Management of patients with multiple myeloma and COVID-19 in the post pandemic era: a consensus paper from the European Myeloma Network (EMN).

In the post-pandemic COVID-19 period, human activities have returned to normal and COVID-19 cases are usually mild. However, patients with multiple myeloma (MM) present an increased risk for breakthrough infections and severe COVID-19 outcomes, including hospitalization and death. The European Myeloma Network has provided an expert consensus to guide patient management in this era. Vaccination with variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4/5 strains, is essential as novel strains emerge and become dominant in the community. Boosters should be administered every 6-12 months after the last vaccine shot or documented COVID-19 infection (hybrid immunity). Booster shots seem to overcome the negative effect of anti-CD38 monoclonal antibodies on humoral responses; however, anti-BCMA treatment remains an adverse predictive factor for humoral immune response. Evaluation of the immune response after vaccination may identify a particularly vulnerable subset of patients who may need additional boosters, prophylactic therapies and prevention measures. Pre-exposure prophylaxis with tixagevimab/cilgavimab is not effective against the new dominant variants and thus is no longer recommended. Oral antivirals (nirmatrelvir/ritonavir and molnupiravir) and remdesivir are effective against Omicron subvariants BA.2.12.1, BA.4, BA.5, BQ.1.1 and/or XBB.1.5 and should be administered in MM patients at the time of a positive COVID-19 test or within 5 days post symptoms onset. Convalescent plasma seems to have low value in the post-pandemic era. Prevention measures during SARS-CoV-2 outbreaks, including mask wearing and avoiding crowded places, seem prudent to continue for MM patients.

Prospective single-center study of health-related quality of life after COVID-19 in ICU and non-ICU patients.

Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19.

Gut microbiome alterations in patients with COVID-19-related coagulopathy.

COVID-19 is characterized by a predominantly prothrombotic state, which underlies severe disease and poor outcomes. Imbalances of the gut microbiome have been linked with abnormal hemostatic processes. Understanding the relationship between the gut microbiome and abnormal coagulation parameters in COVID-19 could provide a novel framework for the diagnosis and management of COVID-related coagulopathies (CRC). This cross-sectional study used shotgun metagenomic sequencing to examine the gut microbiota of patients with CRC (n = 66) and compared it to COVID control (CCs) (n = 27) and non-COVID control (NCs) (n = 22) groups. Three, 1, and 3 taxa were found enriched in CRCs, CCs, and NCs. Next, random forest models using 7 microbial biomarkers and differential clinical characteristics were constructed and achieved strong diagnostic potential in distinguishing CRC. Specifically, the most promising biomarker species for CRC were Streptococcus thermophilus, Enterococcus faecium, and Citrobacter portucalensis. Conversely, Enterobacteriaceae family and Fusicatenibacter genus are potentially protective against CRC in COVID patients. We further identified 4 species contributing to 20 MetaCyc pathways that were differentially abundant among groups, with S. thermophilus as the main coding species in CRCs. Our findings suggest that the alterations of gut microbiota compositional and functional profiles may influence the pathogenesis of CRC and that microbiota-based diagnosis and treatment could potentially benefit COVID patients in preventing and alleviating thrombosis-related clinical outcomes.

Management of Other Toxicities

Secondary haemophagocytic lymphohistiocytosis (sHLH) or macrophage activation syndrome (MAS) is a life-threatening hyperinflammatory syndrome that can occur in patients with severe infections, e.g., COVID-19 infection, malignancy or autoimmune diseases. It is also a rare complication of allogeneic haematopoietic cell transplantation (allo-HCT), independent of the underlying trigger mechanism or underlying disorders associated with high mortality. There have been increasing reports of sHLH/MAS occurrence following CAR-T cell therapy, but its differentiation from cytokine release syndrome (CRS) is often difficult (Sandler et al. 2020).

COVID-19 patients share common, corticosteroid-independent features of impaired host immunity to pathogenic molds.

Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.

Controversies about immunoglobulin replacement therapy in HSCT recipients with hypogammaglobulinemia.

