Extramedullary Relapse of Multiple Myeloma Manifesting as Cutaneous Plasmacytosis and Myelomatous Pleural Effusion: A Rare Case Report

INTRODUCTION

Plasma cell neoplasms are characterised by the clonal proliferation of plasma cells. It includes monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, and solitary osseous or non-osseous plasmacytoma. Multiple myeloma is characterised by the proliferation of plasma cells in the bone marrow and can result in extensive skeletal destruction, whereas plasmacytoma is characterised by the proliferation of plasma cells restricted to one area of the body.

Plasmacytoma is a rare type of neoplasm of plasma cells. It can manifest as a primary plasmacytoma or secondary associated with multiple myeloma. Primary plasmacytoma is of two types: medullary plasmacytoma (involving the bone marrow) and extramedullary plasmacytoma (EMD) (involving the soft tissues).

The incidence of extramedullary plasmacytoma is 3% of all plasma cell neoplasms.^[1–3] About 5% of cases of extramedullary plasmacytomas have coexistent multiple myeloma.^[1] SBP is more prevalent in older populations (50 to 80 years old) compared to young patients. Males are affected more than females. It is also found to affect African American populations more than other races.^[2]

MM (myeloma) relapse rates are influenced by initial therapy, ranging from 30–50% one year following autologous stem cell transplantation (ASCT) (35–38% early relapse within two years) to 80% by five years. Skeletal lesions (70–90%, such as ribs and vertebrae) and bone marrow are common sites of relapse.^[3,4]

Ten to twenty per cent of cases involve uncommon relapse sites, such as the liver (3–5%), breast (1-2%), and central nervous system (<1%). Skin involvement, which appears as cutaneous plasmacytomas, is uncommon at relapse (common in newly diagnosed EMD at 24%, but <2-5% overall in relapsed MM).^[5]

Here we report a rare case of extramedullary relapse of multiple myeloma with cutaneous plasmacytosis and myeloma tonsillar pleural effusion.

CASE REPORT

A 42-year-old male, a cab driver, presented with complaints of low back pain for 3 months. Pain was initially non-severe and relieved by rest, and sometimes needed painkillers. Pain was gradually progressive and progressed to a severity that he was barely able to walk. There were no sensory symptoms and no bladder or bowel involvement. Magnetic resonance imaging (MRI) spine showed partial collapse of D9, D11 & L3 and infiltration of a few ribs bilaterally, and the sacrum was suggestive of neoplastic aetiology. MRI also showed altered signal intensity at C3 vertebral body and a lobulated soft tissue lesion in the anterior mediastinum, which was heterogenous hyperintense on T2 and isointense on T1. Serum prostate specific-antigen (PSA) was normal. General blood picture (GBP) shows microcytic anaemia, roulaux formation, and biochemical examination revealed high LDH and uric acid, with raised serum Ca. Serum creatinine was normal.

Fluorodeoxyglucose positron emission tomography/ computed tomography (FDG PET/CT) was done, which revealed multiple FDG-avid lytic bone lesions and marrow deposits in multiple axial and appendicular skeletons. A heterogeneous FDG-avid and heterogeneous contrast-enhancing soft tissue lesion was noted in the anterior mediastinum of size 6.4 x12.5 x 12.5 cms (SUV max-10.02), abutting major vessels without significant luminal narrowing. FDG avid multiple pleural deposits were noted in both lungs of size 2.1 x 5.0 cm, SUV max 3.58 [Fig 1].

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Fig 1: Baseline and post-salvage chemotherapy FDG PET/CT images. (A–E) Baseline staging FDG PET/CT images demonstrating extensive metabolically active disease. (A) Maximum intensity projection image shows multiple FDG-avid skeletal and marrow lesions involving the axial and appendicular skeleton with an FDG-avid anterior mediastinal soft tissue mass (arrows); (B and C) Axial fused PET/CT and CT images reveal a large heterogeneously enhancing FDG-avid anterior mediastinal mass abutting adjacent mediastinal vessels without significant luminal compromise (arrows); (D) Axial fused PET/CT image demonstrates FDG-avid pleural-based deposits along the left hemithorax (arrow); (E) Axial fused PET/CT image through bilateral knees demonstrates multiple FDG-avid marrow deposits involving the distal femora and proximal tibiae (arrow). (F–J) Restaging FDG PET/CT images after salvage chemotherapy. (F) The maximum intensity projection image demonstrates interval reduction in overall metabolic disease burden (arrow); (G and H) Axial fused PET/CT and CT images show a significant reduction in size and FDG avidity of the previously noted anterior mediastinal lesion (arrows); (I) Axial fused PET/CT image demonstrates resolution of previously noted pleural deposits with residual low-grade uptake in chest wall soft tissue lesions (arrow); (J) Axial fused PET/CT image through bilateral knees demonstrates persistent but metabolically reduced marrow lesions in the lower extremities (arrow), consistent with partial metabolic response. FDG: Fluorodeoxyglucose; PET/CT: Positron emission tomography/

