-hour urine collection for UPEP and immunofixation	Every 3-6 months Urine tests every 6-12 months—may be skipped if negative at diagnosis

Abbreviations: BM, bone marrow; CT, computed tomography; DWI, diffusion-weighted imaging; FISH, fluorescence in situ hybridization; FLC, free light chain; MRI, magnetic resonance imaging; MY-RADS, myeloma response assessment and diagnosis system; NGS, next generation sequencing; PET, positron emission tomography; SBP, solitary bone plasmacytoma; SP, solitary plasmacytoma; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis; US, ultrasound; WB, whole-body.

FIG 2.

Overview of the follow-up strategy for patients with SPs treated with local radiotherapy. (1) Assessment of response requires functional imaging (PET/CT or WB-MRI [DWI]) performed 6-9 months after radiotherapy and interpreted according to MY-RADS and IMPETUS criteria, respectively, yearly up to 5 years or earlier if clinically indicated or residual mass. (2) It is strongly recommended to use the same imaging technique for follow-up that was used at baseline. (3) For residual tumor masses with partial response, re-evaluation every 6 months can be considered, up to complete response or stable residual abnormality; change of imaging method can be considered as cross-check. (4) Clonal immunoglobulin assessments should be followed regularly (every 3-6 months), but its disappearance may be slow (3-12 months). Test should include SPEP, SIFE, SFLC, quantitative immunoglobulins, CBC, CMP; mass spectrometry for the assessment of very small amounts of monoclonal immunoglobulin, only if available. 24-hour urine collection for UPEP and immunofixation every 6-12 months but may be skipped if negative at diagnosis. (5) Persistence of the M-protein/FLC alone should not trigger start of systemic therapy. (6) Routine evaluation of the BM is not recommended. BM, bone marrow; CBC, complete blood count; CMP, comprehensive metabolic panel; CT, computed tomography; DWI, diffusion-weighted imaging; FLC, free light chain; MRI, magnetic resonance imaging; MY-RADS, myeloma response assessment and diagnosis system; PET, positron emission tomography; SFLC, serum free light chains; SIFE, serum immunofixation electrophoresis; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis; WB, whole-body.

Radiographs and Computed Tomography (CT) Scan

Plain x-rays lack sensitivity within the axial skeleton and is not a valid option.^67-71 Low-dose WB CT scan (ldWBCT) can detect even small (<5 mm) lytic bone lesions but has not been studied in SPs. ldWBCT is preferred over plain x-rays,^72,73 but lacks sensitivity for early or nonosteolytic marrow disease, cannot distinguish active from inactive lesions, being unsuitable for response assessment, offers limited soft-tissue contrast, and cannot evaluate SEMPs. ldWBCT can be considered only if WB functional imaging is unavailable, ideally in combination with axial magnetic resonance imaging (MRI).

MRI

MRI detects plasma cell BM or soft tissue infiltration, identifying focal lesions (FLs) or diffuse BM infiltration before osteolysis appearance, paraskeletal disease, spinal cord/nerve root impingement or compression,⁷⁴ and extramedullary lesions. It is the preferred technique for CNS lesions. MRI of the spine and pelvis detected focal or diffuse BM involvement in >25% of patients falsely diagnosed as SBPs based on conventional radiographs^74,75 and was associated with the persistence of monoclonal protein after radiotherapy and higher relapse rates.^70,74-76 Nonetheless, in the study by Paiva et al⁴⁴, MRI was negative in 12/28 (43%) patients with clonal cells detected by next generation flow cytometry (NGF)/multiparametric flow cytometry (MFC).

Diffusion-weighted imaging (DWI-MRI) is sensitive for tumor detection in SMM and MM, but prospective data in SPs remain limited. WB-MRI (DWI) is used for disease staging and response evaluation according to myeloma response assessment and diagnosis system (My-RADS) criteria and included in the revised response criteria and guidelines,⁷⁷ is highly recommended over standard axial MRI, and is strongly considered as alternative to positron emission tomography (PET)/CT.⁷⁸ If WB-MRI (DWI) is not available or expertise in interpreting and reporting is lacking, a combination of axial MRI and PET/CT is alternatively recommended.

PET/CT

¹⁸F-FDG-PET/CT combines valuable metabolic and anatomic assessment for SP evaluation. In small studies, FDG-PET/CT reveals additional lesions in 33%-55% of plain radiographs-presumed SBP cases.⁷⁹ Compared with axial-MRI, PET/CT has lower sensitivity to detect diffuse BM involvement and FLs but has wider coverage.^80-84 Baseline PET/CT provides additional prognostic information with higher avidity lesions associated with an increased risk of progression.^16,79 IMWG acknowledges the value of PET/CT in the management of SP and state that, in the context of limited WB MRI availability, PET/CT should be part of initial SP investigation to exclude additional occult disease.^69,79 In SEMPs, PET/CT is the preferred imaging modality to exclude additional lesions.⁶⁷ PET-CT can be used to evaluate response to therapy applying the standardized Italian Myeloma Criteria for PET Use (IMPeTUs) criteria.⁸⁵ Importantly, lesions may remain FDG-avid for months after radiotherapy, and this should not prompt immediate therapy escalation but close follow-up. Other PET metrics, including total lesion glycolysis, remain investigational.

1. All patients with SPs should have advanced functional imaging at diagnosis.

2. FDG-PET/CT and/or WB MRI (DWI) are preferred imaging modalities to exclude additional lesions and for accurate evaluation of treatment response.

3. The most sensitive available imaging modality should be used at baseline, and the same should be used to assess treatment response, according to standardized criteria

BM Assessment

BM should show no or minimal clonal infiltration (ie, <10% clonal PCs by IHC), reported as SP with minimal marrow involvement.^43,86-90 Sensitive techniques (MFC/NGF, NGS) detect even small clonal populations,⁹¹ more often than IHC (in 21%-68% of patients with SBPs), but less (approximately 38%) in SEMPs.^40,43,44,92 In SBPs, clonal BM PCs detected by MFC/NGF were associated with a higher risk of progression to MM,^43,44 but this was not shown in SEMPs.⁴⁴ In a study of SBPs, the presence of minimal marrow involvement (by IHC or aspirate or by MFC/NGF) was associated with shorter time to MM in univariable (N = 115 patients, 28 v 53 months, P = .018),⁴⁰ but not in multivariable analysis. In a more recent report, from the same center, BM involvement (N=147, mostly patients with SBP) was strongly associated with shorter time to MM progression (15.7 v 79 months; P < .001).¹⁹

High sensitivity of MFC/NGF (10⁻⁵-10⁻⁶) increases detection of minimal marrow involvement. The extent of BM involvement by MFC/NGF may be clinically important but prognostic comparison of minimal marrow involvement by NGF versus IHC is lacking. IMWG strongly encourages BM evaluation with sensitive assays and reporting of the results because they provide prognostic information and may aid treatment evaluation in the context of future clinical, imaging, and biochemical findings. Circulating tumor (plasma) cells are detected in approximately 18% of SPs⁹³; however, their prognostic significance is unknown. NGS-based methods can detect minimal BM involvement using DNA sequencing of the original SP to identify the clone-specific immunoglobulin gene rearrangements in the BM or by high-throughput Ig repertoire sequencing on RNA.⁹¹ However, the clinical implications of such sensitive approaches are unknown.

