# paper.pdf ## Metadata - PDFFormatVersion=1.7 - Language=English - IsLinearized=true - IsAcroFormPresent=false - IsXFAPresent=false - IsCollectionPresent=false - IsSignaturesPresent=false - CreationDate=D:20260610105034+05'30' - Subject=BLOOD ADVANCES, 10 (2026) 4286-4295. doi:10.1182/bloodadvances.2025019136 - Author=Kenneth J. C. Lim - Creator=Elsevier - Producer=PDFlib+PDI 10.0.2p2 (C++/Win64) - Custom.EPSprocessor=PStill version 1.84.42 - Custom.ElsevierWebPDFSpecifications=7.0.1 - Custom.robots=noindex - Custom.doi=10.1182/bloodadvances.2025019136 - ModDate=D:20260610105511+05'30' - Title=A multicenter study of progression risk and outcomes in solitary bone plasmacytoma with and without marrow involvement - dc:format=application/pdf - dc:identifier=doi:10.1182/bloodadvances.2025019136 - dc:title=A multicenter study of progression risk and outcomes in solitary bone plasmacytoma with and without marrow involvement - dc:creator=Kenneth J. C. Lim,Maximilian Steinhardt,Matthew J. Rees,Patricia Greipp,Katalin Kelemen,Angela Dispenzieri,Dragan Jevremovic,Linda Baughn,Francis K. Buadi,David Dingli,Suzanne R. Hayman,Prashant Kapoor,Eli Muchtar,Nelson Leung,Amie Fonder,Miriam Hobbs,Yi Lisa Hwa,Rahma Warsame,Taxiarchis V. Kourelis,Joselle Cook,Moritz Binder,Nadine Abdallah,Saurabh Zanwar,Yi Lin,Ronald S. Go,Mustaqeem A. Siddiqui,Ricardo D. Parrondo,Sikander Ailawadi,Vivek Roy,Rachel Cooke,Karen Dun,Adrian Zordan,Slavisa Ninkovic,Sharene H. Best,Gabriela A. Alatorre,J. E. Wiedmeier-Nutor,K. Martin Kortum,Hermann Einsele,Saurabh Chhabra,P. Leif Bergsagel,Robert A. Kyle,Morie A. Gertz,Shaji K. Kumar,S. Vincent Rajkumar,Rafael Fonseca,Wilson I. Gonsalves,Udit Yadav - dc:description=BLOOD ADVANCES, 10 (2026) 4286-4295. doi:10.1182/bloodadvances.2025019136 - dc:publisher=American Society of Hematology - prism:aggregationtype=journal - prism:publicationname=BLOOD ADVANCES - prism:copyright=© 2026 American Society of Hematology. Published by Elsevier Inc. 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All other rights reserved. - prism:issn=2473-9529 - prism:volume=10 - prism:number=12 - prism:coverdisplaydate=23 June 2026 - prism:coverdate=2026-06-23 - prism:pagerange=4286-4295 - prism:startingpage=4286 - prism:endingpage=4295 - prism:doi=10.1182/bloodadvances.2025019136 - prism:url=https://doi.org/10.1182/bloodadvances.2025019136 - jav:journal_article_version=VoR - pdfx:elsevierwebpdfspecifications=7.0.1 - pdfx:doi=10.1182/bloodadvances.2025019136 - pdfx:robots=noindex - pdfx:epsprocessor=PStill version 1.84.42 - xap:creatortool=Elsevier - xap:createdate=2026-06-10T10:50:34+05:30 - xap:modifydate=2026-06-10T10:55:11+05:30 - xap:metadatadate=2026-06-10T10:55:11+05:30 - xaprights:marked=True - tdm:reservation=1 - tdm:policy=https://www.elsevier.com/tdm/tdmrep-policy.json - pdf:producer=PDFlib+PDI 10.0.2p2 (C++/Win64) - xapmm:documentid=uuid:a7c75cde-3910-4e8a-aff1-22fe52ce86ae - xapmm:instanceid=uuid:0dd29604-c8ba-4517-9f6e-b10d3e2e3a7f - ali:license_ref=https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode ## Contents ### Page 1 # A multicenter study of progression risk and outcomes in solitary bone plasmacytoma with and without marrow involvement Kenneth J. C. Lim, Maximilian Steinhardt,, Matthew J. Rees, Patricia Greipp, Katalin Kelemen, Angela Dispenzieri,Dragan Jevremovic, Linda Baughn, Francis K. Buadi, David Dingli, Suzanne R. Hayman, Prashant Kapoor, Eli Muchtar,Nelson Leung, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Rahma Warsame, Taxiarchis V. Kourelis, Joselle Cook, Moritz Binder,Nadine Abdallah, Saurabh Zanwar, Yi Lin, Ronald S. Go, Mustaqeem A. Siddiqui, Ricardo D. Parrondo, Sikander Ailawadi,Vivek Roy, Rachel Cooke, Karen Dun, Adrian Zordan, Slavisa Ninkovic, Sharene H. Best, Gabriela A. Alatorre,J. E. Wiedmeier-Nutor, K. Martin Kortum, Hermann Einsele, Saurabh Chhabra, P. Leif Bergsagel, Robert A. Kyle, Morie A. Gertz,Shaji K. Kumar, S. Vincent Rajkumar, Rafael Fonseca, Wilson I. Gonsalves, and Udit Yadav 1Division of Hematology/Medical Oncology, Mayo Clinic, Rochester, MN; 2Division of Hematology, St Vincent’s Hospital Melbourne, Melbourne, Australia; 3Division of Hematology, Australian Center for Blood Diseases, Monash University, Melbourne, Australia; 4Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany; 5Division of Hematology/Medical Oncology, Mayo Clinic, Phoenix, AZ; 6Division of Hematology/Medical Oncology, Mayo Clinic, Jacksonville, FL; and 7Division of Hematology, Northern Hospital, Melbourne, Australia ### Key Points - - - - # • Patients with SBPmm are at high risk for early progression to MM. - - - - # • Multifocal lytic bone lesions are the most common myeloma- defining event at progression to MM. Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P < .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P < .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm. ## Introduction Solitary plasmacytoma is a rare plasma cell disorder characterized by localized proliferation of mono-clonal plasma cells in a single bone or in soft tissue/extramedullary site (solitary extramedullary Submitted 18 November 2025; accepted 6 March 2026; prepublished online onBlood Advances First Edition 22 April 2026. Data sets generated during and/or analyzed during the current study are available from the corresponding author, Udit Yadav ( ), on reasonable request. The full-text version of this article contains a data supplement. © 2026 American Society of Hematology. Published by Elsevier Inc. Licensed under , permitting only noncommercial, nonderivative use with attribu-tion. All other rights reserved. ![Cover Image]() REGULAR ARTICLE ### Page 2 plasmacytoma [SEP]), without other evidence of active myeloma. The International Myeloma Working Group defines solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) as distinct entities based on the absence or presence of <10% clonal bone marrow plasma cells, respectively. This distinction is supported by evidence that marrow involvement by clonal plasma cells, demonstrated by immunohistochemistry (IHC) or multiparameter flow cytometry (MFC), confers a greater risk of progression to multiple myeloma (MM). Studies have also shown that patients with SBP have a greater risk of progression compared to SEP., Despite these differences, the current standard of care for SBP—regardless of progression risk—remains definitive radiation therapy (RT), with or without surgical excision, which achieves high rates of local tumor control., Given the low incidence of these diseases, current understanding of progression risk and outcomes is largely informed by retrospective analyses of heterogeneous cohorts, often comprising of a combination of osseous and extra-medullary plasmacytomas and inconsistent separation of patients with and without marrow involvement. In addition, the clinical fea-tures of progression to MM or a second solitary plasmacytoma and outcomes to subsequent therapy are rarely described. Therefore, this multicenter study aimed to describe outcomes of patients with SBP and SBPmm after RT treated across 4 academic centers in the United States, Germany, and Australia. ## Methods The study was conducted with institutional review board approval and in accordance with the Declaration of Helsinki. We identified 296 patients diagnosed with solitary plasmacytoma between 1 January 2010 and 31 December 2024, using an integrated database across partnering institutions. We excluded patients with SEP, multifocal bone lesions, bone marrow plasmacytosis ≥10% on aspirate or IHC, and monoclonal gammopathy of clinical significance, including light chain amyloidosis or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome. We excluded patients with bone marrow biopsies that were not assessed for clonal plasma cells or for whom advanced cross-sectional imaging (positron emission tomography [PET]/computed tomography [CT], whole-body magnetic resonance imaging, or CT) was unavailable or not performed. Clonality testing on bone marrow biopsy was per-formed using MFC (sensitivity, 10−4), IHC, or κ/λ in situ hybridization. Patients who received upfront systemic therapy or had <6 months of follow-up were excluded. After exclusions (n = 53), 243 patients were included in the analysis: 141 with SBP and 102 with SBPmm (). Demographic characteristics, pretreatment laboratory and imaging parameters, treatment variables, response to radiotherapy, disease progression, and survival status were collected through retrospec-tive review of patients’ electronic medical records. Results of fluo-rescence in situ hybridization (FISH) testing for cytogenetic abnormalities performed on clonal plasma cells from formalin-fixed, paraffin-embedded (FFPE) plasmacytoma tissue or bone marrow were consolidated. Clonal plasma cells were assessed for