Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after treatment with cyclophosphamide, α‐interferon and betamethasone in a patient with multiple myeloma

To the Editor: As in the past, the overwhelming majority of patients with multiple myeloma eventually die of their disease. Standard treatment has been chemotherapy with intermittent cycles of melphalan and prednisone (1). Since the median survival after melphalan/prednisone therapy is only around 30 months, numerous attempts have been made to improve upon these results. The most common approach has been more intensive combination chemotherapy; however, a recent meta-analysis comprising 38 14 patients failed to demonstrate an improved prognosis with combination therapy (2). The Myeloma Group of Central Sweden (MGCS) has shown that addition of a-interferon to melphalan/prednisone significantly prolongs the survival of patients with IgA and Bence-Jones myeloma, whereas the prognosis for patients with IgG myeloma was unaffected by the addition of a-interferon (3). Based upon these results MGCS has started a pilot study of a regimen (CIB) consisting of cyclophosphamide 950mg/m2 i.v on d 1 and 3, natural a-interferon ( Wellferon, Wellcome) 7 x lo6 U/m2 S.C. on d 1-4, and betamethasone 30 mg orally on d 1-4, with the addition of granulocyte-macrophage colony-stimulating factor (GMCSF; Leucomax, Schering-Plough) 400 pg S.C. daily from d 5 until nadir values are passed and a WBC count of 1.5 x 109/1 is reached. This regimen has, in a first analysis, given promising results (4). However, we report a patient treated with CIB who developed a syndrome of inappropriate secretion of antidiuretic hormone (SIADH ) and eventually died. A 69-yr-old man consulted a rheumatologist because of pain and stiffness from the neck, shoulder and lumbar regions. The symptoms had evolved during 6 months and were combined with a weight loss of 6 kg. Haemoglobin was 121 g/l, white blood cell count 10.5 x 109/1, sedimentation rate (SR) 42 mm and C-reactive protein (CRP) 116 g/l. Polymyalgia rheumatica was suspected and treatment with prednisolone was initiated. The symptoms somewhat improved and SR and CRP almost normalized. Suddenly an acute pain evolved from the lumbar region. Serum electrophoresis revealed a small monoclonal protein, and urinary electrophoresis showed K light chains 6.7 g/d. Serum potassium was 4.7 mmol/l, sodium 139 mmol/l, calcium 2.55 mmol/l and albumin 33 g/l, whereas creatinine was 75 pmol/l. The patient was admitted to the haematological ward at our hospital, where bone marrow aspiration was shown to be dominated by plasma cells constituting 40% of all nucleic cells. Radiology demonstrated generalized osteopenia with a compression fracture of thoracic vertebrae XI, and magnetic resonance imaging revealed pathological signals from all vertebrae. A diagnosis of Bence-Jones multiple myeloma stage IIIA was thus established, and after informed consent treatment with CIB was initiated according to the MGCS study protocol, which has been approved by the Ethical Committee at the Karolinska Institute. Initially the patient tolerated the treatment well, but on d 4 of CIB he developed nausea. Serum sodium levels were normal on d 1-3 of CIB; however, on d 4 , i.e. after 2 doses of cyclophosphamide, a hyponatraemia evolved (sodium 128 mmol/l). Despite GM-CSF treatment according to the protocol, the patient developed neutropenia (nadir <0.1 x 109/1) and on d 8 he presented with dyspnoea and fever, and a pulmonary X-ray showed infiltrates in the lower left lobe.