Monoclonal gammopathy‐associated thrombotic microangiopathy (2019)

Thrombotic microangiopathy (TMA) represents a heterogeneous group of clinical syndromes with end-organ damage resulting from endothelial injury secondary to a variety of etiologies.1 Manifestations of TMA can be divided into peripheral which include thrombocytopenia and microangiopathic hemolytic anemia (MAHA), and renal including vascular thrombosis, mesangiolysis, endothelial swelling, and subendothelial accumulation of cellular material.2 Malignancy-associated TMAs most commonly involved metastatic solid organ malignancies, usually with bone marrow infiltration.3 There is a growing interest in the relationship between TMA and monoclonal gammopathies. Monoclonal gammopathy can be seen but not exclusive to monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and Waldenström macroglobulinemia (WM). In one study of 146 patients with TMA, monoclonal gammopathy was present in 13.7%.2 MGUS was the most common diagnosis (n = 15), followed by POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome (n = 2) and smoldering MM (n = 1), MM (n = 1), and 1 with a T-cell lymphocytic leukemia. It is important to note that some of these cases occur after infection, chemotherapy or hematopoietic stem cell transplantation in which the TMA cannot be directed attributed to the monoclonal gammopathy. In order to study the relationship between TMA and monoclonal gammopathy, we describe nine cases of TMA that occurred either as an initial presentation or at the time of relapse. Cases were identified from six institutions in the United States and Canada by retrospective chart review. TMA diagnosis was confirmed either by histologic evidence of TMA (most commonly on kidney biopsy) or the presence of thrombocytopenia (platelet count less than 150 x 109/L) and evidence of MAHA (schistocytes on peripheral smear, elevated lactate dehydrogenase [LDH], decreased haptoglobin, and indirect hyperbilirubinemia). Nine patients were identified, three (33.3%) were female. They had a median age of 66 years (Table 1). Five patients had MM, one had WM, and 3 had MGUS. Four of the 5 patients with MM never received prior treatment. Two had newly diagnosed MM and 2 had smoldering MM who were being observed without treatment. The fifth patient had previously received a course of melphalan and prednisone. The patient with WM was previously treated with cyclophosphamide, rituximab, and dexamethasone. No patient had otherwise received any medication associated with drug-induced TMA. All patients had renal involvement based on creatinine elevation from their baselines, and seven patients had renal biopsies performed which all demonstrated TMA. While all patients developed renal TMA with acute kidney injury (AKI), not all patients developed peripheral TMA. Median creatinine was 3.3 mg/dL. Median hemoglobin and platelet count were 108 g/L and 147 x 109/L, respectively. Six patients had thrombocytopenia with platelet count <150 x 109/L, and of those, only four individuals exhibited evidence of MAHA. No patient had GI symptoms, and AST and ALT were normal when obtained (n = 7). ADAMTS13 level was only obtained in one patient and was non-deficient at 27%. Complement levels (C3, C4, total complement) were obtained in six patients, and were normal in all but one patient who had a low C4. Genetic testing for mutations in the alternative complement pathway was performed in two patients and were normal. Three patients were treated initially with plasma exchange (PLEX). One patient (Patient 3) began to improve after initiation of PLEX, but died of multiorgan failure six days after presentation. One patient is awaiting treatment plan from hematology. The others have had resolution of TMA without recurrence. None of the patients received eculizumab. Illustrative Cases Patient 1 was a 70-year-old gentleman with smoldering MM who had been monitored without treatment. He was found to have AKI, so kidney biopsy was performed, which demonstrated acute TMA, but no involvement of MM (Figure 1). There was no evidence of systemic hemolysis. Myeloma directed therapy was initiated, with improvement in renal function. He did not develop any systemic hemolysis. Patient 3 was a 79-year-old woman with a history of MM diagnosed two years prior, who had been treated with melphalan and prednisone with a partial response with a M-spike at 1.4 g/dL. Given this plateau, therapy was held. Two months later, she presented with fatigue and was noted to have significant AKI (Cr 4.9 mg/dL from baseline 0.8 mg/dL), MAHA with progressive cytopenias and LDH of 983 U/L. M-spike had increased from 1.4 g/dL to 4.9 g/dL. PLEX and intravenous fluids were initiated, but she had progressive respiratory distress and hypotension and died six days after