immu-noglobulin heavy chain translocations (t(11;14), t(4;14), and t(14;16)), deletion of 17p (del(17p)), gain or amplification of 1q (1q+), and deletion of 1p (del(1p)). Time to progression (TTP) was defined as the time from SBP/ SBPmm diagnosis to the first progression event after completion of RT with or without surgical resection. Progression events included development of MM (per International Myeloma Working Group consensus criteria), development of a solitary plasmacy-toma at another site (out-of-field progression), or local (in-field) progression on serial imaging. SBP and SBPmm cohorts were analyzed separately. Progression-free survival 1 (PFS-1) was defined as time from diagnosis to first progression event or death. PFS-2 was defined as time from initiation of second-line therapy after the first progression event to the second progression event or death. ### Page 3 ### Statistical analysis Statistical analysis was performed using the SAS biostatistical software JMP, version 18.0 (SAS Institute Inc, Cary, NC). Cate-gorical variables were summarized as proportions and continuous variables as median (interquartile range). Differences in categorical variables were compared using Fisher exact test or χ2 test. Continuous variables were compared using the Kruskal-Wallis test. TTP, PFS, and overall survival (OS) were assessed using the Kaplan-Meier method. The impact of baseline patient and disease characteristics on the TTP curves were compared using the log-rank test. Cox proportional hazard regression was per-formed to examine the effect of variables on TTP and expressed as hazard ratios (HR) with adjusted HRs. A 2-sided P value of < .05 was considered statistically significant. A multivariable model was constructed including only variables that were statistically signifi-cant in univariate analyses. ## Results ### Patient characteristics Baseline characteristics of patients with SBP and SBPmm are summarized in. All patients underwent advanced cross- sectional skeletal imaging, with most (>70%) undergoing PET/ CT. Most SBP and SBPmm lesions involved the axial skeleton (>65%). MFC (sensitivity, 10−4) was used in most patients (>70%) to evaluate for clonal plasma cells in bone marrow biopsies. No differences in TTP were observed for patients diag-nosed between 2010 and 2017 vs 2018 and 2024 in either cohort. Patients with SBPmm had a higher median age compared to those with SBP (median, 62 vs 58 years). Patients with SBPmm also had higher rates of detectable serum M-spike (78% vs 63%) and an abnormal serum free light chain (sFLC) ratio (71% vs 54%) at diagnosis. Among patients with a detectable M-spike and/or abnormal sFLC ratio, median M-spike and involved/uninvolved sFLC ratio were higher in SBPmm. Conversely, patients with SBP had a higher median maximum standardized uptake value on PET/CT than those with SBPmm. Cytogenetic results were avail-able for 37 (26%) patients with SBP and 81 (79%) with SBPmm. All 37 SBP patients had FISH testing performed on the diagnostic FFPE plasmacytoma tissue; among patients with SBPmm, 61 (75%) had FISH performed on clonal bone marrow plasma cells from the staging bone marrow aspirate at diagnosis, and 20 (25%) on the diagnostic FFPE plasmacytoma tissue. ### Survival outcomes: SBP vs SBPmm Median duration of follow-up for all patients was 62 months (95% confidence interval [CI], 52-71) from diagnosis. Estimated median follow-up for the SBP and SBPmm groups were 60 (95% CI, 46- 71) and 64 (95% CI, 52-80) months, respectively. At data cutoff on 30 June 2025, 7 (5%) patients with SBP and 16 (16%) with SBPmm had died; 9 patients (4 SBP and 5 SBPmm) had died from non-MM–related causes and 16 from MM-related causes (3 SBP and 11 SBPmm). A total of 76 patients with SBP and 77 patients with SBPmm had disease progression. The median TTP for patients with SBPmm and SBP was 15.2 months (95% CI, 13.7-20.8) and 43.0 months (95% CI, 34.5-55.2), respectively (P < .0001) (A). The estimated 2-year and 5-year rate of progression was 30% and 61% , respectively, for patients with SBP. The estimated 2-year and 5-year rate of progression was 67% and 77%, respectively, for patients with SBPmm. Patients with SBPmm had a shorter PFS-1 compared to patients with SBP (median, 15 vs 43 months, respectively; P < .0001;B). Patients with SBP had a superior OS compared to those with SBPmm (5-year OS, 98% vs 85%; P = .001;B). ### Modes