Recurrent Cutaneous Manifestation in Multiple Myeloma: A Case Report and Management Approach

doi:10.21203/rs.3.rs-3882128/v1

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Case Report

Recurrent Cutaneous Manifestation in Multiple Myeloma: A Case Report and Management Approach

https://doi.org/10.21203/rs.3.rs-3882128/v1

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Background

Cutaneous involvement in multiple myeloma (MM) is an uncommonly encountered manifestation, more commonly observed in patients with aggressive subtypes, and often resistant to conventional therapies. Owing to its infrequency, reported clinical characteristics have been diverse and relatively nonspecific. Particularly uncommon is lower extremity involvement, where cutaneous MM is found.

Case presentation

In this report, we present a unique case of a middle age lady with refractory IgG lambda MM, who subsequently developed recurrent cutaneous plasmacytoma in the lower leg, while being on systemic therapy. Initially, the lesion resembled squamous cell carcinoma, posing a diagnostic challenge. Through meticulous histopathological and immunohistochemical studies, cutaneous involvement by multiple myeloma was conclusively confirmed.

Conclusion

This case highlights the importance of maintaining a high clinical suspicion for cutaneous MM in patients with MM who present with new skin lesions, as early diagnosis is crucial for appropriate management.

Cutaneous plasmacytoma

multiple myeloma

radiotherapy

chemotherapy

wedge resection

MM is an infrequent type of blood cancer, comprising only 1 to 2% of all cancer cases and 17% of all hematological malignancies (1). It is a plasma cell dyscrasia, characterized by neoplastic proliferation of plasma cells in bone marrow leading to over production of monoclonal immunoglobulins called M-proteins or para-proteins. Cutaneous lesions in MM are rare and are found in fewer than 2% of patients with systemic MM (2). At the time of initial diagnosis, approximately 7% of patients with MM present with extramedullary plasmacytoma. However, 6% of patients may subsequently develop extramedullary symptoms at a later stage of disease. Patients with MM who had direct cutaneous involvement experienced a notable decrease in overall survival (3). The most common cause of cutaneous involvement in MM is metastasis and direct extension of the disease from nearby tumor sites.This typically presents as palpable violaceous nodules on the trunk and extremities. Frequently, cutaneous involvement in MM is observed during advanced stages of the disease, attributed to a higher tumor cell burden (3). These lesions are found in various anatomical locations, with the extremity, trunk and abdomen being the most frequently affected areas (4). Limited medical literature has discussed cutaneous involvement in MM. We present a rare case of a recurrent red, violaceous, and non-tender nodule on the left lower leg in a patient diagnosed with IgG lambda MM and currently undergoing systemic treatment.

A middle aged female with a medical history of hypertension, Eastern Cooperative Oncology Group (ECOG) performance status of 2, and past pulmonary tuberculosis, presented with the complain of pain in left lower leg in tibial region for two months. Imaging revealed an 8.4 x 4.3 x 3.5 cm focal lesion in the proximal metaphysis of the left tibia, leading to a pathological fracture for which intramedullary nailing was done. PET-CT scan indicated hypermetabolic activity in various regions including the left tibia, soft tissue of the neck, right posterior iliac bone, L5 vertebra, multiple left ribs, and manubrium sterni.

She was diagnosed with R-ISS Stage II, Immunoglobulin G (IgG) lambda Multiple Myeloma (MM) with 80% plasma cells observed in the initial bone marrow biopsy. No high-risk chromosomal abnormalities were detected in Fluorescence in Situ Hybridization (FISH) testing.

She was started on treatment and underwent eight cycles of lenalidomide, bortezomib, and dexamethasone, accompanied by monthly intravenous (IV) zoledronic acid. Additionally, 2000 cGy of palliative external beam radiation therapy via Three–dimensional radiation therapy (3CDRT) technique was administered to L4 vertebrae and sacral region to alleviate pain. Clinically patient responded very well and pain subsided. Subsequently, maintenance therapy was started at 10 mg daily dose of lenalidomide, which was later tapered to alternate days.

Over the course of two years, her monthly disease assessments showed a Very Good Partial Response (VGPR). However, she experienced a relapse with M spike, prompting a switch to bortezomib and dexamethasone for 5 cycles. Subsequently, she underwent bortezomib maintenance therapy but it was later changed to lenalidomide maintenance due to gastro-intestinal side effects. (Lenalidomide not discontinued)

After seven months of maintenance therapy with lenalidomide and approximately 2 years after initial diagnosis, a well-circumscribed polypoidal soft tissue lesion appeared on her left knee which was treated with wedge resection. (Fig.1).

