A 77-year-old male nonsmoker with a history of atrial fibrillation and sick sinus syndrome post-pacemaker placement experienced edema, skin rash, and skin tightening. During the initial physical examination, yellow-brown papules and indurated and pendulous skin folds were evident on his face, neck, retroauricular area, chest, trunk, upper extremities, and thighs; he also had difficulty opening his mouth. No gross changes were observed in the digital nail beds (i.e., pitting and capillary loops) but were present in the lower extremities. Edema was present in the lower extremities. Skin biopsies revealed fibrosis and benign fibrocytic proliferation consistent with scleromyxedema. Colloidal iron staining for mucin deposition detected minimal interstitial mucin deposition in one biopsy, although Verhoeff van Gieson elastic stain highlighted fragmentation of superficial dermal collagen bundles. Congo red stain for amyloid deposition was negative. Aside from telangiectasia, there was no evidence of vasculopathy or thrombosis associated with these lesions. Laboratory testing of serum and urine samples detected an elevated level of immunoglobulin G (IgG) production, consistent with a diagnosis of MGUS. Electrophoresis of serum proteins revealed a total IgG level of 1500 mg/dL. Elevated levels of two IgG lambda monoclonal antibodies (~ 0.4 g/dL each) with a kappa to lambda ratio of 0.28 were detected by immunofixation of serum samples. The remaining blood values were normal for hemoglobin and calcium levels, but the patient’s kidney function was slightly above normal (creatinine level was 1.4 mg/dL and estimated glomerular filtration rate [eGFR] was 54 mL/min/1.73 m2). A 24-h urine sample was positive for lambda Bence-Jones protein at levels too low to quantitate by immunofixation. Although a skeletal survey was negative for lytic lesions, bone marrow biopsies contained 4.7% of mature looking plasma cells. Additional diagnostic work-up did not suggest multi-organ involvement with scleromyxedema; initial spirometry testing and diffusion lung capacity for carbon monoxide (DLCO) were within normal limits. An echocardiogram indicated the patient had diastolic dysfunction but otherwise normal right and left cardiac function and size with a normal pulmonary artery systolic pressure of 27 mmHg. He was placed on intravenous immunoglobulin G therapy at a dosage of 40 g/mL administered every 6 weeks, with a daily regimen of 60 mg prednisone and 200 mg hydroxychloroquine twice daily. There was significant improvement in the patient’s skin symptoms, and 8 weeks later, his prednisone regimen was weaned down to 5 mg per day. The patient was also started on a thalidomide regimen with an initial dose of 100 mg per day. His IgG levels decreased to 600 mg/dL after one year of maintenance therapy with this regimen. Over the following 4 years post-scleromyxedema diagnosis, the patient had three recurrences of dermatological symptoms of increasing severity. Episodes of acute symptoms were managed by a burst dose and tapering of steroid medication (prednisone at 60 mg daily until resolution of symptoms then a rapid taper to a maintenance dose of 5 mg daily) and increased dose of IVIG. Thalidomide treatment was discontinued 2 years later due to neuropathy, and hydroxychloroquine treatment was considered inefficient for ameliorating symptoms. During this period of time, the patient’s total IgG levels slowly increased to 1700 mg/dL with concurrent elevations in lambda monoclonal proteins ranging from 0.4–0.5 mg/dL and 0.6–0.7 mg/dL. At 4 years post-diagnosis, he experienced an acute episode of skin symptoms and severe dyspnea. Severely elevated levels of brain natriuretic peptide (BNP) (2650 pg/mL), indicative of cardiac strain, were detected in serum, and echocardiographic analysis revealed an enlarged right heart with depressed systolic function and an elevated pulmonary arterial systolic pressure estimated at 70 mmHg. Left ventricular function and size was normal. Abnormal pulmonary hemodynamics (in mm Hg) were measured by right heart catheterization, specifically, pulmonary artery pressures of 66/30/42, wedge pressure of 12, right ventricular pressures at 66/15, and right atrial pressure at 13. The pulmonary vascular resistance was estimated at 8.2 international units (IU), while the cardiac output was elevated at 3.65 L/min. Pulmonary function testing revealed a low DLCO at 50%. A chest computed tomography (CT) scan excluded embolism and parenchymal lung disease as contributing factors to elevated right heart dimensions and pulmonary hemodynamics. Additional laboratory testing of serum proteins detected elevated levels of IgG proteins (3670 mg/dL) and the two lambda monoclonal proteins (1.6 g/dL and 1.3 g/dL). A follow-up bone marrow biopsy revealed an ~ 10% normal appearing population of plasma cells that were considered reactive to the patient’s underlying scleromyxedema. Based on the cardiovascular, pulmonary, and hematological analyses, the patient was diagnosed with a scleromyxedema flare with associated pulmonary arterial hypertension (PAH). He was initially placed on a dual