of progression and patient outcomes of SBP vs SBPmm Modes of progression differed between SBP and SBPmm (P = .0104) (). Most progressions to MM met the SLiM- CRAB criteria (SBP, 58/76 [76%]; SBPmm, 71/77 [92%];P = .0078). Among the 9 patients who progressed per SLiM criteria, 6 progressed with an sFLC ratio ≥100 and 3 progressed with additional focal lesions on magnetic resonance imaging. Among patients who progressed to MM, median TTP for patients with SBPmm and SBP was 15.1 and 48.3 months, respectively (P < .0001). Rates of in-field progression were low for both SBP (n = 2 [2.6%]) and SBPmm (n = 3 [3.9%]). Among 5 patients who had “in-field” progression, all had progressed within 24 months, with median TTP of 8.3 months (range, 5.0-22.7]). Out-of-field progres-sion with an isolated plasmacytoma was more common in SBP cohort compared to the SBPmm cohort (16/76 [21%] vs 3/77 [4%];P = .0013), with a median TTP of 35 months (95% CI, 12-40). displays clinical and laboratory characteristics at MM progression for the SBP and SBPmm cohorts. Among patients who progressed to MM, most presented with multifocal lytic bone lesions (SBP 51/57 [89%]; SBPmm, 59/70 [83%]). Rates of anemia, hypercalcemia, and renal impairment were low (<10%) in both groups. Importantly, 54% of patients who presented with CRAB features had symptomatic disease, most commonly symp-tomatic lytic lesions; the remaining CRAB progressions were detected on laboratory monitoring and/or imaging surveillance. At progression, patients with preceding SBP had lower median bone marrow plasma cell burden (3% vs 10%) and a lower involved/ uninvolved sFLC ratio (5.26 vs 13.68) compared to those with preceding SBPmm. Traditional high-risk features, such as Inter-national Staging System stage 3 disease (0% vs 1%) and elevated lactate dehydrogenase (9% vs 5%) were not frequent at MM progression and did not differ significantly between groups. Four cases of extramedullary disease were observed, all in patients with preceding SBP. ### Predictors of outcomes in patients with SBP and SBPmm Univariate and multivariate analysis performed on selected vari-ables across the combined SBP and SBPmm cohort, are shown in. Presence of clonal plasma cells in the bone marrow (SBPmm; HR, 2.1; 95% CI, 1.5-2.9), abnormal sFLC ratio (HR, 1.9; 95% CI, 1.3-2.8), serum M-protein level (unit HR, 3.3; 95% CI, 1.2-8.1), plasmacytoma size ≥5 cm (HR, 1.55; 95% CI, 1.05-2.3), and del(17p) (HR, 4.1; 95% CI, 2.4-7.1) were associ-ated with increased risk of progression. We next included SBPmm status, abnormal sFLC ratio, serum M-protein level, and plasma-cytoma size in a multivariable model. Del(17p) status was not included because of substantial missing data in the SBP group. In the multivariate analysis, SBPmm status and abnormal sFLC ratio were found to be independent risk factors for progression. ### Page 4 ### Page 5 We next evaluated risk factors for progression in SBP and SBPmm separately. In patients with SBPmm (), only cytogenetic variables were significantly associated with TTP. The prevalence of immunoglobulin heavy chain translocations, del(17p), and gain or amplificationof 1q was 17%, 17% and 18%, respectively. The presence of del(17p) or gain/amplification of 1q21 was associated with shorter TTP Patients with del(17p) had a median TTP of 5.9 months (95% CI, 3.8-7.7) and patients with 1q21+ without del(17p) had a median TTP of 11.9 months (95% CI, 4.6-24.0), with 2-year progression rates of 100% and 82%, respectively. In contrast, patients without del(17p) or 1q+ had a median TTP of 20.8 months (range, 14.6-42.4) and a 2-year progression rate of 57%. Del(17p) was also associated with shorter OS (5-year OS, 55% vs 86%; P = .0037). Presence of 1q21+ in the absence of del(17p) was not associated with OS. In patients with SBP (), abnormal sFLC ratio, M-protein level, and plasmacytoma size ≥5 cm were associated ### Page 6 with increased risk of progression. However in the multivariate analysis, none of these risk factors remained statistically signifi-cant. Patients with an abnormal sFLC ratio had a median TTP of 40.9 months (95% CI, 26.2-54.3) vs 114.6 months (95% CI, 43.3 to not reached [NR] with a normal sFLC ratio. Although cytoge-netic results were available for only 26% of patients with SBP, the estimated 2-year progression rate among the 6 patients with del(17p) was 73% vs 34% among patients without