The microscopic examination confirmed a relapsed MM in soft tissue with characteristic features of plasmacytoid cells. Immunohistochemical staining confirmed MM with positive reactivity for Mum-1 and CD56. (Fig.2).

She was initiated on the 2nd line of treatment, which included two cycles of carfilzomib, lenalidomide, and dexamethasone. Carfilzomib was later substituted with pomalidomide due to financial limitations. However, the plasmacytoma continued to grow, causing pain and bleeding, a dose of 2000 cGy in 5 fractions was delivered to the left tibial soft tissue lesion via 3DCRT technique to control local symptoms. The disease responded very well and the lesion completely resolved along with palliation of other symptoms.

A year later, while still on pomalidomide and dexamethasone, she developed another polypoidal soft tissue growth on her left leg, 4 cm above the medial malleolus. (Fig.3).

An X-ray of the tibia showed lobulated soft tissue opacity but no involvement of underlying bone. She was planned for radiation therapy (RT) to the soft tissue lesion and received a dose of 2000 cGy in 5 fractions via electron beam therapy and responded very well and is being followed up. Meanwhile, she will continue on pomalidomide and dexamethasone. If the disease progresses, the next step will involve switching to third-line treatment.

Extramedullary disease in MM may manifest in various anatomical sites such as in skin, pleura, lymph nodes, liver or central nervous system (5). Skin is the most frequently affected organ in relapsed MM cases (5). Cutaneous MM arises as a consequence of either hematogenous or lymphatic metastases or local spread of disease from adjacent malignant growth or cortical bone destruction (3, 6). In some rare cases, its growth can be instigated by invasive procedures (5). Cutaneous involvement of MM depicts an aggressive nature of disease signifying the capacity of clonal plasma cells to proliferate outside the confines of bone marrow environment (5). It is associated with high-risk genetic features, augmented cellular proliferation, evasion of apoptosis and a history of extensive prior treatments as exemplified in our case (5). Typically, occurrence of cutaneous MM is observed in patients between ages of 50 to 71 years, as evidenced in our case as well (7). It has been reported that the earlier the disease manifests, the aggressive its course is (8). This condition may manifest on any region of skin, primarily observed on extremities, trunk and abdomen (3, 7). Multiple lesion can be present at the same time (7). They are usually red, violaceous lesions characterized by a diameter of 1-5cm or more (9). Trauma might play a significant role in harboring plasma cells in skin nevertheless, in our patient’s case there was no history of trauma or instrumentation. Several studies have indicated that age, sex, light chain type, prior lines of therapy for MM, time elapsed from MM diagnosis to skin manifestation, and lesion location do not hold significant influence over the development of cutaneous MM (7). Simultaneously, certain studies have demonstrated a predisposition of cutaneous MM towards IgG, IgA, and IgD subtypes, as well as light chain disease (3, 7). Our patient also presented with IgG lambda MM. Cutaneous MM does not exhibit any preferential cytogenetic abnormalities nor does it demonstrate any correlation with CD56 expression (7). Nonetheless, certain studies indicate that the absence of CD56 expression is a significant factor in disease development, as the loss of CD56 may contribute to disease dissemination and hinder the adherence of myeloma cells to the bone marrow (6). However, according to certain studies, more than 50% of cases show positive CD56 expression (3). Our patient also showed positive reactivity for MUM-1 and CD56.

Management:

Due to the rarity of cutaneous MM, there are currently no established treatment guidelines for its management. The most frequently employed approach for relapsed cutaneous MM involves palliative radiation therapy (RT) along with systemic therapy (3). Typically, patients present with cutaneous MM after undergoing an extensive treatment regimen, having already developed refractory disease (10).

Radiation Therapy:

As a local treatment modality, RT has demonstrated favorable responses, providing palliative effects and complete regression in cases of cutaneous MM (9). In a case report by Liu J. et al., a 75-year-old male with secondary cutaneous MM received both 3D conformal photon and electron therapy to multiple sites, resulting in a complete response and palliation of pain at the irradiated site (11). Dose of the therapy ranged from 3000 cGy in 10 fractions to 4140 cGy in 23 fractions (11). Nguyen also documented a near-complete treatment response of the right lower leg using a five-field 6 MeV electron beam with 0.5 cm bolus, administering a radiation dose of 2000 cGy in 5 fractions (12). A palliative total skin electron therapy employing the standard six-field technique with 6 MeV electron beams delivering 2000 cGy in two days, was reported in a 78-year-old male. The patient continued on systemic therapy and exhibited isolated progression in the right canthus, for which he subsequently received an additional 3000 cGy of electron beam therapy, resulting in a complete response at a later stage (13). Studies have shown that RT can effectively achieve complete or near-complete responses, providing palliation of pain and regression of lesions in affected areas. Although cutaneous multiple myeloma is a rare entity, radiation therapy has demonstrated favorable outcomes as a local treatment option, particularly in cases of relapsed disease.