The efficacy of immunoglobulin replacement therapy (IgRT) has been demonstrated for primary immune deficiency diseases and hematological malignancies such as chronic lymphocytic leukemia (CLL) or multiple myeloma with hypogammaglobulinemia. Clinical development of anti-B cell therapies including a monoclonal antibody, bispecific antibody, or chimeric antigen receptor T-cell therapy which could result in severe hypogammaglobulinemia accelerates the argument of prophylactic use of IgRT. Clinical guidelines for CLL describe immunoglobulin administration in patients with a low IgG who have experienced a severe/repeated bacterial infection. The utility in hematopoietic stem-cell transplantation (HSCT) remains unknown. Although an early randomized trial demonstrated that IgRT decreased infection risk and transplant-related mortality after HSCT, subsequent clinical trials could not validate the benefit. Consequently, a meta-analysis did not show the benefit of IgRT in HSCT. Most of the available data derives from matched-related HSCT using myeloablative regimen, and the impact in haploidentical and cord blood transplantation, or reduced-intensity HSCT remains unknown. One crucial issue is that no studies exist for patients with only hypogammaglobulinemia after HSCT. Other challenges are heterogeneous patient characteristics, or immunoglobulin formulation, dosage, schedule, route and duration of IgRT. Without evidence in HSCT, it would be reasonable to follow the guidelines for other diseases with hypogammaglobulinemia.

Molecular Profiling Reveals Characteristic and Decisive Signatures in Patients after Allogeneic Stem Cell Transplantation Suffering from Invasive Pulmonary Aspergillosis.

Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. We performed a longitudinal case-control pilot study to identify host-specific, novel, and immune-relevant molecular candidates indicating IPA in patients post allogeneic stem cell transplantation (alloSCT). Supported by differential gene expression analysis of six relevant in vitro studies, we conducted RNA sequencing of three alloSCT patients categorized as probable IPA cases and their matched controls without Aspergillus infection (66 samples in total). We additionally performed immunoassay analysis for all patient samples to gain a multi-omics perspective. Profiling analysis suggested LGALS2, MMP1, IL-8, and caspase-3 as potential host molecular candidates indicating IPA in investigated alloSCT patients. MMP1, IL-8, and caspase-3 were evaluated further in alloSCT patients for their potential to differentiate possible IPA cases and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and appropriate control patients. Possible IPA cases showed differences in IL-8 and caspase-3 serum levels compared with matched controls. Furthermore, we observed significant differences in IL-8 and caspase-3 levels among CAPA patients compared with control patients. With our conceptual work, we demonstrate the potential value of considering the human immune response during Aspergillus infection to identify immune-relevant molecular candidates indicating IPA in alloSCT patients. These human host candidates together with already established fungal biomarkers might improve the accuracy of IPA diagnostic tools.

A Clinical Case of COVID-19-Associated Pulmonary Aspergillosis (CAPA), Illustrating the Challenges in Diagnosis (Despite Overwhelming Mycological Evidence).

The COVID-19 pandemic has resulted in large numbers of patients requiring critical care management. With the established association between severe respiratory virus infection and invasive pulmonary aspergillosis (7.6% for COVID-19-associated pulmonary aspergillosis (CAPA)), the pandemic places a significant number of patients at potential risk from secondary invasive fungal disease. We described a case of CAPA with substantial supporting mycological evidence, highlighting the need to employ strategic diagnostic algorithms and weighted definitions to improve the accuracy in diagnosing CAPA.

COVID-19 vaccination in patients with multiple myeloma: a consensus of the European Myeloma Network.

Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19 vaccination in patients with multiple myeloma was condensed into this Review.

Reliable and Interpretable Mortality Prediction With Strong Foresight in COVID-19 Patients: An International Study From China and Germany.

