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JCR: Journal of Clinical Rheumatology:
doi: 10.1097/RHU.0b013e3182155e8d
Concise Reports

Type 1 Cryoglobulinemia: Response to Thalidomide and Lenalidomide

Calabrese, Cassandra DO*; Faiman, Beth MSN, CNP†; Martin, David MD‡; Reu, Frederic MD†; Calabrese, Leonard H. DO§

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From the *Ohio University of Osteopathic Medicine; †Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Foundation; ‡Internal Medicine, Northeastern Ohio University College of Medicine; and §Cleveland Clinic Lerner College of Medicine, Cleveland, OH.

The authors declare no conflicts of interest.

Correspondence: Leonard H. Calabrese, DO, Cleveland Clinic Foundation, Institute of Rheumatologic and Immunologic Diseases, Mail Code A50, 9500 Euclid Ave, Cleveland, OH 44195. E-mail:

Among the varying etiologies of cryoglobulinemia (Cg), type I Cg represents the rarest form and is most often associated with lymphoproliferative disorders such as non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, or multiple myeloma. Clinical manifestations are generally those of small-vessel vasculitis and/or hyperviscosity. The treatment of patients with type 1 disease generally consists of chemotherapy directed at the lymphoproliferative disorder or varying levels of empiric immunosuppression including apheresis, glucocorticoids, and cytotoxic agents. In recent years, anecdotes of biologic and/or immunomodulatory therapy with rituximab and thalidomide have been reported.1-4 Occasionally. patients present with severe type 1 cryoglobulinemic disease in the absence of a defined malignancy but with monoclonal gammopathy of otherwise undetermined significance (MGUS); the treatment of such patients is controversial.5,6 We recently treated such a patient with traditional immunosuppressives and rituximab but found him ultimately to respond only to thalidomide and its congener, lenalidomide.

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The patient is a 50-year-old man who had been in good health until February 2003, at which point he developed intermittent pain in the lower extremities that was deep in quality and associated with a purpuric rash. He had no fevers, night sweats, diarrhea, weight loss, hypertension, arthritis, or other symptoms at that time. On physical examination, he had classic palpable purpura with diminished sensation in both lower extremities in a stocking distribution. He underwent extensive evaluations for infections, connective tissue diseases, and other causes of small-vessel vasculitis, which were all negative including serologic tests for antinuclear antibodies, rheumatoid factor, antibodies to hepatitis C and B, and human immunodeficiency virus. A test for serum HCV-RNA was negative. He was found to have high titers of cryoglobulins (13.6 g/L; reference, <0.050 g/L). Immunoelectrophoretic analysis revealed the cryoglobulins to be type I IgG lambda. A bone marrow aspiration and biopsy revealed 4% bone marrow plasma cells with a reversal of the kappa-to-lambda ratio suggestive of a low-level plasma cell dyscrasia. The patient had no evidence for plasma cell-related organ dysfunction according to International Consensus Guidelines7,8; he had no anemia, hypercalcemia, bone disease, or kidney dysfunction. There was no evidence for amyloidosis, and he did not have frequent infections or hyperviscosity.

From 2004 to 2005, he was treated with high-dose glucocorticoids and rituximab (a total of 15 infusions of 375 mg/m2 each) and maintained on prednisone (10 mg daily; Fig. 1). His cryoglobulins remained elevated, and he continued to have recurrent purpura, skin ulcerations, and advancing neuropathy. He also developed asymmetric motor neuropathy with a left foot drop consistent with mononeuritis multiplex. The addition of cyclophosphamide resulted in only minimal improvement in cryoglobulin levels. He underwent several rounds of apheresis with interval improvement, but which resulted in rebound of cryoglobulins to more than 10 g/L.

Figure 1
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On the basis of his lack of clinical or immunologic response to glucocorticoids, alkylators, apheresis, and rituximab, he was started on the immunomodulator thalidomide in 2006. He was treated with 200 mg/d combined with pulse administration of oral dexamethasone (20 mg/d for 4 days with intervals of 14 days off × 6). A progressive improvement was observed and cryoglobulin levels declined to the reference range (Fig. 1). After clearing of his Cg, the patient had no further episodes of purpura or cutaneous ulcerations and experienced gradual but partial increase in left-ankle dorsiflexion strength and was able to restart running 1 to 2 miles per day. After 3 years of complete clinical and immunologic remission, he experienced advancing sensory neuropathy in the feet, which was presumed to be secondary to his thalidomide. The dose was reduced to 50 mg thrice weekly, and he remained in remission. The patient declined the consideration to discontinue his thalidomide and was switched to maintenance with lenalidomide to avoid neurotoxicity. He remains stable and with low level Cg on a dosage of lenalidomide 10 mg/d.

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Optimal management of Type 1 Cg in the presence of benign monoclonal B-cell disorders such as those observed in the present case remains problematic. Failure to respond to B-cell depletion therapy with anti-CD20 monoclonal antibodies is not surprising (assuming the monoclonal antibody stems from mature plasma cells) and has been previously reported.1 Empiric immunosuppression with apheresis, alkylators, and glucocorticoids, although often associated with improvement, is temporizing.

The initial management of our case with apheresis, glucocorticoids, and multiple rounds of the anti-CD20 agent rituximab was met with only partial hematologic remission but no evidence of clinical remission as evidenced by persistent and progressive cutaneous and peripheral neuropathic complications. Interpretation of cryoglobulin levels was confounded by several rounds of apheresis as well as a prolonged course of oral daily cyclophosphamide (Fig. 1). Despite such aggressive therapies, the patient's cryoglobulins, although lower than their peak, were still more 2700 mg/mL before thalidomide initiation.