1. The most sensitive available method should be used to detect clonal BM disease. A BM aspirate without a trephine for IHC or sensitive flow cytometry is inadequate.

2. Evaluation with MFC/NGF (or NGS, if available) is recommended for all patients with SBP and SEMP.

3. BM or the SP assessment for the presence of cytogenic aberrations by FISH or NGS is strongly recommended.

4. The IMWG definition of SPs without and SPs with minimal marrow involvement remain and should be reported separately, along with the methods used to assess BM involvement.

5. Until more data are available, patients with SPs should have a similar treatment approach, irrespective of the presence of minimal marrow involvement.

ASSESSMENT OF MONOCLONAL PROTEINS

All patients with SPs must have complete assessment for the presence of monoclonal immunoglobulin(s) and free light chains in serum and urine before treatment initiation (Table 3; Fig 2). Serial assessments have prognostic value.^{6,11,18,30,75,94-96} Approximately 50%-80% of patients with SBP have a small M-protein (median 0.5-0.9 g/dL) and 40%-60% have abnormal FLC ratio with negative urine and serum immunofixation.^4,18,19,97 In SEMPs, serum and urine immunofixation studies are abnormal in <25%-45% of patients.^18,26,76 Immunoparesis is rare; if present, more extensive disease should be suspected.^75,97 The role of mass spectrometry to detect low M-protein levels or post-therapy monitoring in SPs has not been evaluated.⁹⁸

1. Complete serum and urine tests to detect any monoclonal immunoglobulin is required in all patients before treatment initiation and at follow up post-therapy.

2. Mass spectrometry is not routinely recommended yet, but it is encouraged to be reported.

PROGNOSTIC FACTORS

The Data Supplement (Table S2) summarizes baseline tumor characteristics and treatment-related factors associated with prognosis of SPs. Some prognostic scores (Data Supplement, Table S3) which have been developed in relatively small series lack external validation. IMWG strongly encourages collaboration for identification of prognostic factors.

TREATMENT

Radiotherapy

Local radiotherapy with curative intent is the treatment of choice for SPs with 83%-96% of patients achieving response.^{5-7,9,11,13-15,17,18,25,30,33,42,99-108} No prospective randomized studies define optimal radiation dose. Retrospective data suggest inferior outcomes with doses <40 Gy,^26,42,109 whereas doses >45 Gy do not significantly improve tumor control^{5-7,9,11,14,15,17,30,33,42,99-102} except in few cases.^13,103,104 Few studies suggest a dose-response curve for larger SBPs.¹⁰⁴ Some centers follow a risk-adapted approach delivering 50 Gy over 25 fractions for SPs >5 cm and 40 Gy in 20 fractions for SPs <5 cm.¹⁰⁵ The National Comprehensive Cancer Network guidelines (V.4.2026) recommend 40-50 Gy dose in 1.8-2.0 Gy fractions (20–25 total fractions) to the involved site, with a 35-40 Gy dose acceptable for SPs <5 cm in size. The International Lymphoma Radiation Oncology Group (ILROG) recommends a total dose of 35-40 Gy for SBPs <5 cm (with 35 Gy acceptable for small SBPs) and 40-50 Gy for SBPs ≥5 cm; a 40-50 Gy total dose is recommended for SEMPs, with 40 Gy being acceptable for small, well-defined lesions or with postexcision positive margins.¹¹⁰

Lower doses used for palliation in MM patients with plasmacytomas are insufficient for local control and are not recommended for SPs.^108,111-114

In rare cases with two disease sites and no evidence of systemic involvement, it is unclear whether management should follow MM principles (as in macrofocal MM¹¹⁵) or local therapy only. In one study, survival did not differ between patients with a single or two lesions,¹¹⁶ but patients with >2 lesions had inferior outcomes. For patients with two lesions, especially if located in the same area and without marrow involvement, local therapy for both lesions and close observation with advanced imaging is reasonable; however, this approach is not recommended if one or both are large (ie, >5 cm).

Modern radiotherapy techniques (ie, intensity-modulated radiotherapy [IMRT], volumetric-modulated arc therapy [VMAT], and protons) should be used over conventional radiotherapy to limit toxicity.^12,110,117 Involved-site radiotherapy (ISRT) should be used to avoid large radiation fields,^101,110,118 which should be defined with precision and not on gross anatomic landmarks. ILROG recommends to define a clinical target volume (CTV) that includes the gross tumor volume (GTV), on the basis of the primary imaging of untreated lesions, plus a margin of 0.5-3 cm expanded in all directions, respecting anatomic boundaries; an axial GTV to CTV expansion of 0.5-1 cm may be appropriate for potential microscopic extension in soft tissues.¹¹⁰ Modern techniques allow for definitive radiotherapy in organs such as the aerodigestive tract, eye, etc. The benefit of extensive coverage or prophylactic nodal radiotherapy is controversial,^{9,34,76,101,117,119-123} particularly for SEMPs involving the Waldeyer ring.

If the radiation field is particularly large or includes a tissue/organ at a high risk of subsequent side effects, systemic therapy may be considered instead of RT; however, no prospective comparative data are available. Steroids should be used with caution (ie, for nerve root or spinal cord compression or to prevent pain flare) because they may affect the detection of M-protein after radiotherapy.

1. Radiotherapy remains the recommended treatment for all patients with SPs, irrespective of minimal marrow involvement.

2. Doses of radiotherapy of 40 to 50 Gy in 20-25 fractions are recommended for all SPs

3. Modern radiotherapy techniques (IMRT, VMAT) should be used.

4. Radiation fields should be defined precisely and not by gross anatomic boundaries.

5. Regional lymph nodes irradiation is not required for SEMPs

Surgery

Partial or complete surgical excision may be performed during the diagnostic workup, particularly for SEMPs. For SBPs, surgery may be indicated or considered for vertebral instability, spinal cord compression (laminectomy, vertebroplasty, and kyphoplasty^124-127), or pathologic or imminent fracture risk.¹²⁸ Surgery does not replace radiotherapy either for SBPs nor for SEMPs: Local recurrence rates with tumor excision only are high,¹⁴ and tumor bed radiotherapy should be strongly considered postresection.