treatment regimen for PAH consisting of 40 mg tadalafil once daily and ambrisentan 5 mg daily that was later increased to 10 mg daily. In addition to increasing the ambrisentan dosage, a daily dose of 40 mg lasix was added to the PAH treatment. Scleromyxedema treatment was optimized with the addition of intravenous chimeric antibodies against CD20 (rituximab) at a dosage and frequency similar to a protocol for rheumatoid arthritis, specifically 1 g of rituximab on days 1 and 15 of the treatment cycle over a period of 24 weeks for a total regimen of three cycles. A burst-taper dose of prednisone was also administered (60 mg, tapered over the next 8 weeks). Over the following year, inhaled trepostinil (vasodilator) was added to the PAH regimen for persistently elevated pulmonary arterial systolic pressure at 42 mmHg and right heart strain on cardiac echography. On this treatment regimen, the patient’s acute symptoms improved, and he maintained a New York Heart Association (NYHA) functional status of class II. Although the patient’s serum BNP levels decreased to 300 pg/mL, echocardiographic analysis continued to show depressed right heart function and elevated pulmonary arterial pressure at 43 mmHg. A polysomnographic analysis indicated the patient had developed obstructive sleep apnea (Apnea–Hypopnea Index [AHI] of 24 events/hour), and he was subsequently treated with continuous positive airway pressure (CPAP) at 10 cmH2O. Intravenous prostacyclin therapy was considered for PAH, but the patient declined. Follow-up immunoglobulin analysis revealed decreased IgG levels (2060 mg/dL). Despite maintenance therapy with IVIG and rituximab, the patient developed another severe recurrence of his skin symptoms and worsening dyspnea at 6 years post-scleromyxedema diagnosis (2 years post-PAH diagnosis). Follow-up echocardiography revealed a new left ventricular cardiomyopathy with an ejection fraction of 40%, persistent elevated pulmonary arterial pressure at 44 mmHg, and persistent right ventricular dilation. Serum BNP levels were elevated at 631 pg/mL, and IgG levels had increased to 3420 mg/dL with concurrent elevations of the two monoclonal lambda proteins at 1.48 and 0.37 g/dL. A follow-up bone marrow biopsy revealed an abnormal plasma cell population of 60% consistent with a hematological abnormality. The patient was diagnosed with multiple myeloma associated with an acute episode of scleromyxedema flare up with multi-organ involvement. A treatment regimen of bortezomib (2 mg; dose adjusted per cycle depending on patient-related factors as denoted in Table ) and dexamethasone (20 mg) (4 weeks per cycle of therapy) was initiated to decrease the plasma cell population, and IVIG treatment was continued to alleviate dermatological symptoms. Over the following 2 years, the patient received a total of seven cycles of bortezomib and dexamethasone. There was a dramatic improvement in his PAH, cardiovascular, and dermatological symptoms. Serum analysis revealed decreased BNP and IgG levels at 100 pg/mL and 1300 mg, respectively. A repeat echocardiogram revealed significant improvement in right ventricular size and function as well as left ventricular function, but pulmonary arterial systolic pressure was still elevated at 51 mmHg. However, bortezomib had to be discontinued after the seventh cycle due to worsening neuropathy. A treatment regimen with a lenalidomide derivative (Revlimid) was attempted but also discontinued after 2 months of treatment due to adverse side effects. The patient elected to halt the inhaled trepostinil regimen. The patient was observed for ~ 14 months before he experienced a recurrence of symptoms and cardiopulmonary decline. His IgG levels had again increased to 2000 mg/dL. The patient was placed on a weekly regimen of 3 mg bortezomib, 20 mg dexamethasone, and 600 mg of cyclophosphamide (Cytoxan) (4 weeks per cycle, last dose omitted because of pancytopenia), and IVIG maintenance therapy was continued at a dosage of 40 g/mL. After four cycles, the patient’s symptoms improved, and his IgG levels decreased to the lowest concentration of 1100 mg/dL. Only one monoclonal lambda protein was detected at 0.52 mg/dL. An echocardiogram revealed normalization of left and right ventricular size and function as well as normalization of pulmonary arterial systolic pressure at 23 mmHg. After a treatment break of 6 months, the patient’s symptoms recurred, and his IgG levels increased above 2000 mg/dL. The patient underwent five additional cycles of bortezomib, dexamethasone, and cyclophosphamide. His IgG levels stabilized between 2000 and 2500 mg/dL, and a repeat bone marrow biopsy revealed a decrease in the abnormal plasma cell population to 22%. A follow-up echocardiogram revealed normal right and left ventricular size and function and a mildly elevated pulmonary arterial systolic pressure at 38 mmHg. Future plans for the patient’s care involved slowly weaning him from his vasodilator medications; however, he suffered a sudden and fatal out-of-hospital cardiac arrest of unclear etiology at 9 years post-scleromyxedema diagnosis. No autopsy was performed.