INTRODUCTION Common manifestations of multiple myeloma include osteolytic lesions, cytopenias, hypercalcemia, and renal insufficiency. Patients may also exhibit heart failure which is often associated with either past therapy or cardiac amyloidosis. A less recognized mechanism is high-output heart failure. Diuretic therapy in this setting has little efficacy in treating the congested state. Furthermore, effective pharmacotherapy has not been established. We report two patients with multiple myeloma and high-output heart failure who failed diuretic therapy. The patients were given dexamethasone in conjunction with lenalidomide and thalidomide, respectively. Shortly thereafter, each patient demonstrated a significant improvement in symptoms. This is the first report of successful treatment of multiple myeloma-induced high-output failure via the utilization of these agents. CASE PRESENTATION Two patients with multiple myeloma were evaluated for volume overload. The first was a 50-year-old man with refractory disease. Magnetic resonance imaging demonstrated diffuse marrow replacement throughout the pelvis. Cardiac catheterization conveyed elevated filling pressures and a cardiac output of 15 liters/minute. He quickly decompensated and required mechanical ventilation. The second patient was a 61-year-old man recently diagnosed with multiple myeloma and volume overload. Skeletal survey demonstrated numerous lytic lesions throughout the pelvis. His cardiac catheterization also conveyed elevated filling pressures and a cardiac output of 10 liters/minute. Neither patient responded to diuretic therapy and they were subsequently started on dexamethasone plus lenalidomide and thalidomide, respectively. The first patient's brisk diuresis allowed for extubation within 48 hours after the first dose. He had a net negative fluid balance of 15 liters over 10 days. The second patient also quickly diuresed and on repeat cardiac catheterization, his cardiac output had normalized to 4.7 liters/minute. CONCLUSION Multiple myeloma can cause high-output failure. The mechanism is likely extensive bony involvement causing innumerable intramedullary arteriovenous fistulas. Diuretic therapy is not effective in treating this condition. Lenalidomide and thalidomide, both of which inhibit angiogenesis, seem to be viable treatment options. Based on the rapid and effective results seen in these two patients, a potential novel mechanism of 'pharmacologic fistula ligation' with these agents may be the most effective way to treat this presentation.