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MM-panel shows M-band 2.39gm/dl in γ-region corresponding to λ only with κ/λ ratio-0.01 and β2-M-10271 ng/ml. Bone marrow examination shows -85% atypical plasma cells (CD138+). PET/CT guided biopsy was done, and was diagnosed as a case of multiple myeloma, International Staging System (ISSIII). In fluorescence in situ hybridization (FISH) analysis, loss of Cyclin D1 (CCND1) and del13q was found.

The patient was given 6 cycles of bortezomib, cyclophosphamide and dexamethasone, and posttreatment M-band was not seen by immunofixation electrophoresis (IFEF), and the κ/λ ratio was 1.48. Further patient was planned for auto-SCT, and treatment regimen was changed to Bortezomib, Thalidomide and Dexamethasone and completed 6 cycles. Bone marrow after 1 year of treatment was in remission with 3% plasma cells, and M-band was negative with Serum Protein Electrophoresis (SPEP) and Immunofixation Electrophoresis (IFE).

The patient developed left-sided pleural effusion, and fluid cytology was found to be positive for plasma cells and later developed gradually progressive multiple anterior chest wall swellings. Fine needle aspiration cytology (FNAC) and biopsy of swelling suggestive of plasmacytoma, and a diagnosis of extramedullary plasmacytoma was made.

Patients started treatment with liposomal doxorubicin, karfilzomib, cyclophosphamide and dexamethasone and even after two cycles, the patient developed recurrent pleural effusions, and his chest wall swelling kept on increasing. A multiple myeloma panel was done, which showed a faint M-band corresponding to the λ region with a κ/λ ratio of 0.003 and β2-M-4040 ng/ml. Biopsy was chest wall was taken, which was seen to be infiltrated with atypical plasma cells.

Along with increasing involvement of the chest wall, the patient developed a massive left-sided pleural effusion, and the patient was started on a modified velcade (bortezomib), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD PACE). regimen every 21 days for a maximum of three cycles. In the first cycle of VTD-PACE, half of the Bortezomib dose was given intrapleurally while the other half was given intravenously on day 1 and day 4. Given t (11:14), a positive status venetoclax 50mg/day was added on day1-7 of the third cycle of VTD-PACE.

A repeat PET/CT was done after 6 months and showed a partial response to the treatment with a significant decrease in size and avidity of chest wall and musculoskeletal lesions. Pleural FDG deposits, which were previously present, were not present in the repeat scan [Fig 2].

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Fig 2: Clinical, cytological, and immunohistochemical features of cutaneous extramedullary relapse in multiple myeloma. (A) Clinical photograph demonstrating multiple erythematous-to-violaceous nodular and plaque-like cutaneous swellings involving the anterior chest wall, consistent with cutaneous plasmacytoma. Central ulceration with surrounding infiltrative skin involvement is noted; (B) Fine-needle aspiration cytology smear from the chest wall lesion showing sheets and clusters of atypical plasma cells with eccentrically placed nuclei and basophilic cytoplasm, suggestive of plasmacytoma (H&E at 40X magnification) (H&E at 40X magnification); (C) Immunohistochemistry demonstrating diffuse strong membranous positivity for CD138 in neoplastic plasma cells, confirming plasma cell lineage at 40X magnification; (D) Immunohistochemistry showing negative staining for CD20 in tumour cells, supporting plasmacytic differentiation at 40X magnification. H&E: Hematoxylin and eosin

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The patient’s chest wall plasmacytoma kept on increasing in size despite multiple lines of chemotherapy; thereafter, the patient was given palliative care with radiotherapy followed by melphalan-based chemotherapy, but the patient’s condition kept on deteriorating, and the patient succumbed to death [Fig 3].

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Fig 3: Chronological timeline of disease course, treatment, and extramedullary relapse

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DISCUSSION

This case represents an exceptionally rare presentation of relapsed multiple myeloma (MM), manifesting as synchronous pleural effusions with pleural-based deposits and aggressive anterior chest wall plasmacytomas. Such a presentation occurs in <1% of relapsed cases and is distinctly different from the more common patterns of bony or marrow-dominant disease progression.^[5]

