Successful treatment of acquired von Willebrand syndrome associated with monoclonal gammopathy

Acquired von Willebrand syndrome is exceedingly rare and accounts for only 1–3% of von Willebrand disease cases. In this short report, we present our own cases of acquired von Willebrand syndrome associated with monoclonal gammopathy. Both cases went into complete and sustained remission after intensive antimyeloma treatment. The first patient was not deemed fit for autologous stem cell transplantation and was managed with an extensive multidrug combination including daratumumab, carfilzomib, lenalidomide, cyclophosphamide and dexamethasone. After at least VGPR was achieved the coagulation studies rapidly normalized and remained normal after treatment de-escalation to lenalidomide/dexamethasone maintenance. The second patient successfully underwent ASCT after 5 cycles of induction with daratumumab, bortezomib, cyclophosphamide and dexamethasone and has remained in full hematologic and hemostaseologic remission ever since. The two cases highlight the efficacy of aggressive antimyeloma treatment in monoclonal gammopathy-associated acquired von Willebrand syndrome to achieve normalization of coagulation study, providing a possible way to manage these patients.

The underlying pathogenetic mechanisms of monoclonal gammopathy-associated avWS (MG-avWS) are complex and incompletely understood. They include rapid sequestration especially of large and ultra-large von Willebrand factor (vWF) multimers after binding to monoclonal antibodies [2,3]. Detection of these antibodies is sometimes possible [4]; however, specific tests are not available.
In the setting of avWS due to MGUS, which represents the majority of patients with MG-avWS, treatment has for many years focused on approaches specific for the bleeding diathesis, including desmopressin analogues (DDVAP), vWF concentrates and high-dose intravenous immunoglobulin (IVIG) [5][6][7]. While the coagulation parameters after administration of IVIG may improve for up to 3 weeks, vWF concentrates and DDVAP only produce short-lived responses up to 24 h. Several case series have demonstrated their effectiveness to prevent major bleeding complications during invasive procedures [3,5,[8][9][10]. It is known, however, that avWS in patients with lymphoproliferative neoplasms can be improved by treatment directed against the malignant clone. While 478 Successful treatment of acquired von Willebrand syndrome associated with monoclonal gammopathy K short report in patients with end-organ damage related to MM, immediate treatment is required and recommended according to international guidelines, the approach in avWS patients with MGUS or SMM without end-organ damage or formal treatment indications is less clear [11]. Several groups reported improvement or even normalization of MG-avWS following antimyeloma treatment [12][13][14].
Here, we present two patients with MG-avWS who were successfully treated with antimyeloma treatment. While both patients had a history of spontaneous and trauma-associated bleeding events, the extent and severity of the bleeding disorder differed. They were counseled on their condition and the possible association with the underlying MG. Despite not fulfilling the international myeloma working group criteria for MM, both opted for the initiation of antimyeloma treatment. They provided informed consent and were aware of the experimental nature of this approach. Baseline characteristics at the time of diagnosis of MG-avWS, interventions and outcomes are provided in Table 1.

Discussion
In summary, both patients treated with clonal directed therapy showed a normalization of coagulation tests through eradication of the paraprotein. These findings serve as indirect proof of a causal relationship between the clonal paraprotein and the clinically significant bleeding disorder characterized as avWS.
To date, no standard treatment guidelines are available for this distinct and rare disorder. As for inherited vWS, DDAVP and factor replacement is recommended but results in only very short-lasting effects. The IVIG is also effective with a slightly longer response duration. None of these interventions, however, can induce a stable and durable response because they have no effect on the pathomechanisms of the bleeding disorder.
In the case of avWS-MGUS, a potentially reversible and even curable underlying condition is present, since the monoclonal paraprotein is the primary cause of the disease. Therefore, targeting the malignant plasma-cell clone as the root of evil seems to be of major importance; however, as reflected by both cases partial elimination of the disease-initiating clone seems insufficient. The persistence of paraprotein is associated with persistence of avWS and even small amounts of the paraprotein maintain the pathologic process. Only the full eradication of the clone with undetectable paraprotein levels led to durable responses with complete resolution of the bleeding disorder.
A number of recently published cases reported encouraging results with clonal directed treatment [12][13][14]; however, the experience from these cases showed that remissions were less likely to be durable if single drug regimens were used or if the treatment was discontinued prematurely, i.e. before the causative plasma cell clone was sufficiently eradicated.
Based on these observations, we favor an approach similar to overt MM, where induction therapy is central and should be an intensive multidrug combination-treatment. In recent years, even quadruplet regimens have been tested in phase 3 trials. The aim of defining the most effective first-line therapy is the induction of a long-lasting remission. This holds true in MM and likely in MG with clinical significance. In selected cases, the eradication of a plasma cell clone although rather small could possibly represent a curative approach.
In summary, we successfully treated two avWS-MG patients with intensive but risk-adapted multidrug regimens and eradicated the malignant plasma cell clone. Consequently, the life-threatening MG-related bleeding disorder completely resolved in both patients. Based on our findings, complete eradication of the malignant plasma cell clone seems to be of pivotal importance to achieve durable responses or possibly even cure of the potentially life-threatening bleeding disorder. Given the rarity of the disease we encourage international collaborations for generating larger data sets and prospective clinical trials to build upon our findings.
Author Contribution GJ collected and analyzed the data. GJ, HA, SEH, and MTK reviewed the data and wrote the manuscript. Ethical standards For this article no studies with human participants or animals were performed by any of the authors. All studies performed were in accordance with the ethical standards indicated in each case. The patients provided informed consent to be included in this case report.
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