For SEMPs, local control improves when surgery is followed by radiotherapy.¹⁰ An older literature review reported similar outcomes for surgery with clear margins, radiation, or a combined modality approach¹²⁹; however, given the radiosensitivity of SEMPs, radiation therapy remains the preferred approach.^110,120,130 Radiotherapy is strongly recommended following a surgery without clear margins or when complete excision is associated with functional impairment or has significant risks.^{7,101,120,121} In selected cases, surgery may be considered for special sites or for the management of specific complications.^35,131-133

1. Surgery does not replace radiotherapy but may be done if clinically necessary, followed by radiotherapy

2. Tumor excision alone is an inadequate treatment but may be considered in exceptional cases (small SEMPs excised with adequate margins).

Systemic Therapy

Prospective data on the role of adjuvant or concurrent systemic therapy in SPs are limited. A small, randomized study conducted between 1982 and 1989 favored combined therapy¹³⁴ but lacked modern imaging and used outdated systemic therapy. A US Alliance Cooperative Group study investigated zoledronate with or without ixazomib-(I), lenalidomide-(R), and dexamethasone-(d) for six 28-day cycles following definitive radiation but closed prematurely because of poor accrual; six IRd-treated patients had a 33% (95% CI, 0 to 70) 4-year progression rate to myeloma while five nontreated patients had a 58.3% (95% CI, 0 to 85.3) 2-year progression rate. In a nonrandomized study, 46 patients with SP treated between 2007 and 2018 received IMRT (median total dose of 40 Gy) while concurrent lenalidomide-dexamethasone (starting with radiation therapy, for four cycles, in n = 19) was given per physician's discretion. The 5-year myeloma-free survival was 100% with the combination versus 77.1%, P = .02 and progression-free survival was 81.7% versus 48.4%, P = .047, respectively.¹² A retrospective SBP series (N= 77) treated with radiation with or without systemic therapy showed marginal benefit,⁹⁶ but patients who received adjuvant therapy had more frequently minimal marrow involvement and almost all persistent M-protein after radiotherapy.⁹⁶ Other case series provide conflicting results with few indicating some^{7,13,42,135-137} and most no benefit^{4-6,8,9,18,95,100,117,138-140} of systemic therapy. Retrospective studies lack information on imaging, BM assessment, and occult systemic disease and use systemic therapy more frequent in patients with larger plasmacytomas or with nonoptimal imaging response after radiotherapy, and most have not used novel agents. Most regimens are of fixed duration. Systemic use of bisphosphonates has not been studied in SPs. The optimal regimen with respect to adjuvant therapy is unknown, given the available options. There are anecdotal reports of anti-CD38 monoclonal antibodies use or their combinations, but lacking prospective data. Ongoing trials evaluate combined approaches (ClinicalTrials.gov identifiers: NCT06863584, NCT05248633, NCT02544308).

Given the availability of advanced imaging to assess response and detect progression early, the effective salvage options, and limited data, we do not recommend systemic adjuvant therapy outside clinical trials. IMWG acknowledges that there may be situations where clinical judgment favors systemic treatment for individual cases, for example in patients in which radiation therapy may not be feasible or deemed too toxic. Further studies are needed to bring clarity on this topic.

1. Adjuvant or concurrent systemic therapy is not recommended when adequate radiotherapy is delivered, irrespective of SP size or minimal marrow involvement.

2. Decisions on systemic therapy should be based on postradiotherapy response evaluation. This approach may change as data on novel combinations, especially in patients with minimal marrow involvement, emerge.

RESPONSE ASSESSMENT AND FOLLOW-UP

The goal of therapy is complete tumor disappearance and laboratory normalization. Functional/advanced WB imaging combined with biochemical evaluation is recommended after therapy (Fig 2).

Response assessment requires functional imaging, performed 6-9 months after radiotherapy, with the same imaging modality as baseline, following local availability and interpretative expertise, and guided by clinical circumstances. Physicians should be aware that early assessment (ie, at 3 months), sometimes considered for specific clinical reasons or in case of suspected progression, can result in false-positive scans because of radiotherapy-induced changes or BM regeneration. Both bone destruction/regeneration in SBPs and fibrotic tissue in SEMPs vary among patients, and visible alterations may persist for years. Standard MRI may give false-positive results for months following radiotherapy and should be interpreted cautiously. Functional imaging using WB-MRI (DWI) or FDG-PET/CT are the recommended imaging modalities according to the standardized interpretative criteria (MY-RADS and IMPETUS).^78,141 Each evaluation should be compared with the pretreatment imaging results.

In case of imaging complete remission (per the above criteria), repeat functional imaging, ideally using the same method/machine as baseline, is suggested annually for the first 5 years, or sooner if signs of progression emerge.

For those with residual or doubtful tumor mass at the 6-9 months evaluation (ie, partial response/stable disease by PET or RAC-2 and 3 by MRI, per standardized criteria), reimaging every 6 months can be considered, until complete response or any residual abnormality remains stable on consecutive scans (meaning false-positive imaging results, mostly because of tissue remodeling). It is generally not beneficial to continue to reimage stable minor residual abnormalities frequently, unless there are clinical indications; switching imaging method can be considered as cross-check. Only PET-defined progression or RAC 4-5 by MRI should be considered as progressive disease (Fig 2).

M-protein should disappear with successful treatment, but can be slow (median 3-6 months, or longer⁶), requiring serial measurements. Persisting M-protein is more frequent among patients with minimal marrow involvement and predicts a higher progression risk.^{6,11,30,75,94-96} Isolated presence of M-protein should not trigger immediate start of systemic therapy, and careful follow-up is recommended.

The follow-up should include regular clinical assessment with serum and urine testing for persistent M-protein (eg, at 3 months postradiotherapy and every 6 months thereafter). There are no data to support frequent BM reassessment after radiotherapy, especially in patients with negative baseline tests.

1. Response assessment requires advanced functional imaging (PET/CT or WB-MRI-(DWI)) performed 6-9 months after radiotherapy, interpreted according to MY-RADS and IMPETUS criteria, respectively.

2. In patients with imaging complete remission, annual functional reimaging is suggested for the first 5 years, or earlier if clinically indicated.

3. For residual tumor masses with partial response, re-evaluation every 6 months can be considered, until complete response or stable residual disease; switching imaging modality can be considered as cross-check.

4. M-protein should be followed every 3-6 months; delayed disappearance is common, and its persistence is associated with a higher risk of progression to MM but should not trigger immediate start of systemic therapy.

5. BM re-evaluation is not recommended routinely, unless clinically indicated.

OUTCOMES AND PROGRESSIVE DISEASE

Patients with SPs generally have favorable overall survival (OS), although outcomes vary by subtype, lesion location, and individual prognostic factors. Population-based data from the United States,^10,142 Germany,¹⁴² Sweden,²⁴ Mayo Clinic,^19,89 and Greece^4,18 consistently demonstrate better 10-year survival than patients with MM treated in the same era. These findings suggest that SPs carry a more favorable prognosis compared with MM, underscoring the importance of avoiding unnecessary systemic therapy to preserve quality of life and limit late complications.

