TTP disease course is independent of myeloma treatment and response

To the editor: Thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia, hemolytic anemia, and microvascular thrombosis with ischemic injury to organs. Multiple myeloma is a B-cell malignancy with a terminally differentiated plasma cell phenotype characterized by lytic bone lesions, renal insufficiency, anemia, hypercalcemia, and humoral as well as cell-mediated immunodeficiency. In this report, we provide a longitudinal study of two cases of acquired TTP associated with multiple myeloma. Both patients had severe ADAMTS13 deficiency and an elevated ADAMTS13 inhibitor titer at diagnosis, but the diagnosis of TTP and response to plasma exchange (PE) appeared to be independent of the patient’s myeloma disease state. The first patient is a 50 year old African American male with no significant past medical history that complained of low back pain for three months prior to inpatient admission for multiple thoracic and lumbar compression fractures, serum calcium of 10.4 mg/dL, and creatinine 3.6 mg/dL. Bone marrow biopsy showed 75% plasma cells and a normal karyotype. Thalidomide and weekly dexamethasone led to a very good partial response (VGPR)(1), but a monoclonal protein plateau and the development of peripheral neuropathy led to a switch to lenalidomide and weekly dexamethasone for six months. At a time when his monoclonal protein level was stable, he was admitted to the hospital for three episodes of syncope, chest pain, mental status changes, and admission studies showed a non ST-segment elevation myocardial infarction with a troponin of 6 mg/dL, LDH 2046 U/L, platelets of 8,000/mm3, hemoglobin of 9.9 g/dL, and 3+ schistocytes per high power field. Dipyridamole sestamibi cardiac perfusion study and transthoracic echocardiogram were both normal and it was felt the NSTEMI was due to microthrombi from TTP. He initially improved with daily PE for six days with normalizing platelet and LDH, but when PE was held for one day, he suffered mental status changes, a 50% rise in LDH, and a 50% drop in his platelet count. He was started on cyclosporine 2 mg/kg twice daily as we have previously reported (2–3) and the volume of his exchanges were increased. He subsequently achieved clinical response after 7 additional daily exchange treatments. At the time of discharge his LDH and platelet count were both normal and he continued cyclosporine twice daily. Five months later his monoclonal protein continued to rise without symptoms, his TTP remained in remission, and cyclosporine was discontinued. As shown in the figure panels A–C, we examined ADAMTS13 activity, ADAMTS13 antigen levels, ADAMTS13 antibody (IgG) concentration, as well as the antibody inhibitory titer, over the entire course of the disease and follow up visits. Figure Longitudinal evaluation of laboratory values in patients with multiple myeloma and TTP. Panels A–C reference a patient who has TTP diagnosed during a period of disease stability of his myeloma and responds to plasma exchange (PE) and cyclosporine ... The second patient is a 50 year old female with a history of major depression who developed TTP in 1993 with a platelet count of 37,000/mm3 and an LDH of 376 U/L. She was successfully treated with an infusion of three units of fresh frozen plasma per day for five consecutive days. Because of a monoclonal IgA-kappa paraprotein (IgA 903 mg/dL) without other signs or symptoms of myeloma, she was thought to have an IgA monoclonal gammopathy of undetermined significance (MGUS). Thirteen years later she was seen in our medical center with a platelet count of 25,000/mm3, LDH of 390 U/L, and she complained of abdominal pain. Her ADAMTS13 activity was found to be 0.7% with an inhibitory titer of 1.0 BU. Daily infusions of fresh frozen plasma were attempted with an improvement in her abdominal pain, but without a complete clinical recovery of her TTP. Her platelet count remained at approximately 80,000/mm3 with an LDH at 300 U/L. Cyclosporine was added at 2 mg/kg twice daily (2–3) and over the next two months her platelet count stabilized at 60,000–80,000/mm3 but with an ADAMTS13 activity less than 5.5%. Her cyclosporine was then increased to 2.5 mg/kg twice daily, but there was a gradual decrease over the next six months in her platelet count with an increasing creatinine and calcium. She