EMD in multiple myeloma is a biologically separate and severe disease subtype driven by clonal development and loss of dependence on the bone marrow. This transition is accompanied by downregulation of adhesion molecules (e.g. CD56), altered chemokine receptor expression and acquisition of mutations enabling plasma cells to survive and multiply in extramedullary niches. Such clones generally have significant proliferative potential and resistance to therapy, contributing to the discrepancy between an initial profound marrow response and later severe recurrence.^[5] The most common manifestation of pleural involvement in MM-EMD is unilateral pleural effusion with plasma cell-positive cytology. Pleural involvement is reported in 0.2– 2% of all patients and in less than 1% at relapse. The rarity of this presentation is further increased by the anterior mediastinal mass at diagnosis (6.4 x12.5 x 12.5 cm; SUV max 10.02), which abuts great vessels without definite invasion. In just 0.5–1% of de novo cases, mediastinal EMD precedes or coexists with multiple myeloma. In this case, EMD later developed into pleural and chest wall-predominant involvement, a pattern lacking in over 95% of relapses.^[5-8] PET-CT FDG avidity revealed aggressive EMD, directing cytology and ruling out mimics of other metastasis in this low back pain presentation, whereas the initial MRI failed to detect the functional extent.

The patient achieved a stringent complete response (sCR), characterised by undetectable M-band, κ/λ ratio of 1.48, and 3% plasma cells in bone marrow, following induction with bortezomib, cyclophosphamide, and dexamethasone (VCd) (×6 cycles) and consolidation with bortezomib, thalidomide, and dexamethasone (VTd) (×6 cycles), with autologous stem cell transplantation planned and remission maintained at 1 year. This outcome highlights the efficacy of proteasome inhibitor–thalidomide–based regimens in standard-risk disease, with PET/CT negativity reported in the literature to correlate with progression-free survival exceeding 18 months.^[9] The development of refractoriness after exposure to several therapeutic classes is reflected in sequential treatment failures, such as liposomal doxorubicin-KRd (with progressive pleural effusions despite two cycles), VTD-PACE (modified with intrapleural bortezomib), and subsequent addition of venetoclax in view of t(11;14) positivity.

The involvement of FDG PET/CT was essential and diverse in this case. Beyond traditional imaging, it allowed whole-body functional characterisation of disease burden and biology. Baseline PET/CT demonstrated the full extent of disease with recognition of not only extensive skeletal disease but also unknown extramedullary locations, including mediastinal and pleural deposits, which were not appreciated on MRI. FDG PET/ CT-guided biopsy by targeting the most avid extramedullary lesion, enhancing diagnostic yield. Cytogenetics (FISH) was marrow-based, but PET showed regional heterogeneity at relapses. It also spurred acceleration of therapy for aggressive extramedullary illness and facilitated response assessment, identifying a heterogeneous metabolic response that guided ongoing management. The post-therapy scan further enabled objective quantification of partial response through reduction in lesion size and metabolic activity, and has been shown to outperform CT in assessing lesion viability (sensitivity ~92% vs. 57%) as well as in prognostication, where an SUV max >4 is associated with inferior progression-free survival.^[10,11] Pleural and chest wall involvement in EMD is exceedingly rare, with an incidence of <1%, although only a few prior series have reported cutaneous or pleural relapse in approximately 0.5–2% of cases. Nonetheless, the current case is characterised by rapid progression and the failure of multiple therapeutic approaches, despite an initial stringent complete response. This highlights the significance of PET-directed biopsy and cytogenetic-guided therapeutic strategies, such as venetoclax- or BCMA-targeted regimens, especially in younger patients.^[12]

Recent advances include BCMA-directed immune effector therapies, such as B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) cell therapy (Idecabtagene vicleucel, Ciltacabtagene autoleucel) and BCMA bispecific antibodies, which have demonstrated substantial response rates in relapsed/refractory EMD, but responses are often transient, and EMD remains associated with a 44% increased risk of progression after CAR-T. These therapies constitute a paradigm shift, with a move into earlier lines of treatment and partial overcoming of resistance to standard chemo-immunotherapy in this biologically unique subset.^[13]

This case emphasises the essential importance of individualised, imaging-guided therapy in refractory MMEMD. It further underscores the significance of prompt FDG PET/CT assessment in patients exhibiting chronic back pain and lytic skeletal changes, especially within high-risk occupational cohorts where symptoms are commonly overlooked and diagnosis is often delayed.

CONCLUSION

Synchronous cutaneous plasmacytosis and myelomatous pleural effusion mark an exceedingly rare, biologically aggressive pattern of extramedullary relapse in multiple myeloma, carrying grave prognostic implications. This case demonstrates that ¹⁸F-FDG PET/CT serves not only as a staging tool but also accurately delineates the true degree of disease, identifies ideal biopsy targets, and monitors metabolic response more effectively than conventional imaging methods. As myeloma increasingly demonstrates its ability for extramedullary transformation, whole-body metabolic imaging becomes essential for the early detection of relapse, facilitating prompt intervention and informed selection of targeted or cellular therapies in refractory disease.