Approximately 50% of patients with SBP progress to MM within 3-5 years after local radiotherapy, with 10-year progression rate reaching 65%-84%.^4,5,11-18 Despite their accuracy, even patients with negative WB-MRI or PET/CT may eventually develop MM. Patients with SBPs can develop new lesions without evidence of diffuse marrow involvement, either solitary or multiple (as in macrofocal MM),^{7,25,88,89,95,103,115,140} or progress to typical MM with marrow involvement^42,136; even localized recurrences can occur within or near the radiation field^7,9,30 (Fig 3). The majority, however, will present with new focal/lytic lesion(s) and low tumor burden disease.

FIG 3.

Approach to the management of confirmed relapse in a patient with SP previously treated with local radiotherapy. (1) In cases of progression to overt MM, systemic treatment is indicated and the principles of MM therapy apply. (2) Patients who progress to overt myeloma should not be excluded from frontline trials. ^aRadiotherapy may not be feasible, and systemic therapy should be strongly considered. ^bAs defined by the 2014 IMWG criteria, ^cit is common to progress with low tumor burden disease, as in macrofocal myeloma. CT, computed tomography; DWI, diffusion-weighted imaging; MM, multiple myeloma; PET, positron emission tomography; SP, solitary plasmacytoma; WB, whole-body.

Local recurrence rates for SEMPs are around 10%,^{15,27,76,94,99,143} and progression to MM ranges from 11% to 36% (significantly lower than with SBPs).^15,26,94 Relapse may manifest with lymph node infiltration, skin and subcutaneous tissues involvement, or development of lytic bone lesions. Patients progressing to MM usually have relatively indolent disease with features of low tumor burden.^94,115,144

Isolated localized relapses should be carefully re-evaluated with advanced imaging. Radiotherapy can still be used for a solitary lesion outside the radiation field. For recurrences near or within the radiation field, previous radiotherapy dose and fields must be reviewed to evaluate the possibility of additional doses at the same location. Primary resistance to radiotherapy is exceptionally rare; such cases should be reviewed carefully (including revisiting the diagnosis and imaging), especially if the evaluation included only one imaging modality that was repeated early after radiation.^{16,69,79,80,85,145-149} Localized amyloid deposits within the plasmacytoma may limit a response in size after radiotherapy. Close observation with repeated imaging is advisable before characterizing the disease as radiotherapy resistant. In cases of true resistant disease or if an effective radiation dose cannot be delivered, systemic therapy should be considered after restaging for MM and ruling out other diagnoses. Some data suggest a role of percutaneous cryoablation in selected patients with recurrent plasmacytomas after radiotherapy.¹⁵⁰

If progression to overt MM occurs, standard MM systemic treatment principles apply. The prognostic impact of prior SBP or SEMP to the outcome of MM therapy (compared with patients with MM without a history of SP) is unknown, but many patients who progress after SPs tend to have relatively low-stage disease; close monitoring and early identification of the disease may also contribute to better prognosis. Patients progressing to overt myeloma should not be excluded from MM frontline trials.

