A 77-year-old man presented to an outpatient dermatology clinic primarily concerned with skin rashes that persisted for about a year, mainly on his knees, feet, and hands. Some lesions on his feet exhibited minor skin changes suggestive of ischemia. Skin biopsies were performed from a purpura on the feet and an erythema on the hand, revealing numerous fibrin thrombi within small vessels and intravascular inflammatory findings, indicative of leukocytoclastic vasculitis. Regarding vascular risk factors, the patient was an ex-smoker with a history of 20 pack-years and had no history of hypertension, diabetes, or hyperlipidemia. Blood tests showed an elevated IgG level (4208 mg/dl) with other immunoglobulin classes near the lower limits of normal, along with cryoglobulinemia (Fig. 1a). Autoimmune and viral serologies, including hepatitis C, were negative. Immunofixation electrophoresis (IFE) identified two bands of IgG-λ type, indicating aggregation of cryoglobulin (Fig. 1a). The bone marrow examination revealed 3.8% of plasma cells with CD38 + , CD19−, and light chain restriction to lambda, suggesting an abnormal plasma cell population. These findings indicated type I cryoglobulinemia. Upon PET-CT evaluation, no evidence of lymphadenopathy, hepatic or splenic involvement, or other extramedullary manifestations was detected.

A comparative visualization of cryoclots and serum immunofixation electrophoresis at diagnosis and post-treatment. B Timeline of the clinical progression and treatment interventions. IFE immunofixation electrophoresis, PE plasma exchange, FLC free light chain

Immunosuppressive therapies, including methylprednisolone pulse therapy (1000 mg/day, 3 days) followed by oral prednisone, high-dose cyclophosphamide (500 mg/m2), and weekly rituximab (375 mg/m2) for 4 weeks, were initially applied by the Dermatology department, ending in a modest reduction in the IgG level to 2005 mg/dl.

A few months later, the patient was emergently hospitalized due to a high fever and subsequently transferred to our department. There was no clinical, laboratory, or imaging evidence of infection. Severe progression of skin necrosis suggested exacerbation of cryoglobulinemia-associated vasculitis. Re-elevation of the IgG level (4,238 mg/dl) prompted the initiation of plasma exchange therapy to reduce cryoglobulins. The bone marrow examination revealed 10% CD138-positive plasma cells in the marrow clot section, while the smear showed 9%. These findings fulfill the diagnostic criteria for multiple myeloma, with anemia serving as a myeloma-defining event.

As causative therapy, we initiated Vd therapy with doses adjusted for frailty comprising bortezomib (1.0 mg/m2) and dexamethasone (20 mg/body) on days 1, 8, and 15 of a 28-day cycle [16,17,18]. The use of immunomodulatory drugs was precluded by deep vein thrombosis detected on ultrasound examination. Despite the initiation of this therapy, there was a gradual increase in IgG levels. Bone marrow aspiration performed 20 days after treatment initiation revealed 11% plasma cells, indicating a lack of response to the therapy. We added weekly daratumumab (16 mg/kg), transitioning to DVd therapy [19] and escalated bortezomib to 1.3 mg/m2 to intensify treatment, while maintaining a 28-day cycle. Although the regimen moderately reduced serum IgG levels and temporarily made cryoclots undetectable during the first two cycles, a recurrence in IgG levels and the reappearance of cryoclots was observed during the subsequent two cycles. The progression of skin necrosis, particularly in the knees and feet, persisted, leading us to prepare for above-knee amputation of both legs. We altered the regimen to KCd therapy in unfit doses, comprising carfilzomib (36 mg/m2), cyclophosphamide (150 mg/m2) administered on days 1, 8, and 15 of a 28-day cycle with weekly dexamethasone (20 mg/body) [13,14,15, 18]. Cyclophosphamide was included to enhance therapeutic efficacy, as dose escalation of carfilzomib was limited by frailty and immunomodulatory drugs were contraindicated due to persistent deep vein thrombosis. It quickly decreased serum IgG levels and eliminated cryoglobulins, enabling discontinuation of plasma exchange therapy. The ischemic lesions showed marked improvement. The necrosis in the lesions below the ankles had already progressed to an irreversible stage, still requiring amputation. However, as the blood flow in the knees had improved, the amputation was performed below the knees on both lower limbs. As a representative indicator of the necrotic lesions, the time-series images of the knee lesions are illustrated in the clinical chart (Fig. 1b).

Nine cycles in total were completed without severe non-hematological toxicity. With the subsequent ongoing carfilzomib maintenance, no progression of symptoms or re-emergence of cryoclots has been detected for over 3 years, while IFE remained positive for IgG-λ throughout the entire clinical course.