Systemic Therapy:

In subsequent lines of therapy for cutaneous multiple myeloma, drugs such as Bortezomib or Lenalidomide combined with dexamethasone, as well as novel agents like Carfilzomib and Pomalidomide, have exhibited promising responses. Additionally, the incorporation of Bortezomib has been associated with a notable increase in progression-free survival (PFS) and improved overall survival (OS) over a 4-year timeframe for patients presenting with extramedullary disease (10). Furthermore, it has demonstrated enhanced outcomes even in transplant ineligible patients. Carfilzomib, in combination with Lenalidomide and dexamethasone, has also exhibited superior results in achieving complete response (CR), partial response (pCR), and very good partial response (VGPR) (10). Cutaneous MM treatment also incorporates a range of proteasome inhibitors and immune-modulatory agents as part of the regimen (7). However, immune-modulatory agents may not exhibit substantial efficacy in targeting soft tissue lesions (10).

According to the reported findings, more than 10% of patients undergo RT during their initial relapse treatment, while over 50% receive RT and immune-modulatory agents (IMIDs) during treatment for their second relapse. Additionally, it has been documented that more than 50% of individuals who receive second-line therapy will proceed to receive third-line therapy. However, no specific treatment modality has been associated with achieving complete or partial response in these cases (7).

The overall survival rate for cutaneous MM is notably low, with majority of patients succumbing to the disease within 9 to 12 months of initial diagnosis (3, 7, 4). However, our patient exhibits a different outcome in this regard. Cutaneous MM has been identified as an independent prognostic factor for MM (3). The principal causes of mortality comprise disease progression, involving liver involvement, infections, and pancreatic obstruction (6, 7). The absence of prospective studies renders it challenging to substantiate robust recommendations for any particular treatment approach.

In conclusion, cutaneous multiple myeloma presents as a rare and challenging entity with a poor overall survival rate. Skin is the most commonly affected organ in relapsed cases just as our case demonstrates. While radiation therapy and systemic therapies have shown promising responses, the lack of prospective studies limits the establishment of robust treatment recommendations. A multidisciplinary approach is crucial to tailor treatment plans according to each patient's unique clinical profile. The exploration of innovative treatment approaches exhibit promise in enhancing the overall outcomes for these patients.

MM: Multiple Myeloma

IgG: Immunoglobulin G

3CDRT: Three-Dimensional Conformal Radiation Therapy

PET-CT: Positron Emission Tomography-Computed Tomography

R-ISS: Revised International Staging System

IV: Intravenous

VGPR: Very Good Partial Response

FISH: Fluorescence in Situ Hybridization

RT: Radiation Therapy

CR: Complete Response

pCR: Partial Complete Response

OS: Overall Survival

PFS: Progression-Free Survival

CD56: Cluster of Differentiation 56

IMIDs: Immune-Modulatory Agents

ECOG: Eastern Cooperative Oncology Group

Author Contribution

M.S.S. Naviwala and M. Hina primarily contributed to writing the main manuscript text, while N. Ali and M. Moosajee focused on manuscript review and provided critical insights. All authors participated in the manuscript's overall review process.

• Ethical Approval and Consent to participate: Has taken ethical approval and consent from Aga Khan University Hospital ethical review committee. Patients signed informed consent regarding publishing their data and photographs.

• Consent for publication: I hereby provide consent for the publication of the manuscript detailed above, including any accompanying imag- es or data contained within the manuscript.

• Availability of supporting data: On behalf of all the contributors I will act as guarantor and will correspond with the journal from this point onward.We hereby transfer, assign, or otherwise convey all copyright ownership, including any and all rights incidental thereto, exclusively to the journal, in the event that such work is published by the journal.

• Competing interests/Authors' contributions:M.S.S. Naviwala and M. Hina primarily contributed to writing the main manuscript text, while N. Ali and M. Moosajee focused on manuscript review and provided critical insights. All authors participated in the manuscript's overall review process.

• Funding: No funding received.

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No competing interests reported.

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Recurrent Cutaneous Manifestation in Multiple Myeloma: A Case Report and Management Approach

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Abstract

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Introduction

Case Presentation

Discussion

Management:

Radiation Therapy:

Systemic Therapy:

Conclusion

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