del(17p). We evaluated factors associated with progression among patients with SBP who had not progressed by 12 months after RT using a 12-month landmark analysis (supplemental Table 2). Patients with a persistent abnormal sFLC ratio at 12 months had a higher risk of progression compared to those without, with median TTP of 20.1 vs 100.6 months, respectively (P < .0001). In the multivariate analysis that included plasmacytoma size >5 cm, persistent abnormal sFLC ratio at 12 months remained a poor prognostic factor (adjusted HR, 4.01; 95% CI, 1.65-9.73; P = .002). ### Outcomes of patients with second isolated plasmacytoma at progression Nineteen patients developed a second isolated plasmacytoma (16 with preceding SBP and 3 with preceding SBPmm). Seven patients received systemic therapy and 12 received a second course of RT. At a median follow-up of 66 months (range, 43-94) from start of second-line therapy, all 19 patients were alive, but 10 had pro-gressed to MM. Among patients who received systemic therapy, 5 of 7 received a triplet regimen and 1 of 7 received a quadruplet regimen; median PFS was 73 months (95% CI, 11 to NR). The 12 patients treated with a second course of RT had a median PFS-2 of 16 months (95% CI, 4 to NR). Patients with a shorter initial response duration (TTP < 36 months; n = 6) had a significantly shorter PFS-2 than those with a prior TTP ≥36 months (n = 6) (estimated 24-month progression rate, 83% vs 0%). Of the 6 patients with prior TTP ≥36 months, all had preceding SBP, and 5 remained progression-free at 12, 31, 39, 43, and 70 months of follow-up, respectively. ### MM treatment outcomes in patients with preceding SBP or SBPmm Choice of induction regimen and rates of autologous stem cell transplantation (ASCT) did not differ between MM cases with pre-ceding SBP vs SBPmm. Most patients received non-CD38 antibody–based triplet induction regimens (51%), followed by quadruplet regimens (31%); 67% underwent frontline ASCT. Among 111 evaluable patients, overall response rate to first-line MM therapy was 96%, with 87% achieving very good partial response or better. At a median follow-up of 48 months (range, 32-61), 36 patients had progressed or died; estimated 48-month PFS-2 was 64% (95% CI, 53-74). There were no differences in PFS-2 between patients with preceding SBP vs SBPmm (48-month PFS-2, 68% vs 62%; P = .99). Patients who received upfront ASCT had an esti-mated 48-month PFS-2 of 72% (95% CI, 58-82) vs 42% (95% CI, 36-73) for those who did not. FISH testing was not performed universally at MM progression; among 32 patients with successful FISH testing at MM diagnosis, 6 (19%) had newly detected del(17p) abnormality. Median PFS-2 was 39 months (range, 16 to NR) among patients with del(17p) either at SBP/SBPmm diagnosis or at progression to MM vs 73 months (range, 29 to NR) among patients without del(17p) at progression. ## Discussion Given the rarity of SBP and SBPmm, earlier studies assessing outcomes and risk factors for progression included heterogenous cohorts of SEP and SBP, often combining patients with and without marrow involvement and including some who received upfront systemic therapy., Here, we present the largest multi-center study to date, including a uniformly treated cohort managed with RT alone in the era of novel agents. By combining patients treated across different centers, we assembled a large enough population to analyze SBP and SBPmm as 2 independent cohorts. Furthermore, diagnoses were confirmed using modern cross-sectional imaging techniques with clear characterization of minimal marrow involvement at baseline. In this study, we confirm that patients with SBPmm have a significantly greater risk for early progression to MM: 67% pro-gressed within 2 years of initial diagnosis compared to 30% of patients with SBP. Notably, del(17p) and 1q+ in SBPmm were associated with 2-year progression rates of 100% and 82%, respectively. Even among patients without these abnormalities, 57% progressed within 2 years of diagnosis. Therefore, these ### Page 7 ### Page 8 findings suggest that SBPmm represents a distinct high-risk clin-ical entity compared with SBP. In a recent study analyzing genomic data from 374 patients with monoclonal gammopathy of undeter-mined significance (MGUS) and smoldering MM (SMM), the concept of genomic MM vs genomic MGUS was introduced, where a subset of patients harboring a