Bone Marrow Transplantation (2001) 27, 1215–1217  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Case report Dermatomyositis and sarcoid-like reaction associated with multiple myeloma treated effectively by high-dose chemotherapy and autologous peripheral blood stem cell transplantation

R Chakraverty1, N Rabin2, K Peggs2, S Robinson2, JR Duncan3 and K Yong2

1Institute of Cancer Studies, University of Birmingham, Birmingham; 2Department of Haematology, University College Hospital, London; and 3Royal Sussex County Hospital, Brighton, UK

Summary: Case report

We report the case of a 46-year-old male who developed A 46-year-old man presented with a 3 month history of dermatomyositis and a sarcoid-like reaction in associ- general malaise and 2 week history of vomiting in March ation with testicular relapse of multiple myeloma. The 1998. There was no significant past medical history. On myositis progressed despite chemotherapy directed at examination he appeared unwell and short of breath at rest. the underlying malignant disorder and immunosuppres- He had a raised venous pressure, peripheral oedema and sive treatment. There was, however, a dramatic and sus- bilateral inspiratory crepitations on chest examination. FBC tained response to high-dose chemotherapy and autolog- at presentation was: Hb 8.2 g/dl, white cell count 5.2 × 109/l ous peripheral blood stem cell transplantation which and platelets 163 ϫ 109/l. Renal function tests confirmed resulted in resolution of the myopathy and partial resol- acute renal failure with a creatinine of 844 umol/l (normal ution of the sarcoid-like reaction. This case report high- range 62–130) and urea 46.4 mmol/l (normal range 2.8– lights the potential of autologous stem cell transplan- 7.6). Corrected serum calcium was 3.43 mmol/l. Chest X- tation as treatment for para-neoplastic disorders ray showed changes consistent with pulmonary oedema. associated with haematological malignancies. Bone Mar- Serum electrophoresis confirmed an IgG lambda paraprot- row Transplantation (2001) 27, 1215–1217. ein of 70 g/l. No urinary Bence–Jones protein was detected. Keywords: multiple myeloma; autologous PBSCT; Skeletal survey revealed no lytic lesions. Bone marrow tre- dermatomyositis; sarcoidosis phine was diffusely fibrotic with deposition of collagen (grade 4) and heavy infiltration by neoplastic plasma cells (CD138 positive, lambda light chain restriction). Most plasma cells had the features of plasmblasts. Renal biopsy The presenting clinical features of multiple myeloma are showed a cast nephropathy. protean and reflect the direct effects of clonal plasma cell The diagnosis was of IgG lambda myeloma complicated proliferation (eg bone marrow failure), the activity of by hypercalcaemia and acute renal failure. He was treated monoclonal antibody (eg amyloid deposition), or the conse- initially with an infusion of sodium pamidronate to correct quence of a complex inter-relationship between the abnor- the hypercalcaemia, and serial plasma exchange and mal clone and the host bone marrow micro-environment haemodialysis over the next 8 days. He also received three (eg bone disease). The pathogenesis of the various ‘para- pulses in quick succession of dexamethasone 40 mg daily neoplastic’ disorders which occur in association with mye- for 4 days. His renal function improved rapidly and he loma, such as axonal or demyelinating neuropathy, is less required no further dialysis. He subsequently received five certain although antibodies with specificity for proteins courses of VAD chemotherapy (vincristine 0.4 mg daily expressed by affected tissues, amyloid deposition or intravenously over 4 days (total dose 1.6 mg), adriamycin changes in cytokine production patterns have all been pro- 9 mg/m2 intravenously over 4 days (total dose 36 mg/m2) posed as potential mechanisms. The optimal treatment for and dexamethasone orally 40 mg once daily for 4 days), this group of disorders has not been defined and their completing therapy in September 1998. After five courses impact upon prognosis is not known. We report for the first of therapy he entered complete remission with no excess time the effectiveness of high-dose chemotherapy and per- of plasma cells detectable on bone marrow aspirate and no ipheral blood stem cell transplantation (PBSCT) as treat- detectable paraprotein. In November 1998 he underwent a ment for a para-neoplastic disorder associated with successful peripheral blood stem cell harvest following multiple myeloma. cyclophosphamide (1.5 g/m2) and G-CSF priming, with a view to proceeding to high-dose melphalan and PBSCT. Correspondence: R Chakraverty, Institute of Cancer Studies, University In January 1999, when admitted for PBSCT, he of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TH, UK described a 6-week history of progressive weakness of both Received 17 November 2000; accepted 7 March 2001 the upper and lower limbs associated with severe myalgia. Autologus PBSCT for para-neoplastic disorder R Chakraverty et al 1216 He also reported the development of a rash over his face was 60%. The post-transplant course was complicated by and the dorsal aspect of his hands. On examination he had severe grade III mucositis and a single episode of febrile a bilateral symmetric violaceous rash over his knuckles and neutropenia, but was otherwise uneventful. Over the next over his cheeks and peri-orbital region. There was bilateral 4–6 weeks his condition improved dramatically with com- symmetrical MRC grade 4/5 weakness of proximal upper plete resolution of both the rash and clinical evidence of and lower limb muscle groups without wasting or fascicul- myopathy. At 18 months post PBSCT he has a Karnofsky ation. There was no other