Cohort-independent robust mortality prediction model in patients with COVID-19 infection is not yet established. To build up a reliable, interpretable mortality prediction model with strong foresight, we have performed an international, bi-institutional study from China (Wuhan cohort, collected from January to March) and Germany (Würzburg cohort, collected from March to September). A Random Forest-based machine learning approach was applied to 1,352 patients from the Wuhan cohort, generating a mortality prediction model based on their clinical features. The results showed that five clinical features at admission, including lymphocyte (%), neutrophil count, C-reactive protein, lactate dehydrogenase, and α-hydroxybutyrate dehydrogenase, could be used for mortality prediction of COVID-19 patients with more than 91% accuracy and 99% AUC. Additionally, the time-series analysis revealed that the predictive model based on these clinical features is very robust over time when patients are in the hospital, indicating the strong association of these five clinical features with the progression of treatment as well. Moreover, for different preexisting diseases, this model also demonstrated high predictive power. Finally, the mortality prediction model has been applied to the independent Würzburg cohort, resulting in high prediction accuracy (with above 90% accuracy and 85% AUC) as well, indicating the robustness of the model in different cohorts. In summary, this study has established the mortality prediction model that allowed early classification of COVID-19 patients, not only at admission but also along the treatment timeline, not only cohort-independent but also highly interpretable. This model represents a valuable tool for triaging and optimizing the resources in COVID-19 patients.

Clinical features associated with COVID-19 outcome in multiple myeloma: first results from the International Myeloma Society data set.

The primary cause of morbidity and mortality in patients with multiple myeloma (MM) is an infection. Therefore, there is great concern about susceptibility to the outcome of COVID-19-infected patients with MM. This retrospective study describes the baseline characteristics and outcome data of COVID-19 infection in 650 patients with plasma cell disorders, collected by the International Myeloma Society to understand the initial challenges faced by myeloma patients during the COVID-19 pandemic. Analyses were performed for hospitalized MM patients. Among hospitalized patients, the median age was 69 years, and nearly all patients (96%) had MM. Approximately 36% were recently diagnosed (2019-2020), and 54% of patients were receiving first-line therapy. Thirty-three percent of patients have died, with significant geographic variability, ranging from 27% to 57% of hospitalized patients. Univariate analysis identified age, International Staging System stage 3 (ISS3), high-risk disease, renal disease, suboptimal myeloma control (active or progressive disease), and 1 or more comorbidities as risk factors for higher rates of death. Neither history of transplant, including within a year of COVID-19 diagnosis, nor other anti-MM treatments were associated with outcomes. Multivariate analysis found that only age, high-risk MM, renal disease, and suboptimal MM control remained independent predictors of adverse outcome with COVID-19 infection. The management of MM in the era of COVID-19 requires careful consideration of patient- and disease-related factors to decrease the risk of acquiring COVID-19 infection, while not compromising disease control through appropriate MM treatment. This study provides initial data to develop recommendations for the management of MM patients with COVID-19 infection.

Management of patients with multiple myeloma in the era of COVID-19 pandemic: a consensus paper from the European Myeloma Network (EMN).

Patients with multiple myeloma (MM) seem to be at increased risk for more severe COVID-19 infection and associated complications due to their immunocompromised state, the older age and comorbidities. The European Myeloma Network has provided an expert consensus statement in order to guide therapeutic decisions in the era of the COVID-19 pandemic. Patient education for personal hygiene and social distancing measures, along with treatment individualization, telemedicine and continuous surveillance for early diagnosis of COVID-19 are essential. In countries or local communities where COVID-19 infection is widely spread, MM patients should have a PCR test of nasopharyngeal swab for SARS-CoV-2 before hospital admission, starting a new treatment line, cell apheresis or ASCT in order to avoid ward or community spread and infections. Oral agent-based regimens should be considered, especially for the elderly and frail patients with standard risk disease, whereas de-intensified regimens for dexamethasone, bortezomib, carfilzomib and daratumumab should be used based on patient risk and response. Treatment initiation should not be postponed for patients with end organ damage, myeloma emergencies and aggressive relapses. Autologous (and especially allogeneic) transplantation should be delayed and extended induction should be administered, especially in standard risk patients and those with adequate MM response to induction. Watchful waiting should be considered for standard risk relapsed patients with low tumor burden, and slow biochemical relapses. The conduction of clinical trials should continue with appropriate adaptations to the current circumstances. Patients with MM and symptomatic COVID-19 disease should interrupt anti-myeloma treatment until recovery. For patients with positive PCR test for SARS-CoV-2, but with no symptoms for COVID-19, a 14-day quarantine should be considered if myeloma-related events allow the delay of treatment. The need for surveillance for drug interactions due to polypharmacy is highlighted. The participation in international COVID-19 cancer registries is greatly encouraged.