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The pathological increase of clonal IgM in Waldenström macroglobulinemia can be associated with acquired von Willebrand syndrome and can be a major risk of bleeding symptoms in this subgroup of patients with Waldenström macroglobulinemia. The Bruton tyrosine kinase inhibitor ibrutinib is one of the approved treatments for symptomatic Waldenström macroglobulinemia. However, some controversy exists regarding the use of ibrutinib in these patients with high risk of bleeding because of its antiaggregant effect that could increase the risk of bleeding. Here, we present the case of a patient with Waldenström macroglobulinemia with associated acquired von Willebrand syndrome and progressively significant bleeding symptoms, who experienced a rapid increase in von Willebrand factor with ibrutinib treatment, despite only reaching a partial response in IgM levels similar to those reached with other previous treatments. We suggest that the control over the monoclonal protein is not the only mechanism that explains the good response, improvement in the bleeding symptoms and von Willebrand factor levels. This fact could be explained by the reduced glycoprotein Ib receptor expression induced by ibrutinib and the consequent von Willebrand factor increase in peripheral blood.

The assessment of measurable residual disease (MRD) in bone marrow has proven of prognostic relevance in patients with multiple myeloma (MM). Nevertheless, and unlike other hematologic malignancies, the use of MRD results to make clinical decisions in MM has been underexplored to date. In this retrospective study, we present the results from a multinational and multicenter series of 400 patients with MRD monitoring during front-line therapy with the aim of exploring how clinical decisions made based on those MRD results affected outcomes. As expected, achievement of MRD negativity at any point was associated with improved PFS versus persistent MRD positivity (median PFS 104 vs. 45 months, p p = 0.005). In patients who achieved MRD negativity during maintenance (n = 186) on at least one occasion, stopping therapy in 24 patients vs. continuing in 162 did not alter PFS (mPFS 120 months vs. 82 months, p = 0.1). Most importantly, however, in patients with a positive MRD during maintenance (n = 214), a clinical decision (either intensification or change of therapy) (n = 43) resulted in better PFS compared to patients in whom no adjustment was made (n = 171) (mPFS NA vs. 39 months, p = 0.02). Interestingly, there were no significant differences when MRD was assessed by flow cytometry or by next-generation sequencing. Herein, we find that MRD is useful in guiding clinical decisions during initial therapy and has a positive impact on PFS in MM patients. This potentially opens a new dimension for the use of MRD in MM, but this role still remains to be confirmed in prospective, randomized clinical trials.

Background Anti-CD38 monoclonal antibodies (Mab) have significantly improved the prognosis of patients with multiple myeloma. However, not all patients sustain durable responses. Patients relapsed or refractory (R/R) to anti-CD38 Mab present dismal prognosis and constitute a group for whom therapeutic needs are still not defined. We aimed to describe the natural history of patients relapsed or refractory to CD38 monoclonal antibodies. Methods Unicentric retrospective analysis of 57 MM patients R/R to anti-CD38 Mab. Refractoriness was defined as progression within the first two months of treatment. We used chi-square test to compare categorical variables, the Kaplan-Meier method and log rank test for the survival analysis and multivariable analysis using logistic regression. IBM SPSS (v25.0) was used for the statistical analysis. Results The median age was 66 years, 57.9% were female. The cohort received a median of 2; R(0-11) lines of treatment previous to anti-CD38 Mab. 49% had undergone autologous transplant and 64.9% had received a proteasome inhibitor and an immunomodulatory previously. 21 patients (37%) were refractory and 20 (35%) achieved very good partial response or better response. The most frequent combinations were with lenalidomide (DRd; 11%), bortezomib (DVd; 16%), bortezomib and melphalan (D-VMP; 13%) and with carfilzomib (KDd; 27%). 26% received daratumumab in monotherapy or with corticosteroids. Median time to treatment progression was 7 months and median overall survival (OS) was 12 months for the global cohort. OS was longer in patients who achieved a deeper response (49, 12 and 4 months for patients with complete response, partial response and stable disease or progression respectively; p=0.001). High cytogenetic risk was related to poor outcomes, with an OS of 5 months and more frequent CD38 Mab refractoriness (63% vs 37% for the global cohort; p=0.007). Resistance to daratumumab as a first line treatment was observed in 8 patients. 7 of them were treated within a clinical trial for non eligible AHCT patients Median time to daratumumab progression within this group was 12 months and median OS was 49 months. 49 (86%) of the patients received at least one line of treatment after anti-CD38 Mab R/R and 47% of them had and objective response to at least one of the subsequent therapies employed, with median progression free survival (PFS) of 5 months. Daratumumab-resistant patients had longer OS when treated with regimens containing pomalidomide compared to other agents (median OS 26 vs 6 months respectively; p= 0.021). Conclusion Patients R/R to CD38 targeted monoclonal antibodies present dismal prognosis, with a median OS of 12 months. Patients with high cytogenetic risk have worse outcomes, with shorter OS and higher probability to anti-CD38 Mab refractoriness. Treatment with pomalidomide-based regimens may be an interesting option for this population. The authors declare no conflicts of interest.