focal neurological deficit. An score of 100% and remains in remission from his myeloma, incidental finding was of a hard irregular enlargement of with no features of DM and significant (Ͼ50%) reduction the left testis. in the degree of hilar lymphadenopathy. A bone marrow aspirate showed no excess of plasma cells and serum electrophoresis revealed a very faint, but non-quantifiable IgG lambda paraprotein. He underwent a Discussion left orchidectomy and histology of the testicular mass showed a plasmacytoma with the same monoclonal light This is the first case report to highlight the durable chain restriction as at diagnosis. remission of a myeloma-associated para-neoplastic disorder Serum creatinine kinase levels were consistently normal. following autologous stem cell transplant (SCT). The pre- A general auto-antibody screen (anti-thyroglobulin, -thy- cise role of autologous SCT in the treatment of the auto- roid microsomal, -gastric parietal cell, -smooth muscle, immune inflammatory myopathies has yet to be determined, -mitochondrial and -DNA) was negative. A screen of anti- but this case study and another recent report1 illustrate that bodies to extractable nuclear antigen (anti-Ro/SSA, it may be feasible in patients with disease refractory to con- -La/SSB, -Sm, -RNP, -Jo-1 and -Sc170) was also negative. ventional immunosuppression. It is also consistent with the Electromyelograph studies of the right iliopsoas and tibialis reported efficacy of autologous SCT for other auto-immune anterior confirmed a moderate proximal myopathy with diseases.2 The mechanisms of disease response to autolog- polyphasic stable units. A muscle biopsy from the vastus ous SCT are not known but may include the eradication lateralis showed an excess of small atrophic, angulated of auto-reactive T cell clones or thymic re-education. This fibres scattered throughout the biopsy and in some areas patient received a non-manipulated, T cell-replete PBSCT, the distribution was perifasicular. Fibre typing showed type suggesting that physical removal of auto-reactive T cells I predominance with some areas of grouping of type I and from the graft is not a pre-requisite for a response in this type II fibres. There was no significant inflammatory infil- setting. It is currently uncertain whether T cell depletion tration and the blood vessels appeared normal. Oxidative confers any overall benefit in the context of auto-immune stains were normal. No inclusions or vacuoles were disease. observed in the muscle fibres. Stains for glycogen, lipid, The diagnosis of DM in this case was made using the phosphorylase, acid phosphatase and adenylate deaminase criteria of Bohan and Peter:3 symmetrical proximal muscle were non-contributory. weakness, specific muscle biopsy findings, elevation of A serum amyloid protein scan was performed, which was muscle-derived serum enzymes, typical electromyographic negative and an ECG and echocardiogram showed no evi- findings and characteristic cutaneous lesions. The diagnosis dence of a restrictive cardiomyopathy. of DM can be made using four of these five criteria, as in CXR at this stage showed a small right-sided pleural this case where the serum creatinine kinase was consist- effusion and bilateral hilar lymphadenopathy, neither of ently normal. The absence of inflammation in the muscle which had been present at diagnosis. CT scan of chest, biopsy does not exclude the diagnosis.3 Although the find- abdomen and pelvis demonstrated no evidence of lympha- ing of hilar lymphadenopathy and biopsy finding of non- denopathy elsewhere. Pleural fluid cytology was unremark- caseating epithelioid granulomata indicate an SLR, this able. In order to identify the cause of the hilar lymphadeno- case did not fulfil the criteria for systemic sarcoidosis since pathy, a mediastinoscopy and lymph node biopsy were there was no objective evidence of involvement of more performed. Lymph node histology showed complete efface- than one organ system. The association between multiple ment of the normal lymph node architecture by non-caseat- myeloma and both DM and the SLR are suggested first, by ing granulomata. No acid alkali-fast bacilli were identified. the temporal relationship of their onset and second, by a Serum angiotensin converting enzyme levels were consist- parallel clinical course. The durable regression of the myo- ently normal. sitis and decrease in hilar lymphadenopathy following auto- The diagnoses were of dermatomyositis (DM) and a sar- logous SCT would be consistent with the significant coid-like reaction (SLR) complicating testicular relapse of immune suppression induced by this treatment and/or by multiple myeloma. Over the next 8 weeks the symptoms reduction in the myeloma tumour load. An estimation of of myalagia and muscle weakness became more pro- the degree of tumour reduction in this case is difficult since, nounced. He received a further course of VAD chemo- at the time of transplant, the testicular mass had been therapy which resulted in a minor, but only transient removed and paraprotein was present but at such a low improvement in his symptoms. He was therefore com- level as to be non-quantifiable. menced on prednisolone 1 mg/kg orally but his symptoms Although individual associations between lymphopro- continued to progress such that he had difficulty climbing liferative disorders (LPDs) and both DM4 or SLRs5 have stairs or carrying any significant weight. He proceeded to been reported previously, to our knowledge there are no melphalan 200 mg/m2 given intravenously and non- descriptions of this triad. DM is associated with a five- to manipulated PBSCT, at which time his Karnofsky score seven-fold increase in the incidence of malignancy4 includ-