genomic MM-like clone had a significantly higher risk of progression to MM. Similarly, in many patients with SBPmm, the plasma cell clone may be destined to progress to MM, with the plasmacytoma representing an initial event that precedes eventual progression to MM. Acquisition of second-ary genomic abnormalities such as del(17p) and 1q+ may reflect disease evolution and supports this concept. This interpretation is also supported by genomic evaluation of SBP tumors by a French group, which found that TP53 or RAS mutations were associated with earlier progression. Further studies are needed to investigate differences in the tumor microenvironment and biological pathways of clonal plasma cells originating from the bone marrow compared to those in plasmacytomas. Distinguishing these processes from other plasma cell dyscrasias such as MGUS and SMM may provide valuable insights into mechanisms underlying the development, evolution, and progression of SBP and SBPmm. It has been previously demonstrated that in SBP, larger lesion size and an abnormal sFLC ratio may be predictors for progression to MM.,,,,, In our cohort, neither factor was associated with progression. In contrast, aside from high-risk cytogenetics, no other biochemical or radiological risk factors were associated with increased risk of progression in patients with SBPmm. In our exploratory analysis of the impact of cytogenetic abnormalities on progression in patients with SBP, 73% of patients with del(17p) had progressed within 2 years, highlighting the role of these secondary cytogenetic abnormalities in clonal evolution and clin-ical progression, as seen in MM. However, FISH results were available for only 26% of the SBP cohort, and larger cohorts are needed for more reliable conclusions. To our knowledge, this is also the largest study to describe and to differentiate in detail, the clinical characteristics at progression for SBP and SBPmm. Most progressions in both entities were to MM (>70%). Multifocal bone disease was the most common MDE (>80%), whereas anemia, renal failure, and hypercalcemia were uncommon (≤10%). In contrast, in the AQUILA study group, most progressions from high-risk sMM occurred by SLiM criteria, most commonly an sFLC ratio ≥100. We also noted that rates of traditional high-risk features such as advanced International Staging System stage, high bone marrow burden, or elevated lactate dehydrogenase) were low, consistent with the favorable response rates and PFS observed with frontline MM treatment compared with historical MM cohorts. This pattern of progression resembles macrofocal MM, characterized by limited bone marrow infiltration, advanced bone disease, and frequent plasmacytomas, and suggests that a substantial proportion of SBP and SBPmm may be precursors to this MM subgroup., A significant proportion of patients with SBP (21%) developed a second solitary plasmacytoma. Although the number of patients was limited, we observed that patients with longer TTP (>36 months) after RT to the first plasmacytoma, had durable responses to the second plasmacytoma, with 5 of 6 patients not progressing after the second RT. This could be considered as a potential line of action for these patients before proceeding with systemic therapy. Given the high risk of progression and long-term morbidity asso-ciated with multifocal lytic lesions and spinal fractures, patients with SBPmm in particular may benefit from strategies that incor-porate systemic therapy as part of frontline management. For example, patients earlier classified as SMM were reclassified as MM requiring therapy, if they had any SLiM feature, based on studies showing a 70% to 80% 2-year risk of progression to active myeloma., In our cohort, SBPmm—particularly among patients with high-risk cytogenetic abnormalities appeared to approach or exceed this level of risk. In addition, using a clonal bone marrow plasma cell cutoff of ≥10% may not be indicative of the “myeloma-genecity” of the clone, as upon progression, the median clonal plasma cell burden was 10% in patients with SBPmm. In addition, when patients with SBPmm were treated for MM, they appeared to have high rates of response and similar outcomes compared to historical data. The rarity of SBP and SBPmm makes prospective studies chal-lenging; 2 prior randomized trials investigating upfront systemic therapy closed prematurely because of poor