then presented with abdominal pain, petechiae, and bruising with a platelet count 28,000/mm3, hemoglobin 8.8 g/dL, creatinine 2.1 mg/dL, LDH of 398 U/L, and new onset hypercalcemia (12.1 mg/dL); schistocytes were not present on her peripheral smear. Urgent PE was initiated. Further testing revealed new thoracic and lumbar compression fractures and an IgA of 2623 mg/dL due to an IgA kappa myeloma with 40% kappa light chain restricted plasma cells on bone marrow biopsy. Daily PE for three sessions did not yield an improvement by any parameter and, after bone marrow biopsy results were available, she was started on bortezomib 1.3mg/m2 with 20 mg intravenous dexamethasone prior to each infusion. After one cycle her platelets had doubled and creatinine normalized. After three cycles her platelets were normal and remained normal afterward as she received a total of eight cycles of bortezomib and dexamethasone. In the meantime, her ADAMTS13 antibody (IgG) concentration and inhibitory titer were remarkably reduced but her ADAMTS13 activity and antigen remained low. Her serum immunofixation remained positive and approximately 10 months later she went on to autologous hematopoietic stem cell transplantation with melphalan 200 mg/m2. She had a very good partial response (VGPR)(1) to autologous transplant, but, for the first time, her ADAMTS13 activity level normalized along with a parallel increase of her ADAMTS13 antigen level. Her serial ADAMTS13 activity, antigen, autoantibody, and inhibitor titers are shown in the figure panels D–F. Five months after transplant, her monoclonal protein level was barely detectable, signifying stable myeloma disease, but her ADAMTS13 activity disappeared with a rise in her ADAMTS inhibitor titer. In summary, this study reports the first two cases of a comprehensive longitudinal evaluation of acquired TTP arising in association with multiple myeloma. We have carefully documented the clinical evolution of TTP, collected serial specimens from these patients, and performed a comprehensive study of the ADAMTS13 biomarkers with respect to the clinical course of TTP. The development of idiopathic TTP is related to the impairment of the activity of ADAMTS13, a key metalloprotease that cleaves von Willebrand factor (vWF) multimers and prevents vWF-induced platelet thrombosis (4). The majority of idiopathic adult TTP patients have detectable levels of autoantibodies to ADAMTS13 (5) and respond well to PE. Differing from idiopathic TTP, secondary TTP associated with stem cell transplantation, also known as transplant-associated thrombotic microangiopathy (TA-TMA), is not associated with severe ADAMTS13 deficiency (6) and typically does not respond to PE (7). In the two reported cases of secondary TTP after autologous stem cell transplant in patients with myeloma, no ADAMTS13 deficiency was documented and PE failed (8). In our first patient, during a period of disease stabilization, the patient’s immune system was able to mount a sufficient ADAMTS13 autoantibody response that required treatment with both PE and cyclosporine. In the second patient, at the time of progression from MGUS to multiple myeloma, her clinical presentation had features of both TTP and myeloma. Her symptoms and hematologic parameters did not resolve until she received effective treatment for her myeloma, but her ADAMTS13 activity remained low. Interestingly, bortezomib, a drug known to cause significant thrombocytopenia in patients with relapsed myeloma, normalized her platelet count within two cycles. After high dose melphalan followed by autologous stem cell rescue, her ADAMTS13 activity level normalized. We hypothesize that high dose chemotherapy prior to autologous stem cell transplantation depleted the B-cell clone responsible for ADAMTS13 autoantibody production, theoretically in agreement with the immune reset hypothesis for autologous transplant in refractory autoimmune disease (9–10). Unfortunately high dose intravenous melphalan followed by stem cell rescue did not prevent a biochemical recurrence of her TTP five months after transplant. In conclusion, the response to treatment of each of the patient’s TTP was independent of the myeloma disease state. The second patient’s course reveals that high dose intravenous melphalan followed by autologous stem cell rescue has activity in both myeloma and TTP.