APPENDIX: List of International Myeloma Working Group Members

1. Hikmat Abdel-Razeq, King Hussein Cancer Center, Amman, Jordan

2. Nadine Abdullah, Mayo Clinic, Rochester, MN

3. Masahiro Abe, Tokushima University, Tokushima, Japan

4. Niels Abildgaard, Odense University Hospital, Odense C, Denmark

5. Rafat Abonour, University of Miami, Miami, FL

6. Ingerid Abrahamsen, Oslo University Hospital, Oslo, Norway

7. Aimaz Afrough, University of Texas Southwestern Medical Center, Dallas, TX

8. Sikander Ailawadhi, Mayo Clinic, Jacksonville, FL

9. Samer Al Hadidi, University of Arkansas for Medical Sciences, Little Rock, AR

10. Adrian Alegre, Universitary Hospital La Princesa, Madrid, Spain

11. Melissa Alsina, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

12. Kenneth Anderson, Dana-Farber Cancer Institute, Boston, MA

13. Larry D. Anderson Jr., UT Southwestern Medical Center, Dallas, TX

14. Frida Askeland, Oslo University Hospital, Oslo, Norway

15. Shelbi Atrash, Levine Cancer Center, Charlotte, NC

16. Hervé Avet-Loiseau, Institut Universitaire du cancer de Toulouse Oncopole, Toulouse, France

17. David Avignon, Dana Farber Cancer Institute, Boston, MA

18. Ashraf Badros, University of Maryland, Baltimore, MD

19. Nizar Jacques Bahlis, University of Calgary—Arnie Charbonneau Cancer Institute, Calgary, Canada

20. Susan Bal, University of Alabama at Birmingham, Birmingham, AL

21. Muahamed Baljevic, Vanderbilt University Medical Center, Nashville, TN

22. Rahul Banerjee, Fred Hutchinson Cancer Center, Seattle, WA

23. Linda Baughn, Mayo Clinic, Rochester, MN

24. Rachid Baz, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

25. Meral Beksaç, Ankara Liv Hospital, Istinye University, Ankara, Turkey

26. Dina Ben-Yehuda, Hadassah University Hospital, Jerusalem, Israel

27. William Bensinger, Swedish Cancer Institute, Seattle, WA

28. Jesús G. Berdeja, Sarah Cannon Research Institute, Nashville, TN

29. P. Leif Bergsagel, Mayo Clinic, Scottsdale, AZ

30. Manisha Bhutani, Atrium Health Levine Cancer Institute, Charlotte, NC

31. Giada Bianchi, Dana Farber Cancer Institute, Boston, MA

32. Noa Biran, Hackensack University Medical Center, Hackensack, NJ

33. Jenny Bird, University Hospitals Bristol and Weston NHS Trust, Bristol, United Kingdom

34. Joan Blade, Hospital Clínic Barcelona, Barcelona, Spain

35. Maria Jesus Blanchard, H.U Ramon y Cajal, Spain

36. Mario Boccadoro, Città della Salute e della Scienza di Torino and University of Turin, Turin, Italy

37. Thorstein Boxaspen, Oslo University Hospital, Oslo, Norway

38. Andrew Branagan, Massachusetts General Hospital, Boston, MA

39. Annamaria Brioli, Hannover Medical School, Greifswald, Germany

40. Annemiek Broyl, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

41. Christian Bryant, NSW Health Pathology, Australia

42. Francis Buadi, Mayo Clinic, Rochester, MN

43. Mark Bustoros, Weill Cornell Medicine, New York, NY

44. Jo Caers, Centre Hospitalier Universitaire de Liège, Liège, Belgium

45. Natalie Callander, University of Wisconsin Carbone Cancer Center, Madison, WI

46. Michele Cavo, Bologna University School of Medicine—S.Orsola Hospital, Bologna, Italy

47. Claudio Cerchione, Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori”—IRST IRCCS, Italy

48. Rajshekhar Chakraborty, Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY

49. Asher Chanan-Khan, Mayo Clinic, Jacksonville, FL

50. Ajai Chari, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA

51. Wen-Ming Chen, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China

52. Marta Chesi, Mayo Clinic, Scottsdale, AZ

53. J. Anthony Child, University of Leeds, Leeds, United Kingdom

54. Chor Sang (James) Chim, University of Hong Kong, Queen Mary Hospital, Hong Kong, China

55. Wee Joo Chng, National University Cancer Institute, Singapore

56. Diana Cirstea, Mass General Hospital, Boston, MA

57. Adam Cohen, University of Pennsylvania, Philadelphia, PA

58. Yael Cohen, Tel Aviv Sourasky Medical Center, Isreal

59. Craig Cole, Karmanos Cancer Institute, Detroit, MI

60. Raymond Comenzo, Tufts University School of Medicine, Boston, MA

61. Rebecca Connor, UpToDate, Waltham, MA

62. Gordon Cook, University of Leeds, England, United Kingdom

63. Joselle Cook, Mayo Clinic, Rochester, MN

64. Jill Corre, Centre Hospitalier Universitaire de Toulouse, Toulouse, France

65. Luciano Costa, University of Alabama at Birmingham, Birmingham, AL

66. Caitlin Costello, University of California San Diego Health, La Jolla, CA

67. Andrew Cowan, Fred Hutchinson Cancer Center, Seattle, WA

68. Peter Croucher, Garvan Institute of Medical Research, Australia

69. Edvan Crusoe, Federal University of Bahia University Hospital, Salvador, Brazil

70. Anita D'Souza, Medical College of Wisconsin, Wauwatosa, WI

71. Faith Davies, NYU Langone Health Perlmutter Cancer Center, New York, NY

72. Javier de la Rubia, Hospital Universitario La Fe, València, Spain

73. Carmino de Souza, Univeridade de Campinas, Caminas, Brazil

74. Michel Delforge, Leuven Cancer Institute at Leuven University College, Leuven, Belgium

75. Binod Dhakal, Medical College of Wisconsin, Milwaukee, WI

76. Madhav V. Dhodapkar, Winship Cancer Institute of Emory University, Atlanta, GA

77. Meletios A. Dimopoulos, National and Kapodistrian University of Athens, Athens, Greece

78. David Dingli, Mayo Clinic, Rochester, MN

79. Angela Dispenzieri, Mayo Clinic, Rochester, MN

80. Kimberly Doucette, Medstar Georgetown University Hospital, Washington, DC

81. Johannes Drach, Confraternität Privatklinik Josefstadt, Wien, Austria

82. Matthew Drake, Hospital for Special Surgery, New York, NY

83. Christoph Driessen, Knatosspital St.Gallen, Gallen, Switzerland

84. Juan Du, Changzheng Hospital; Naval Medical University, Shanghai, China

85. Dominik Dytfeld, Poznań University of Medical Sciences, Pozán, Poland

86. Hermann Einsele, University Hospital Würzburg, Würzburg, Germany

87. Cristina Encinas, Hospital General Universitario Gregorio Marañón, Spain

88. Monika Engelhardt, Freiburg University Medical Center, Göttingen, Germany

89. Elías Eythorsson, University of Iceland, Reykjavík, Iceland

90. Thierry Facon, University of Lille, Lille, France

91. Dorotea Fantl, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

92. Jean-Paul Fermand, Hôpital Saint Louis, Paris, France

93. Carlos Fernández de Larrea, Hospital Clínic de Barcelona, Barcelona, Spain

94. Rafael Fonseca, Mayo Clinic, Scottsdale, AZ

95. Ciara Freeman, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

96. Reed Friend, Atrium Levine Cancer Center, Charlotte, NC

97. Gösta Gahrton, Karolinska Institute for Medicine, Huddinge, Sweden

98. Zhubin Gahvari, Medical College of Wisconsin, Madison, WI

99. Ramón García-Sanz, University Hospital of Salamanca, Salamanca, Spain

100. Laurent Garderet, Hôpital Pitié Salpêtrière, Paris, France