accrual., Future international collaborative efforts are needed to study the impact of systemic therapy in these patients. This study has limitations inherent to a retrospective design, including missing data that may reduce statistical power, particu-larly for risk factor analysis. There were also imaging modality and methodical differences in determining clonal bone marrow involvement in our cohort. However, sensitivity analysis showed no significant difference in TTP between the different modalities. Through limiting our cases to patients diagnosed after 2010, we also reduced the risk of survivorship bias, allowing for more accurate estimation of TTP and OS. In conclusion, SBP and SBPmm are distinct, rare plasma cell disorders with clear differences in progression rates, patterns, and risk factors. Patients with del17(p) mutation, detected by FISH either in the clonal plasma cells of the bone marrow or plasma-cytoma tend to have the worst outcomes, highlighting the impor-tance of cytogenetic testing for this mutation at diagnosis. Most patients with SBPmm progressed to MM within 2 years of diag-nosis, most commonly with multifocal lytic bone disease rather than other SLiM-CRAB criteria. A different management paradigm is needed to improve outcomes in this high-risk population. ## Acknowledgments The authors thank individual technologists Carolyn Brandt and Ryan Knudson for performing the cytogenetic analyses. Some of the data in this publication were produced in the Victorian Cancer Cytogenetic Service, Melbourne Australia and the authors thank the technologists who performed the analyses. This work was supported in part by the Clinical and Translational Science Award grant UL1 TR000135 from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health (NIH), and by the Marion Schwartz Foundation for Multiple Myeloma. The research reported in this publication was also supported by Mayo Clinic Hematological Malignancies Program, the Mayo Clinic Cancer Comprehensive Cancer Center (P30CA118100), and the NCI Clinical Proteomic Tumor Analysis Consortium program (U01CA271410). This work was supported in part by the National Cancer Institute at the NIH under award num-ber R01 CA254961 (W.I.G.). This research is partly supported by ### Page 9 generous funding from philanthropic donations to the Mayo Clinic. K.J.L. received support from the Haematology Society of Australia and New Zealand to perform this research. Some of the data in this publication were produced in the Mayo Clinic Cytogenetics Core Laboratory, which is supported in part by the Mayo Clinic Comprehensive Cancer Center Grant, funded by the National Can-cer Institute (P30CA15083). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. ## Authorship Contribution: K.J.L., W.I.G., and U.Y. conceived and designed the study, collected and curated data, and drafted the manuscript; K.J.L. performed the statistical analyses; M.S. and M.J.R. collected and curated data and critically revised the manuscript; K.K., A.D., D.J., F.K.B., D.D., S.R.H, P.K., E.M., N.L., A.F., M.H., Y.L.H., R.W., T.V.K., J.C., M.B., N.A., S.Z., Y.L., R.S.G., M.A.S., R.D.P., S.A., V.R., R.C., K.D., A.Z., S.N., L.B., S.H.B., G.A.A., S.C., E.W.N., K.M.K., H.E., H.E., P.L.B., R.A.K., M.A.G., S.K.K., S.V.R., and R.F. curated data and critically revised the manuscript; and all authors approved the final version of the manuscript for submission. Conflict-of-interest disclosure: R.F. reports consulting for Abb-Vie, Adaptive Biotechnologies, Amgen, AstraZeneca, Bayer, The Binding Site, Bristol Myers Squibb (Celgene), Millenium Takeda, Janssen, Juno, Kite, Merck, Pfizer, Pharmacyclics, Regeneron, and Sanofi; is a member of scientific advisory boards for Adaptive Biotechnologies, Caris Life Sciences, and ONCOtracker; is a member of board of directors for Antengene (for profit) and AZBio (not for profit); and has a patent for fluorescence in situ hybridiza-tion in multiple myeloma, for which the author receives ~$2000 per year. The remaining authors declare no competing financial interests. ORCID profiles: K.J.C.L.,; M.J.R.,; P.G.,; A.D.,; F.K.B.,; E.M.,; N.L.,; A.F.,; R.W.,; T.V.K.,; J.C.,; M.B.,; N.A.,; S.Z.,; M.A.S.,; R.D.P.,; V.R.,; R.C.,; K.M.K.,; S.C.,; P.L.B.,; M.A.G.,; S.K.K.,; R.F.,; U.Y.,. Correspondence: Udit Yadav, Division of Hematology & Oncology, Mayo Clinic, 5881 E. 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