Review
Extramedullary Disease in Multiple Myeloma
Sumit Madan, MD, and Shaji Kumar, MD
Divisions of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota
Subbiah and colleagues1 provide an intriguing account of a 52-year-old male with an extramedullary (EM) relapse of multiple myeloma (MM) soon after a nonmyeloablative (NMA) allogeneic stem cell transplant (allo-SCT). His relapse manifested as a diffuse, erythematous papulovesicular skin rash on bilateral lower extremities with biopsy-proven plasma cell infiltrate involving the upper and deep dermis, concurrent with biochemical progression of MM.
MM is characterized by uncontrolled clonal proliferation of plasma cells, mainly in bone marrow, and EM involvement is infrequent. EM disease can occur either at initial diagnosis of MM or later during the disease course.2-4 In a recent study, an overall incidence of EM disease of 13% (7% at diagnosis and 6% during follow-up) was observed among 1,003 MM patients from a single institution at a median follow up of 30 months from diagnosis.2 Among those with EM disease, 7% were found to have plasma cell leukemia, which has been closely linked with EM disease in previous reports as well.5,6 EM involvement commonly affects the pleura, lymph nodes, soft tissue, liver, skin, lungs, central nervous system (CNS), genitourinary system, breast, and pancreas, and involvement of multiple sites can occur.3,7,8 The presence of EM involvement in MM indicates aggressive disease with shorter overall survival (OS) and progression free survival,2 especially when the EM tumor occurs at the same time as MM.3,9 In a study of 19 patients with EM and extraosseous disease at various sites, the observed median OS was 15 months from diagnosis after treatment with conventional chemotherapy or thalidomide and/or high-dose therapy.3 Another study observed an overall incidence of approximately 1% for CNS involvement in MM4; all but 1 patient died at a median of 5 months from the diagnosis of CNS involvement.
Symptomatic myeloma presenting with EM involvement should be distinguished from a solitary nonosseous plasmacytoma. EM plasmacytoma is a soft tissue plasma cell tumor that arises outside the bone marrow. It is characterized by normal bone marrow, little or no monoclonal protein (mostly IgA), and no evidence of myelomarelated end organ damage.10 The median age at diagnosis of EM plasmacytoma is approximately 60 years, with a strong male preponderance.11 It usually occurs (>80%) in the upper aerodigestive tract,3,11 producing symptoms such as epistaxis, rhinorrhea, and nasal obstruction. It frequently remains localized and has a favorable prognosis after treatment with radiation therapy and/or surgery. Cutaneous involvement with EM plasmacytoma (solitary or multiple) is rare,11 and carries a favorable prognosis with a survival rate of greater than 90% at 5 years.12 These patients require close surveillance and regular testing to determine if overt MM will develop.
EM Disease Post-allogeneic Transplantation
Recent reports suggests higher rates of EM relapses, either alone or concurrent with systemic relapse, in MM patients undergoing allo- and autologous (auto)-SCT,8,13,14 especially those receiving NMA (reduced intensity) therapy.15 Although the mechanisms of EM relapse after allo-SCT are largely unclear, the potential reasons include a less potent graft versus myeloma (GVM) effect outside the bone marrow, clonal evolution of the tumor cell enabling independence from the supportive effect of the bone marrow microenvironment, and/or the escape of myeloma cells from the GVM effect of immunocompetent allogeneic T cells in extramedullary sites. A recent report observed a 9.3% incidence of isolated EM relapse and a cumulative 20.4% incidence of EM relapses among MM patients treated with sequential auto- and NMA allo-SCT.16 The authors of this study suggest that a worsening disease status at transplant may be related to a higher incidence of EM relapse. In another study, where fewer patients were treated with the sequential transplantation approach and one-third had progressive disease at the time of allo-SCT, an even higher rate of EM relapse (37%) was observed, mainly involving the cranial and periorbital sites without medullary disease recurrence.15
The presence of chromosome 13 deletion at diagnosis, a well-recognized poor prognostic factor in MM, has also been implicated in the increased incidence of EM relapse in several studies.4,8,16 Although other risk factors such as increased tumor burden and stage of disease,3,4,16 elevated lactate dehydrogenase levels,2-4,8,16 type of immunoglobulin, 3,16,17 and the development of chronic graft versus host disease (GVHD)14-16 have been linked to the development of EM disease and/or relapse, their exact role still remains under investigation due to conflicting reports from various studies.