101. Alfred Garfall, University of Pennsylvania, Philadelphia, PA

102. Christina Gasparetto, Duke University Medical Center, Durham, NC

103. Maria Gavriatopoulou, Alexandra Hospital and Athens Medical School, Athens, Greece

104. Francesca Gay, University of Torino, Turin, Italy

105. Morie Gertz, Mayo Clinic, Rochester, MN

106. Irene Ghobrial, Dana-Farber Cancer Institute, Boston, MA

107. John Gibson, The University of Sydney, Camperdown, New South Wales, Australia

108. Peter Gimsing, Aarhus University Hospital, Aarhus, Denmark

109. Sergio A. Giralt, Memorial Sloan-Kettering Cancer Center, New York, NY

110. Siobhan Glavey, RCSI University of Medicine and Health Sciences, Dublin 9, Ireland

111. Hartmut Goldschmidt, University Hospital Heidelberg, Heidelberg, Germany

112. Wilson I. Gonsalves, Mayo Clinic, Rochester, MN

113. Verónica González de la Calle, University of Salamanca, Salamanca, Spain

114. Alessandro Gozzetti, University of Siena, Siena, Italy

115. Damian Green, Fred Hutchinson Cancer Research Center, Seattle, WA

116. Jingli Gu, The First Affiliated Hospital of Sun Yat-Sen University, Guangdong, China

117. Nina Gulbrandsen, Oslo Univesity Hospital, Oslo, Norway

118. Roman Hájek, University Hospital Ostrava, Ostrava, Czech Republic

119. Yervand Hakobyan, Armenian Hematology Association, Yerevan, Armenia

120. Doris Hansen, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

121. Izhar Hardan, Meir Medical Center, Kfar Saba, Israel

122. Jean-Luc Harousseau, University of Nantes, Nantes, France

123. Simon Harrison, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia

124. Hamza Hashmi, Memorial Sloan-Kettering Cancer Center, New York, NY

125. Hamza Hassan, Roswell Park Comprehensive Cancer Center, Buffalo, NY

126. Hiroyuki Hata, Kumamoto University Hospital, Kumamoto, Japan

127. Yutaka Hattori, Keio University Faculty of Pharmacy, Tokyo, Japan

128. Patrick Hayden, St. James' Hospital, Dublin, Ireland

129. Leonard Heffner, Emory University, Atlanta, GA

130. Sylvie Hermouet, Centre Hospitalier Universitaire de Nantes, Nantes, France

131. Jens Hillengass, Roswell Park Comprehensive Cancer Center, Buffalo, NY

132. Joy Ho, Royal Prince Alfred Hospital, Sydney, Australia

133. Antje Hoering, Cancer Research and Biostatistics, Seattle, WA

134. James E. Hoffman, The University of Miami, Miami, FL

135. Sarah Holstein, University of Nebraska Medical Center, Omaha, NE

136. Dirk Hose, Vrije Universiteit Brussel, Brussels, Belgium

137. Jian Hou, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

138. Myo Htut, City of Hope National Medical Center, United States

139. Jeffrey (Shang-yi) Huang, National Taiwan University Hospital, Taipei, Taiwan

140. Malin Hultcrantz, Memorial Sloan Kettering Cancer Center, New York, NY

141. Vania Hungria, Clínica São Germano, São Paulo, Brazil

142. Shinsuke Iida, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

143. Sundar Jagannath, Icahn School of Medicine at Mount Sinai, New York, NY

144. Ishmael Jaiyesimi, William Beaumont Hospital, Royal Oak, MI

145. Andrzej J. Jakubowiak, University of Chicago, Chicago, IL

146. Murali Janakiram, City of Hope National Medical Center, Duarte, CA

147. Tomas Jelinek, University Hospital Ostrava, Ostrava, Czech Republic

148. Yogesh Jethava, Indiana Blood and Marrow Transplant Institute, Indianapolis, IN

149. Dragan Jevremovic, Mayo Clinic, Rochester, MN

150. Cristina João, Fundação Champalimaud and Champalimaud Center For The Unknown, Lisboa, Portugal

151. Nisha Joseph, Winship Cancer Institute of Emory University, Atlanta, GA

152. Douglas Joshua, The University of Sydney, New South Wales, Australia

153. Sung-Hoon Jung, Chonnam National University Hwasun Hospital, Jeollanam-do, South Korea

154. Artur Jurczyszyn, Jagiellonian University Department of Hematology, Kraków, Poland

155. Martin Kaiser, The Institute of Cancer Research, England, United Kingdom

156. Prashant Kapoor, Mayo Clinic, Rochester, MN

157. Efstathios Kastritis, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

158. Eirini Katodritou, Theagenio Cancer Hospital, Thessaloniki, Greece

159. Jonathan Kaufman, Emory University School of Medicine, Atlanta, GA

160. Gurbakhash Kaur, University of Texas- Southwestern Medical Center, Dallas, TX

161. Michio Kawano, Kyoto University of Education, Ube, Japan

162. Leylagül Kaynar, Erciyes University, Kayseri, Turkey

163. Jonathon Keats, Translational Genomics Research Institute (TGen), Scottsdale, AZ

164. Jack Khouri, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

165. Kihyun Kim, Samsung Medical Center and Sungkyunkwan University School of Medicine, Suwon, South Korea

166. Neha Korde, Memorial Sloan Kettering Cancer Center, New York, NY

167. Taxiarchis Kourelis, Mayo Clinic, Rochester, MN

168. Eva Kovacs, Cancer Immunology Research-Life, Birsfelden, Switzerland

169. Maria Krauth, Medical University Vienna, Austria

170. Amrita Krishnan, City of Hope Medical Center, Newport Beach, CA

171. Sigurdur Y. Kristinsson, University of Iceland, Reykjavík, Iceland

172. Nicolaus Kröger, University Hospital Hamburg, Hamburg, Germany

173. Shaji Kumar, Mayo Clinic, MN

174. Robert Kyle, Mayo Clinic, MN

175. Chara Kyriakou, University College London Hospitals NHS Trust, England, United Kingdom

176. Martha Lacy, Mayo Clinic, Rochester, MN

177. Juan José Lahuerta, Hospital Universitario 12 de Octubre, Madrid, Spain

178. Ola Landgren, Sylvester Comprehensive Cancer Center University of Miami, Miami, FL

179. Alessandra Larocca, Divisione Universitaria di Ematologia, University of Torino, Torino, Italy

180. Jacob Laubach, Dana-Farber Cancer Institute, Boston, MA

181. Fernando Leal da Costa, Instituto Portugues De Oncologia, Lisboa, Portugal

182. Hans C. Lee, MD Anderson Cancer Center, Houston, TX

183. Jae-Hoon Lee, Gachon University Gil Medical Center, Incheon, South Korea

184. Je Jung Lee, Chonnam National University Hwasun Hospital, Gwangju, South Korea

185. Ji Hyun Lee, Dong-A University College of Medicine, Busan, South Korea

186. Merav Leiba, Chaim Sheba Medical Center, Tel Hashomer, Israel

187. Xavier Leleu, Hôpital La Mileterie at Centre Hospitalier Univeraitaire, Poitiers, France

188. Suzanne Lentzsch, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY

189. Nelson Leung, Mayo Clinic, Rochester, MN

190. Lisa Leypoldt, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

191. Edward N. Libby, Seattle Cancer Care Alliance, Seattle, WA

192. Eben Lichtman, The University of North Carolina at Chapel Hill, Chapel Hill, NC

193. Yi Lin, Mayo Clinic, Rochester, MN

194. Brea Lipe, University of Rochester Medical Center, Rochester, NY

195. Thorir Einarsson Long, University of ICELAND, Reykjavík, Iceland

196. Sagar Lonial, Winship Cancer Institute of Emory University, Atlanta, GA

197. Thorvardur Jon Love, University of ICELAND, Reykjavík, Iceland

