Survival in multiple myeloma and SARS‐COV‐2 infection through the COVID‐19 pandemic: Results from the EPICOVIDEHA registry

Patients affected by multiple myeloma (MM) have an increased risk of severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) infection and subsequent coronavirus (20)19 disease (COVID‐19)‐related death. The changing epidemiological and therapeutic scenarios suggest that there has been an improvement in severity and survival of COVID‐19 during the different waves of the pandemic in the general population, but this has not been investigated yet in MM patients. Here we analyzed a large cohort of 1221 patients with MM and confirmed SARS‐CoV‐2 infection observed between February 2020, and August 2022, in the EPICOVIDEHA registry from 132 centers around the world. Median follow‐up was 52 days for the entire cohort and 83 days for survivors. Three‐hundred and three patients died (24%) and COVID‐19 was the primary reason for death of around 89% of them. Overall survival (OS) was significantly higher in vaccinated patients with both stable and active MM versus unvaccinated, while only a trend favoring vaccinated patients was observed in subjects with responsive MM. Vaccinated patients with at least 2 doses showed a better OS than those with one or no vaccine dose. Overall, according to pandemic waves, mortality rate decreased over time from 34% to 10%. In multivariable analysis, age, renal failure, active disease, hospital, and intensive care unit admission, were independently associated with a higher number of deaths, while a neutrophil count above 0.5 × 109/L was found to be protective. This data suggests that MM patients remain at risk of SARS‐CoV‐2 infection even in the vaccination era, but their clinical outcome, in terms of OS, has progressively improved throughout the different viral phases of the pandemic.


| INTRODUCTION
During the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, infected patients with hematologic malignancies (HM) have clearly shown a significantly poorer outcome compared to the general population, [1][2][3] mainly due to inherent immunosuppression and effects of some treatments.In this regard, multiple myeloma (MM) represents a good example, since in this neoplastic disorder both humoral and cellular immunity are particularly compromised because of malignancy itself and plasma cellsdirected therapies.[7][8] Thus, vaccines against SARS-CoV-2 have become the most important preventive strategy to protect these patients from severe complications deriving from SARS-CoV-2 infections. 95][26] On the other hand, studies would suggest that severity of disease and mortality rates are ameliorated also in this category of patients, mainly thanks to appropriate vaccination policies. 2,27Furthermore, some preliminary, encouraging data, has been reported about preexposure prophylaxis with monoclonal antibodies against SARS-CoV-2 [28][29][30] and early start after SARS-CoV-2 infection with antiviral drugs 31,32 to prevent the progression to critical disease in severely immuno-compromised populations, such as MM patients.

Several investigations published about MM patients with SARS-
CoV-2 infection during the first phases of pandemic have reported impressive mortality rates following infection up to 55% 2,5-8 and consensus guidelines have been produced to manage these parts of pandemic. 33Here we describe the largest survey on MM patients with SARS-CoV-2 infection, also including individuals developing COVID-19 during the most recent waves of pandemic, with   was graded according to international standards, as previously described. 36e primary objective of this study was to evaluate OS and its  Estimated OS was significantly higher in vaccinated patients with both stable and active MM versus the unvaccinated (Figure 2, p = 0.002 and p = 0.003, respectively), while only a trend favoring vaccinated patients was observed in subjects with controlled disease (p = 0.078).A sub-analysis focused on the number of vaccine doses received, and revealed that vaccinated patients with ≥2 doses (Figure 3) showed a better outcome (particularly with 3 or 4 doses) than those with ≤1 dose.

Between
Finally, when treatment for SARS-CoV-2 infection was evaluated, we found that OS was significantly longer in patients receiving a combination of antivirals and monoclonal antibodies, with or without adjunct corticosteroids and/or plasma (Figure 4).
At univariable analysis (Table 2) age, chronic cardiopathy, chronic pulmonary disease, renal failure, active MM at SARS-CoV-2 infection onset, use of steroids, hospital admission and ICU admission were significantly associated with a worse OS.On the contrary, neutrophil or lymphocyte count above 0.5 � 10 9 /L, extrapulmonary symptoms or absence of symptoms, use of antivirals þ/− monoclonal antibodies and ≥2 vaccine doses were associated with reduced mortality.
However, at multivariable Cox regression analysis, only age, renal failure, active disease, hospital and ICU admission were independently associated with poor survival.At the opposite, neutrophil count above 0.5 � 10 9 /L was found to be protective.

| DISCUSSION
Here we present, to the best of our knowledge, the largest survey of MM patients infected by SARS-CoV-2, followed during the different phases of the COVID-19 pandemic, with the longest follow-up encompassing subsequent infection periods with different viral VOC (WT, Alpha/Beta/Gamma, Delta, and Omicron).Overall, our data suggest that MM patients remain vulnerable to SARS-CoV-2 infection even in the vaccination era, but also that these patients have progressively improved their OS throughout the different viral phases of pandemic.