Treatment
A GVM effect achieved by donor leukocyte infusion (DLI) has been described in patients with progressive or relapsed MM after allogeneic bone marrow transplantation, 18,19 and some reports suggest its efficacy even in EM disease relapse after allo-SCT.16,20 In a subgroup of MM patients who underwent allo-SCT and received DLI, a treatment response was observed in 5 of 9 and 3 of 4 patients who developed bone marrow and EM relapse, respectively.8 The use of thalidomide, an agent with antiangiogenic properties, has been described with variable efficacy in EM disease. Biagi and associates reported on 3 patients who developed EM disease after allo-SCT and were able to achieve complete resolution with thalidomide21; however, other reports have observed poor efficacy with thalidomide in EM disease.22-24 Bortezomib, a potent proteasome inhibitor, appears to be promising, with several clinical reports suggesting its effectiveness in EM relapse.25,26 Minemma and coworkers reported on a group of 54 MM patients who relapsed after undergoing sequential auto- and allo-SCT, and observed no significant difference in the response rates and survival of those with EM disease relapse treated with DLI, chemotherapy with novel agents, and radiotherapy compared with those without EM disease,16 a finding also corroborated by another study.8
Skin Lesions in MM and Other Monoclonal Gammopathies
Skin involvement from MM is uncommon. Cutaneous lesions in MM usually appear as multiple erythematous nodules or papules, or plaques that show a nodular or diffuse interstitial pattern on histopathologic exam.27 In descending order, these lesions appear on the trunk and abdomen, head and neck, and the extremities. Skin involvement in MM usually manifests itself later in the disease course when the tumor burden is high, and is associated with a poor prognosis.27 On the other hand, cutaneous eruptions are a frequent complication after allo-SCT, and most commonly occur due to immunologic reactions (GVHD), infections (staphylococcus aureus, herpes simplex virus type 1, varicella zoster virus, cytomegalovirus, Epstein-Barr virus), and drug reactions (cytotoxic drugs, antibiotics and nonsteroidal anti-inflammatory drugs).28 Among a subgroup of 247 patients who underwent transplantation (both autologous and allogeneic), 159 skin biopsies were obtained less than 2 months from the transplant.29 The cutaneous manifestations included GVHD (31%), drug-related phenomenon (15%), infections (8%), bullous diseases (7%), papulosquamous lesions (5%), and neoplasm (4%), while others had thrombocytopenia-related events?,
Sweet’s syndrome, and other nonspecific diagnoses (30%). An excellent review by Daoud and co-authors divided skin disorders associated with monoclonal gammopathies into 4 distinct groups.30 Group 1 diseases (amyloidosis, cryoglobulinemia, plasmacytoma, osteosclerotic myeloma, WaldenstroÅNm macroglobulinemia cutis) are characterized by infiltration and proliferation of skin by malignant plasma cells or a product of these plasma cells; group 2 disease have a strong association with monoclonal gammopathies (scleromyxedema, scleredema, necrobiotic xanthogranuloma, plane xanthoma, Schnitzler syndrome, pyoderma gangrenosum, Sweet’s syndrome, and erythema elevatum diutinum, among others); group 3 represents various dermatoses linked to paraproteinemia without a clear association; and group 4 comprises nonspecific cutaneous conditions, symptoms, and complications related to M protein.
In conclusion, this case serves to highlight several important clinical points. Disease relapse in MM can occur outside the bone marrow in diverse EM sites, including the skin. While rare, tumor recurrence should be considered in the differential diagnosis of skin rash in patients with MM, especially in the context of aggressive disease, and a biopsy should be performed in order to correctly diagnose and guide treatment in these patients.
References
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