198. Jin Lu, Peking University People's Hospital; Beijing University, Beijing, China

199. Heinz Ludwig, Wilhelminen Cancer Research Institute; Clinic Ottakring, Vienna, Austria

200. Deepu Madduri, Stanford University, Stanford, CA

201. Anuj Mahindra, Scripps Green Hospital, La Jolla, CA

202. Elias Mai, Heidelberg University Hospital, Heidelberg, Germany

203. Sham Mailankody, Memorial Sloan Kettering, New York, NY

204. Angelo Maiolino, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

205. Ehsan Malek, Case Western Reserve University, Cleveland, OH

206. Salomon Manier, University of Lille, Lille, France

207. Tomer Mark, University of Colorado—Anschutz Medical Campus, Aurora, CO

208. Thomas Martin, UCSF Helen Diller Family Comprehensive Cancer Center, CA

209. Deborah Martínez-Baños, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico

210. Joaquin Martinez-Lopez, Hospital 12 de Octubre, Madrid, Spain

211. Borja Puertas Martínez, University Hospital of Salamanca, Spain

212. Deborah Martínez-Baños, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico

213. María-Victoria Mateos, University Hospital of Salamanca, Salamanca, Spain

214. William Matsui, The University of Texas at Austin: Dell Medical School, Austin, TX

215. Francesco Maura, Memorial Sloan Kettering Cancer Center, New York, NY

216. Amitabha Mazumder, The Oncology Institute of Hope and Innovation, Pasadena, CA

217. Philip McCarthy, Roswell Park Comprehensive Cancer Center, Buffalo, NY

218. Georgia McCaughan, St Vincent's Hospital, Sydney, Australia

219. Arleigh McCurdy, The Ottawa Hospital, Ontario, Canada

220. Jayesh Mehta, Northwestern Memorial Hospital, Chicago, IL

221. Ulf-Henrik Mellqvist, Sahlgrenska University Hospital, Gothenburg, Sweden

222. Giampaolo Merlini, University of Pavia, Pavia, Italy

223. Christina Messiou, Institute of Cancer Research Biomedical Research Centre, Surrey, United Kingdom

224. Hira Mian, McMaster University, Hamilton, Ontario, Canada

225. Shonali Midha, Dana-Farber Cancer Institute, Boston, MA

226. Gábor Mikala, Centre Hospital of South-Pest, Budapest, Hungary

227. Joseph Mikhael, Translational Genomics Research Institute, Phoenix, AZ

228. Roberto Mina, AOU Città Della Salute E Della Scienza, University Of Torino, Torino, Italy

229. Monique Minnema, University Medical Center Utrecht, Utrecht, The Netherlands

230. Meera Mohan, Medical College of Wisconsin, Milwaukee, WI

231. Mohamad Mohty, Saint-Antoine Hospital, Paris, France

232. Jorge Monge, University of Colorado Anschutz Medical Campus, Aurora, CO

233. Kari Moore, Stavanger University Hospital, Stavanger, Norway

234. Philippe Moreau, University Hospital of Nantes, Nantes, France

235. Gareth Morgan, NYU Langone Health Perlmutter Cancer Center, New York, NY

236. Nikhil Munshi, Dana Farber Cancer Institute, Boston, MA

237. David Murray, Mayo Clinic, Rochester, MN

238. Juliane Garcez Musacchio, Casa de Saúde São José, Rio de Janeiro, Brazil

239. Omar Nadeem, Dana-Farber Cancer Institute, Boston, MA

240. Chandramouli Nagarajan, Singapore General Hospital, Singapore, Singapore

241. Hareth Nahi, Karolinska Institutet and Linköping University hospital, Stockholm, Sweden

242. Cristina Nanni, PET Centre in Bologna, Bologna, Italy

243. Weerasak Nawarawong, Chiang Mai University, Thailand

244. Paola Neri, University of Calgary: Arnie Charbonneau Cancer Institute, Alberta, Canada

245. Ruben Niesvizky, Weill Cornell Medicine, New York, NY

246. Ajay Nooka, Winship Cancer Institute of Emory University, Atlanta, GA

247. Hanne Norseth, Oslo University Hospital, Oslo, Norway

248. Amara Nouel, Hospital Ruiz y Paez, Universidad de oriente, Otro, Venezuela

249. Yana Novis, Hospital Sirio Libanes, São Paulo, Brazil

250. Ioannis Ntanasis-Stathopoulos, National and Kapodistrian University of Athens, Athens, Greece

251. Jakob Nørgaard, Oslo University Hospital, Oslo, Norway

252. Elizabeth O'Donnell, Massachusetts General Hospital, Boston, MA

253. Michael O'Dwyer, National University of IRELAND-Galway, Galway, Ireland

254. Peter O'Gorman, Mater Misericordiae University Hospital, Dublin, Ireland

255. Enrique Ocio, Marqués de Valdecilla University Hospital, Santander, Spain

256. Stefania Oliva, Università degli Studi di Torino, Piemonte, Italy

257. Alberto Orfao, University of Salamanca, Salamanca, Spain

258. Robert Orlowski, MD Anderson Cancer Center, Houston, TX

259. Jón Þórir Óskarsson, University of Iceland, Reykjavik, Iceland

260. Bruno Paiva, Clínica Universidad de Navarra: CIMA, Pamplona, Spain

261. Darren Pan, University of California San Francisco, San Francisco, CA

262. Samir Parekh, Icahn School of Medicine at Mount Sinai, New York, NY

263. Sung Soo Park, Seoul St. Mary’s Hospital, The Catholic University of Korea, Souel, South Korea

264. Harsh Parmar, Hackensack University Medical Center, Hackensack, NJ

265. Ricardo Parrondo, Mayo Clinic, Jacksonville, FL

266. Barry Paul, Levine Cancer Institute, Charlotte, NC

267. Krina Patel, MD Anderson Cancer Center, Houston, TX

268. Charlote Pawlyn, The Institute of Cancer Research, London, England, United Kingdom

269. Aurore Perrot, CHU de Toulouse, Toulouse Cedex, France

270. Pooja Phull, Hackensack University Medical Center, Hackensack, NJ

271. Linda Pilarski, University of Alberta, Alberta, Canada

272. Romanos Pistofidis, City of Hope, Duarte, CA

273. Rashesh Popat, University College London Hospitals NHS Foundation Trust, London, England, United Kingdom

274. Raymond Powles, Cancer Centre London, London, England, United Kingdom

275. Guy Pratt, Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom

276. Noemí Puig, Hospital Universitario de Salamanca, Salamanca, Spain

277. Ben Puliafito, Massachusetts General Hospital, Boston, MA

278. Lugui Qiu, Institute of Hematology & Blood Diseases Hospital, Tianjin, China

279. Hang Quach, St.Vincent's Hospital, University of Melbourne, Melbourne, Australia

280. Marc Raab, Heidelberg University Hospital, Heidelberg, Germany

281. Noopur Raje, Massachusetts General Hospital, Boston, MA

282. S. Vincent Rajkumar, Mayo Clinic, Rochester, MN

283. Karthik Ramasamy, University of Oxford, Oxford, United Kingdom

284. Leo Rasche, University Hospital Würzburg, Würzburg, Germany

285. Donna Reece, Princess Margaret Cancer Centre, Toronto, Ontario, Canada

286. Anthony Reiman, Saint John Regional Hospital, Stain John, New Brunswick, Canada

287. Guillermina Remaggi, Fundaleu, Buenos Aires, Argentina

288. Shambavi Richard, Icahn School of Medicine at Mount Sinai, New York, NY

289. Paul G. Richardson, Dana-Farber Cancer Institute, Boston, MA

290. Joshua Richter, Icahn School of Medicine at Mount Sinai: Tisch Cancer Institute, New York, NY

291. Eloísa Riva Serra, Hospital de Clinicas, Montevideo, Uruguay

292. Cesar Rodríguez, Icahn School of Medicine at Mount Sinai: Tisch Cancer Institute, New York, NY

