Thrombotic microangiopathy during carfilzomib use: case series in Singapore

Carfilzomib is an irreversible proteasome inhibitor and is an effective treatment for multiple myeloma (MM). It received US Food and Drug Administration approval based on a single-arm multicenter trial of carfilzomib monotherapy in 266 patients with relapsed MM following at least two prior lines of treatment including bortezomib and immunomodulators. Safety analyses from four phase II carfilzomib trials (N= 526) that included heavily pre-treated MM patients suggested a favorable risk-benefit profile with no specific signal of thrombotic microangiopathy (TMA) reported. However, serious adverse events of anemia, thrombocytopenia and increased serum creatinine comprised 1.3%, 1.1% and 1.3%, respectively. Over 350 subjects have been enrolled in randomized phase III trials in Asian countries. Herein, we report four cases of TMA related to carfilzomib use among 24 patients from 2 tertiary hospitals in Singapore (Table 1). All patients who started carfilzomib had a creatinine clearance 430 ml/min and platelet counts450 × 10/l at the start of treatment. Patients 1 (70/Chinese/Male) and 2 (66/Chinese/Female) had newly diagnosed MM and were treated in an institutional review board-approved investigator-initiated study (IIS) using carfilzomib in combination with cyclophosphamide and dexamethasone as frontline therapy for high-risk MM (SGHMM1, NCT02217163). Within this trial, carfilzomib is given at 20 mg/m in cycle (C) 1, days (D) 1 and 2 followed by 56 mg/m for all subsequent doses as tolerated. Patient 1 had reported fever and flu-like symptoms on C2D2. The carfilzomib dose on C2D2 was postponed to C2D3 after fever resolved. He developed grade 1 diarrhea the day after, and on C2D6 hemoglobin declined from 7.5 to 5.3 g/dl and platelets dropped from 105 × 10 to 5 × 10/l. This was accompanied by emergence of schistocytes on the blood film and an acute rise in serum creatinine (209 μmol/l from 97 μmol/l). Hemolytic screen was positive (LDH 1833 U/l, bilirubin 24 μmol/l, reticulocyte index 2.6, haptoglobino0.1 g/l) with a negative Coomb’s reaction. Prothrombin time (PT) was 11.7 s and activated partial thromboplastin time (APTT) was 27.2 s. The diagnosis of TMA was made, and carfilzomib was discontinued. Rhinovirus was tested positive from throat swabs, stool cultures were negative and ADAMTS13 activity was normal. Platelet counts and renal function recovered to baseline 4 days after diagnosis of TMA and cessation of carfilzomib. Patient 2 presented on C2D8 with symptoms of anemia and a dry cough. Investigations showed Hb 6.1 g/dl (from 9 g/dl), WCC 2.88 × 10/l and platelets 55 × 10/l (from 351 × 10/l) with schistocytes seen on blood film and positive hemolytic screen. Acute kidney injury was noted with a rise in serum creatinine from 93 to 573 μmol/l. The patient had no evidence of infection and ADAMTS13 activity was 88% and there was no coagulopathy. The last dose of carfilzomib was on C2D2 and no further carfilzomib was administered. The patient required temporary hemodialysis but not plasmapheresis. Her platelet counts recovered after 7 days and renal function normalized after 1 month. Patient 3 (63/Chinese/Male) had a 10-year history of MM and had previously received multiple lines of therapy including VAD (vincristine, doxorubicin and dexamethasone), high-dose melphalan (HDM) with autologous hematopoietic stem cell transplant (HSCT), bortezomib and immunomodulatory agents. Carfilzomib 27 mg/m and dexamethasone were commenced. Blood counts at treatment initiation were: Hb 10.5 g/dl, WCC 3.13 × 10/l and platelets 224 × 10/l. On C2D15, he presented with fever, diarrhea, cough and tested positive for parainfluenza B virus. Three days later, he developed acute kidney injury (creatinine 403 μmol/l from 76 μmol/l) accompanied by thrombocytopenia (platelets 3 × 10/l) and non-immune hemolytic anemia. There was no coagulopathy (PT 9.9s, APTT 34.0s). Stool was negative for Escherichia coli. Carfilzomib was held off and he was expectantly monitored. He did not require plasma exchange. Platelet counts recovered to baseline after 25 days and renal function recovered after 60 days. Patient 4 (58/Chinese/Male) had a 2-year history of MM and had received induction with bortezomib, cyclophosphamide, dexamethasone followed by HDM and autologous HSCT. He had relapsed within 12 months of HDM, while receiving lenalidomide maintenance and was given two cycles of bortezomib-DCEP (velcade, dexamethasone, cyclophosphamide, etoposide and