Background: The impact of coronavirus disease 2019 (COVID-19) on hematological patients has not been comprehensively reported to date. Methods: We analyzed 39 hematological patients diagnosed with SARS-CoV-2 infection at our institution from March 7 to April 7, 2020. Clinical characteristics and outcomes were compared to a matched contemporary control group of 53 non-cancer patients hospitalized at our center. Univariate and multivariate analyses were carried out to assess the risk factors associated with poor outcome. Results: Median patient age was 64.7 years (range 36-88 years). The most frequent hematological diseases were lymphoma (30%), multiple myeloma (30%), and chronic lymphocytic leukemia (15%). On the WHO severity scale, 12.8% of the cancer patients were classified as mild, 41% as moderate, and 46.2% as severe. Most of the hematological patients were treated with hydroxychloroquine (89%) and lopinavir/ritonavir (79.5%); 51% of the patients received corticoids and 30.8% (n=12) received tocilizumab. In the multivariate analysis, we observed that only age >70 years and C reactive protein >10 mg/dl were associated with higher risk of death (odds ratio 34.86 (3.407-356.8) and 13.56 (1.28-143.45), respectively). An unfavorable impact of chemotherapy administration on COVID-19 outcome was not demonstrated. The non-hematological and hematological patients had similar clinical and laboratory characteristics; however, but mortality was higher in hematological patients (35.9% vs. 13.2%; Odds Ratio 6.5; 95% CI=1.868-23.688; P=0.003). Conclusion: Patients with hematological malignancies had a similar incidence of COVID-19, but the severity and mortality were much higher than in non-cancer patients even in the absence of therapy. Funding Statement: This work received funding from the research contract COV20/00181 from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III. Our research group was supported by the Fundacion Cris contra el cancer. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This retrospective study was approved by the Hospital Universitario 12 de Octubre Institutional Review Board (n 20/182).

Background Multiple myeloma (MM) constitutes approximately 10% of haematological malignancies, with a median age at diagnosis of 65 years. Patient survival has improved considerably over the last 20 years with the introduction of new drugs. In 1999, the first immunomodulatory drug, thalidomide, was approved, followed by lenalidomide in 2005 and pomalidomide in 2013. In 2003, proteosome inhibitors such as bortezomib were introduced and carfilzomib in 2014. In 2015, anti-CD38 monoclonal antibodies such as daratumumab were added to the treatment schemes. We have analyzed the impact on the outcome of the introduction new drugs for MM in the last 20 years in our institution. Methods A total of 862 patients diagnosed with symptomatic multiple myeloma between 1999 and 2020 in a tertiary care hospital in Spain, Hospital 12 de Octubre in Madrid, were retrospectively analysed. Survival by age was evaluated over the years, establishing three groups: 1999-2005, 2005-2015 and 2015-2020. Kaplan-Meier analysis was used for analyzing overall survival, and differences between groups were tested for statistical significance using the log-rank test. Results A total of 862 patients were included in the study. There were 409 men (47.45%) and 453 women (52.55%). The median age at diagnosis was 69 years. Among the group of patients younger than 65 years, the median survival among patients treated between the period 1999 to 2005 was 49.28 months (16.86-81.70; 95%); 78.42 months (49.83-107.01; 95%) between the years 2005 to 2015 and the median is not reached between the years 2015 to 2020 (p=0.001). Equally significantly, patients younger than 75 years have improved survival over the years. Median survival among patients treated between 1999 and 2005 was 43.43 months (23.86. 63.00; 95%); 58.80 months (43.38-74.23; 95%) between 2005 and 2015 and the median is not reached between 2015 and 2020 (p Conclusion The introduction of new agents in the treatment of multiple myeloma has transformed the natural history of the disease, achieving long survival times in younger patients. Thus, it is essential to continue to advance and develop new therapies, as has been the case in recent years with the emergence of antiBCMA therapies.