Bone Marrow Transplantation Autologus PBSCT for para-neoplastic disorder R Chakraverty et al 1217 ing in some, but not all studies, associations with LPDs. In We conclude that autologous SCT may be an effective the majority of these cases there is a close temporal associ- therapeutic option for patients with para-neoplastic dis- ation between the development of the LPD and DM. How- orders associated with multiple myeloma. Since other para- ever, in contrast to other malignancies and this particular neoplastic phenomena, such as demyelinating or axonal case report, few cases of DM are reported after the develop- neuropathies are relatively common complications of the ment of the LPD. To date, descriptions linking plasma cell plasma cell dyscrasias it should be feasible to study system- dyscrasias and polymyositis or DM are rare with only a few atically whether dose escalation and autologous SCT confer reported cases (see Refs 6 and 7 and references therein). It any significant benefit in terms of outcome. is noteworthy that in three patients, including this one, the plasma cell dyscrasia was present at an extramedullary site (thyroid, gastric and testicular).6,7 SLRs have been described in patients with LPDs, either References at the site of malignancy or at sites distinct from the reac- tion.8 The reported frequency of non-caseating granulomas 1 Baron F, Ribbens C, Kaye O et al. Effective treatment of Jo-1- in patients with lymphoproliferative disorders is in the associated polymyositis with T-cell-depleted autologous per- range of 7–14%.8 Typically, these reactions are associated ipheral blood stem cell transplantation. Br J Haematol 2000; with local non-caseating granulomata and lack of symp- 110: 339–342. toms, but their presence can cause diagnostic confusion or 2 Tyndall A, Fassas A, Passweg J et al. Autologous haematopo- ietic stem cell transplants for autoimmune disease – feasibility lead to inappropriate disease staging. Although a distinction and transplant-related mortality. Autoimmune Disease and is often made between an SLR and systemic sarcoidosis, it Lymphoma Working Parties of the European Group for Blood is possible that these two entities represent the clinical and Marrow Transplantation, the European League Against extremes of a common pathological process. Indeed, the Rheumatism and the International Stem Cell Project for Auto- existence of a ‘sarcoid-lymphoma’ syndrome has been pro- immune Disease. Bone Marrow Transplant 1999; 24: 729– posed which is characterised by onset of lymphoma after 734. the development of sarcoidosis.5 In general, these features 3 Bohan A, Peter JB. Polymyositis and dermatomyositis. New hold true for the reported associations between plasma cell Engl J Med 1975; 292: 403–407. dyscrasias and sarcoidosis.8 4 Maoz CR, Langevitz P, Livneh A et al. High incidence of The pathogenesis of DM or SLRs associated with malig- malignancies in patients with dermatomyositis and polymyos- itis: an 11-year analysis. Semin Arthritis Rheum 1998; 27: nancy is not known, but presumably involves a host 319–324. immune response to tumour antigens. Granulomatous 5 Brincker H. The sarcoidosis-lymphoma syndrome. Br J Can- inflammation is driven by T helper 1 (Th1) cytokines such cer 1986; 54: 467–473. as IFN gamma and interleukin-2, a pattern consistent with 6 Beck P. Myelomatosis presenting as dermatomyositis. Br Med the immuno-histochemical pattern of local cytokine J 1968; 1: 747–748. expression demonstrable in the inflammatory myopathies.9 7 Caron P, Lassoued S, Thibaut I et al. Thyroid plasmacytoma The demonstration that idiotype-specific T cells in patients with dermatomyositis and palmar fasciitis. J Rheumatol 1989; with myeloma frequently express Th1 cytokines10 raises the 16: 997–999. possibility that a skewed immune response to myeloma- 8 Brincker H. Sarcoid reactions in malignant tumours. Cancer specific antigens leads to a perturbation of the cytokine mil- Treat Rev 1986; 13: 147–156. 9 Lepidi H, Frances V, Figarella-Branger D et al. Local ieu which, in turn, is capable of inducing a granulomatous expression of cytokines in idiopathic inflammatory myo- reaction or inflammatory myopathy. Whether or not specific pathies. Neuropathol Appl Neurobiol 1998; 24: 73–79. biological features of extramedullary disease influence the 10 Osterborg A, Yi Q, Bergenbrant S et al. Idiotype-specific T host immune response or increase the risk of certain para- cells in multiple myeloma stage I: an evaluation by four differ- neoplastic complications is not known. ent functional tests. Br J Haematol 1995; 89: 110–116.

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