presentation. Patient 6 was a 57-year-old gentleman admitted for lethargy and weakness. He was noted to have new pancytopenia and AKI, and WM was confirmed by bone marrow biopsy and labs (IgM 4791 mg/dL). At diagnosis, LDH was 255 U/L, and no other markers of hemolysis were obtained at that time. He was treated with cyclophosphamide, rituximab, and dexamethasone, with improvement in symptoms and blood counts. Five months later, he was admitted with dyspnea and was found to have recurrence of WM. At that time, he was found to have new hemolysis with LDH 554 U/L, undetectable haptoglobin, and schistocytosis. He also developed new seizures. Renal biopsy was consistent with TMA, and he was treated with PLEX and disease directed therapy with rituximab, bortezomib, and dexamethasone, with resolution of TMA. We describe here nine cases of TMA in patients with newly diagnosed or relapsed hematologic conditions with monoclonal gammopathy. These patients were selected because they lack recent chemotherapeutic therapy or exposure to medications prior to development of TMA. TMA associated with monoclonal gammopathy in the absence of confounders such as treatment with chemotherapy, proteasome inhibitors, or hematopoietic stem cell transplant are rare in the literature. The reduction of confounder factors hopefully suggests a stronger association between monoclonal gammopathy and TMA. The mechanisms of monoclonal gammopathy-associated TMA are not fully understood. Cases involving inhibitors to ADAMTS13 or complement component (anti-factor H antibody) have been reported.4, 5 These patients presented with features of thrombotic thrombocytopenia (TTP) or atypical hemolytic uremic syndrome (aHUS). Similar to the patients in our series, the TMA in these cases resolved with treatment of the MM. Other mechanisms involving interactions between the monoclonal immunoglobulin and von Willebrand factor or platelet membrane glycoprotein 1b have also been suggested. It seems likely the monoclonal proteins can mimic the behaviors of the polyclonal immunoglobulins that are involved in pathogenesis of TTP and aHUS. Limitations of this study include the small number of cases obtained. Monoclonal gammopathy associated TMA appears to be a rare complication. Ravindran et al.2 noted that in their series, the frequency of monoclonal gammopathy in patients with TMA was approximately five times what would be expected based on the frequency of monoclonal gammopathy in the general population. There are certainly plausible potential mechanisms for TMA related to paraproteinemia, though further study is needed here, and the improvement in TMA after treatment of the plasma cell disorder argues for an association. Another limitation is the incomplete evaluation for alternate etiology of TMA in the patients. While medication lists, comorbidities, and a history of hematopoietic stem cell transplant were considered and did not demonstrate any clear other cause of TMA, a more thorough evaluation with ADAMTS13 and alternate complement pathway testing including genetic mutation studies would help clarify the pathogenic mechanisms involved in monoclonal gammopathy associated TMA. In the absence of this information, these other etiologies cannot be excluded. It is also unclear if there are differences in pathogenesis or response to treatment for patients who only have renal-involvement of TMA, compared to those with peripheral TMA. In conclusion, we presented nine cases of TMA that strongly suggest the involvement of the monoclonal gammopathy. In addition to the typical association with solid tumors and bone marrow infiltration, monoclonal gammopathy from B-cell lymphoproliferative disorder and plasma cell disorders should also be considered a potential etiology of malignancy-associated TMA. While peripheral TMA with significant MAHA was not seen in all cases, kidney dysfunction was prominent, and TMA should be considered as another potential mechanism of kidney injury in patients with monoclonal gammopathy. It is in this context that the International Kidney and Monoclonal Gammopathy Research Group (IKMG) recently gave TMA a provisional status as one of the kidney lesions associated with monoclonal gammopathy of renal significance (MGRS).6 In these cases, disease-directed therapy should be considered first-line treatment of TMA, in addition to PLEX if there is ADAMTS13 deficiency. AD has received clinical trial funding from Takeda, Pfizer, Prothena, Celgene, Janssen, and Alnylam. She is also a consultant of the Alnylam Disease Progression Advisory Board. NL has research funding from Omeros and is on an advisory board for Takeda, BTG, Aduro and Prothena. IG has Pfizer stocks. IG is also supported by NIH/NCI Cancer Center Support Grant P30 CA008748. KDJ is a consultant for Astex Pharmaceuticals.