293. Angelina Rodríguez Morales, Banco Municipal de Sangre de la Region Capital Caracas, Caracas, Venezuela

294. Paula Rodriguez Otero, Clinica Universidad de Navarra, Pamplona, Spain

295. David Roodman, Indiana University, Indianapolis, IN

296. Sæmundur Rögnvaldsson, University of Iceland, Reykjavík, Iceland

297. Catherine Rosales, St. Luke's Medical Center, Metro Manila, Philippines

298. Laura Rosiñol, Hospital Clínic Barcelona, Barcelona, Spain

299. Ashley Rosko, The Ohio State University, Columbus, OH

300. Adriana Rossi, Icahn School of Medicine at Mount Sinai, New York, NY

301. Murielle Roussel, University of Toulouse, Toulouse, France

302. Samuel M. Rubenstein, University of North Carolina-Chapel Hill, Chapel Hill, NC

303. Stephen Russell, Mayo Clinic, Rochester, MN

304. Mehmet Samur, Dana-Farber Cancer Institute, Boston, MA

305. Jesús San-Miguel, Clínica Universidad de Navarra, CCUN, Pamplona, Spain

306. Larysa Sanchez, Icahn School of Medicine at Mount Sinai: Tisch Cancer Institute, New York, NY

307. Douglas W. Sborov, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT

308. Christoph Schaefers, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

309. Christof Scheid, University Hospital of Cologne, Germany

310. Fredrik Schjesvold, Oslo University Hospital, Oslo, Norway

311. Timothy Schmidt, University of Wisconsin School of Medicine and Public Health, Madison, WI

312. Rik Schots, Universitair Ziekenhuis Brussel, Brussel, Belgium

313. Natalia Schütz, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

314. Anja Seckinger, Vrije Universiteit Brussels, Brussel, Belgium

315. Sabina Sevcikova, Masaryk University, Brno, Czech Republic

316. Orhan Sezer, University Medical Center Hamburg—Eppendorf, Hamburg, Germany

317. Parth S. Shah, Dartmouth University Medical Center, Lebanon, NH

318. Mansi Shah, Rutgers Cancer Institute, New Brunswick, NJ

319. Kenneth Shain, H. Lee Moffitt Cancer Center, Tampa, FL

320. Kazuyuki Shimizu, Higashi Nagoya National Hospital, Nagoya, Japan

321. Karen Shires, University of Cape Town Medical School, Cape Town, South Africa

322. Chaim Shustik, McGill University Health Center, Montreal, Quebec, Canada

323. Surbhi Sidana, Stanford University, Stanford, CA

324. David Siegel, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ

325. Raija Silvennoinen, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland

326. Seema Singhal, Northwestern Medicine, Chicago, IL

327. Tobias Slordahl, Norwegian University of Science and Technology, Trondheim, Norway

328. Pieter Sonneveld, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands

329. Andrew Spencer, The Alfred Hospital; Monash University, Melbourne, Australia

330. Adam Sperling, Dana-Farber Cancer Institute, Boston, MA

331. Edward Stadtmauer, University of Pennsylvania, Philadelphia, PA

332. Keith Stewart, University Health Network: Princess Margaret Cancer Centre, Toronto, Ontario, Canada

333. Agoston Szabo, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

334. Raphael E. Szalat, Boston University Medical Center, Boston, MA

335. Paola Tacchetti, Bologna University School of Medicine, Bologna, Italy

336. Hiroyuki Takamatsu, Institute of Transdisciplinary Sciences for Innovation, Kanazawa University, Japan

337. Alexis Talbot, Saint Louis Hospital, Paris, France

338. Carlyn Tan, Memorial Sloan Kettering Cancer Center, New York, NY

339. Daryl Tan, Clinic for Lymphoma, Myeloma and Blood Disorders, Singapore

340. Evangelos Terpos, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

341. Carolina Terragna, University of Bologna, Bologna, Italy

342. Santiago Thibaud, The Tisch Cancer Institute: Icahn School of Medicine at Mount Sinai, New York, NY

343. Sigrun Thorsteinsdóttir, University of Iceland, Reykjavik, Iceland

344. Patrizia Tosi, Italian Cooperative Group, Istituto di Ematologia Seragnoli, Bologna, Italy

345. Guido Tricot, University of Iowa Hospital and Clinics, Iowa City, IA

346. Suzanne Trudel, University Health Network: Princess Margaret Cancer Centre, Ontario, Canada

347. Sascha A. Tuchman, University of North Carolina—Chapel Hill, Chapel Hill, NC

348. Ingemar Turesson, Lund University Cancer Centre, Lund, Sweden

349. Saad Z. Usmani, Memorial Sloan Kettering Cancer Center, New York, NY

350. Ben Van Camp, Vrije Universiteit Brussels, Brussels, Belgium

351. Niels van de Donk, Vrije Universiteit Amsterdam Department of Hematology, Amsterdam, The Netherlands

352. Brian Van Ness, University of Minnesota, Minneapolis, MN

353. Ivan Van Riet, Vrine Universiteit Brussel, Brussels, Belgium

354. Isabelle Vande Broek, Vrije Universiteit Brussel, Brussels, Belgium

355. Karin Vanderkerken, Vrije Universiteit Brussel, Brussels, Belgium

356. Annette Vangsted, Copenhagen University Hospital, Copenhagen, Denmark

357. Cindy Varga, Levine Cancer Institute, Charlotte, NC

358. Robert Vescio, Cedars-Sinai Medical Center, Los Angeles, CA

359. David Vesole, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ

360. Ravi Vij, Washington University of Medicine, St Louis, MO

361. Alissa Visram, McMaster University, Canada

362. Dan Vogl, University of Pennsylvania, Philadelphia, PA

363. Peter Voorhees, Levine Cancer Institute, Charlotte, NC

364. Anders Waage, Norwegian University of Science and Technology, Trondheim, Norway

365. Brian Walker, University of Miami, Miami, FL

366. Michael Wang, The University of Texas M.D. Anderson Cancer Center, Houston, TX

367. Rahma Warsame, Mayo Clinic, Rochester, MN

368. Donna Weber, MD Anderson Cancer Center, Houston, TX

369. Neils Weinhold, University of Heidelberg, Heidelberg, Germany

370. Katja C. Weisel, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

371. Jan Westin, University of Gothenburg, Göteborg, Sweden

372. Baldeep Mona Wirk, Penn State Cancer Institute, Hershey, PA

373. Ralph Wäsch, University of Freiburg, Germany

374. Jing Christine Ye, MD Anderson Cancer Center, Houston, TX

375. Andrew Yee, Massachusetts General Hospital, Boston, MA

376. Kwee Yong, University College Hospital, London, England, United Kingdom

377. Dok Hyum Yoon, Asan Medical Center; University of Ulsan College of Medicine, Soeul, South Korea

378. Elena Zamagni, Seragnoli Institute of Hematology Università di Bologna, Bologna, Italy

379. Saurabh Zanwar, Mayo Clinic, Rochester, MN

380. Jeffrey Zonder, Karmanos Cancer Institute, Detroit, MI

381. Sonja Zweegman, VU University Medical Center, Amsterdam, The Netherlands

AUTHOR CONTRIBUTIONS

Conception and design: Efstathios Kastritis, Meletios A. Dimopoulos, Elena Zamagni

Collection and assembly of data: All authors

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

International Myeloma Working Group Recommendations for the Diagnosis and Management of Solitary Plasmacytomas

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