The immunomodulatory drugs thalidomide and lenalidomide can stimulate T cells, have antiangiogenic activities, modulate cytokine secretion in the bone marrow, and exert epigenetic effects.9-12 They are now part of the standard of care for the treatment of multiple myeloma13 and myelodysplastic syndromes and have shown promise in other diseases.9 The use of thalidomide has previously been reported in 2 other cases of type 1 Cg.2,3 The first patient was initially thought to have IgG kappa MGUS but, after repeat bone marrow examination, had to be classified as asymptomatic myeloma based on the absence of bone lesions, azotemia, hypercalcemia, and an increase in bone marrow plasma cells from 8% to 32%. This patient was treated successfully with a combination of thalidomide 200 mg/d plus dexamethasone.2 The other case was similar to ours with a clonal IgG kappa with 5% to 6% bone marrow plasma cells and no other criteria for myeloma. This patient responded to thalidomide at an initial dose of only 50 mg/d, later tapered to 50 mg every other day.3 A recent case of myeloma complicated by undifferentiated spondyloarthropathy and cryoglobulinemic vasculitis responding to lenalidomide 25 mg/d plus pulse dexamethasone has recently been reported.14 Unlike our case, in this report, there was clear evidence of a plasma cell malignancy, and thus, the use of lenalidomide, now considered a first-line therapy for this condition, would be considered standard of care.15 Our case, in contrast, met no criteria for myeloma and continued to demonstrate only a low level of monoclonal gammopathy for several years after therapy with no evidence of hematologic progression. Few other treatments have been cited in MGUS associated Cg, but 1 group reported resolution of vasculitic symptoms with high-dose melphalan and autologous stem cell transplant.16

Although the mechanism of action remains poorly understood, thalidomide was effective in both cases. Our case also represents the first use of the congener lenalidomide, which is effective for the treatment of plasma cell dyscrasias with an improved safety profile, and has also been reported effective in Behçet disease.4,17-20 In our case, it seems to maintain remission. MGUS may be of significance when it causes Cg or immune thrombocytopenic purpura,13 and conventional approaches that fail to durably control the causative plasma cells do not yield satisfactory results. With the availability of tolerable therapies for multiple myeloma, the time has come for their formal evaluation in more benign conditions mediated by clonal plasma cells.

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1. Nehme-Schuster H, Korganow A-S, Pasquali J-L, et al. Rituximab inefficiency during type I cryoglobulinaemia. Rheumatology. 2005;44:410-411.

2. Cem Ar M, Soysal T, Hatemi G, et al. Successful management of cryoglobulinemia-induced leukocytoclastic vasculitis with thalidomide in a patient with multiple myeloma. Ann Hematol. 2005;84:609-613.

3. Sampson A, Callen JP. Thalidomide for type 1 cryoglobulinemic vasculopathy. Arch Dermatol. 2006;142:972-974.

4. Shah SR, Tran TM. Lenalidomide in myelodysplastic syndrome and multiple myeloma. Drugs. 2007;67:1869-1881.

5. Kyle RA, Treon SP, Alexanian R, et al. Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: Consensus Panel Recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003;30:116-120.

6. Dimopoulos M, Merlini G, Leblond V, et al. How we treat Waldenstrom's macroglobulinemia. Haematologica. 2005;90:117-125.

7. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3-9.

8. IMW Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the international myeloma working group. Br J Haematol. 2003;121:749-757.

9. Knight R. IMiDs: a novel class of immunomodulators. Semin Oncol. 2005;32:24-30.

10. Escoubet-Lozach L, Lin I-L, Jensen-Pergakes K, et al. Pomalidomide and lenalidomide induce p21WAF-1 expression in both lymphoma and multiple myeloma through a LSD1-mediated epigenetic mechanism. Cancer Res. 2009;69:7347-7356.

11. Moutouh-de Parseval LA, Verhelle D, Glezer E, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Investig. 2008;118:248-258.

12. Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2009;24:22-32.

13. Rossi D, De Paoli L, Franceschetti S, et al. Prevalence and clinical characteristics of immune thrombocytopenic purpura in a cohort of monoclonal gammopathy of uncertain significance. Br J Haematol. 2007;138:249-252.

14. Lin RJ, Curran JJ, Zimmerman TM, et al. Lenalidomide for the treatment of cryoglobulinemia and undifferentiated spondyloarthropathy in a patient with multiple myeloma. J Clin Rheumatol. 2010;16:90-91.

15. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111:2962-2972.

16. Hillengass J, Ho A, Goldschmidt H, et al. Clinical evidence for immunomodulation induced by high-dose melphalan and autologous blood stem cell transplantation as cause for complete clinical remission of multiple myeloma-associated cryoglobulin-vasculitis. Int J Hematol. 2008;88:454-456.

17. Green J, Upjohn E, McCormack C, et al. Successful treatment of Behçet's disease with lenalidomide. Br J Dermatol. 2008;158:197-198.

18. Dispenzieri A, Klein CJ, Mauermann ML. Lenalidomide therapy in a patient with POEMS syndrome. Blood. 2007;110:1075-1076.

19. Sethi S, Tageja N, Arabi H, et al. Lenalidomide therapy in a rare case of POEMS syndrome with kappa restriction. South Med J. 2009;102:1092-1093.

20. Jaccard A, Abraham J, Recher C, et al. Lenalidomide therapy in nine patients with POEMS syndrome. Blood. 2009. [Abstract 3872].

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