F I G U R E 3 Survival probability by vaccine doses.
6][7][8] In particular, hospital and/or ICU admission had the most significant negative impact on COVID-19 outcome, showing a strong correlation with an increased mortality at multivariable analysis, along with older age, renal failure and active MM disease.By contrast, neutrophil count above 0.5 � 10 9 /L was found to be significantly protective.Notably, most recent line of treatment received, other comorbidities (including pulmonary disorders) and absolute lymphocyte count did not impact on OS at multivariable analysis.
Regarding anti-SARS-CoV-2 treatments, combination of antivirals and monoclonal antibodies (þ/− steroids and/or plasma) apparently resulted in a better survival, but available data were too heterogeneous and imprecise to draw definitive conclusions.Curiously, and differently from recent data reported in the general population, 37 the use of steroids was associated with a worse outcome at univariate analysis, a fact that was not confirmed, however, at multivariable analysis.Steroid-related further immune-suppression, in addition to that intrinsic to MM, and concomitant treatments, could explain this quite unexpected finding that requires, however, further confirmation.Notably, while the effects of steroids in the Survival probability by SARS-CoV-2 infection treatment.

of 15
- inflammatory phase of SARS-CoV-2 infection needing oxygen administration would be positive, their use in the earlier viral infection phase not requiring oxygen therapy was reported to be associated to detrimental results. 37,38[44][45] Notwithstanding, even full vaccinations, though statistically significant at univariable analysis, did not enter into the multivariable model, where other clinical variables, in particular age, active disease, and COVID-19 severity requiring hospital/ICU admission, had a major impact.In this setting, more recent VOC, 46 reduced production of neutralizing antibodies 47,48 and impaired T-cell response, 49 as well increasing hybrid 50   still mandatory to maintain attention on these individuals. 53In this setting, the European Myeloma Network has recently provided an updated expert consensus to guide MM patient management also in this "post-pandemic" era.
web-based registry.The respective local ethics committee of each participating institution approved as appropriate.The electronic case report form is accessible online via www.clinicalsurveys.net(EFS Summer 2021, TIVIAN GmbH, Cologne, Germany).35Each entry was reviewed and validated by infectious diseases and hematology experts.Patient conditions at SARS-CoV-2 infection diagnosis (i.e., age, sex, comorbidities, MM status and clinical management, vaccination status, SARS-CoV-2 infection management and outcome) were recorded.Disease status of MM at SARS-CoV-2 infection onset and last follow up was defined as active (progressive disease, newly diagnosed MM), controlled (at least partial response or stable disease), according to IMWG criteria and based on reports from the respective participating institution.COVID-19 severity possible changes of MM patients with SARS-CoV-2 infection during the different epidemic waves.The secondary objective was to evaluate the factors possibly affecting OS, mainly according to disease phase, laboratory analyses, most recent MM treatment received, comorbidities, vaccine status, severity, and treatments of COVID-19.Continuous data are presented as median, interquartile range (IQR) and absolute range, and categorical variables are as counts and percentages.Cox regression model was used for mortality analysis.Variables with a p-value of 0.1 in the univariable analyses were included in the multivariable analysis.A backward Wald method was used in the multivariable Cox regression model.The Kaplan-Meier survival curve was also used to assess mortality.A log-rank test was performed to compare the survival probabilities of patients included in the different models.Statistical significance was defined as a p-value of 0.05.SPSSv25.0 (IBM Corp.) was used for statistical analysis.

2
infection infected by these strains, antiviral treatments and vaccine efficiency in MM patients.51,52However, these more recent dominant Omicron SARS-CoV-2 variants usually also often induce mild or asymptomatic disease with respect to the first waves of pandemic, sustained by SARS-CoV-2 ancestral WT, alpha and delta strains (all currently considered "de-escalated" variants), thus mimicking, though clearly to a lesser extent, what has been observed in the general population and also in other types of hematological and nonhematological cancers.3These findings suffer from the unavoidable limitations of the observational nature of the study and the heterogeneity of the examined population, that is, incomplete dataset regarding some laboratory features; lack of evidence about humoral and cellular response to vaccines and VOC; variability of MM and SARS-CoV-2 infection management, and diverse vaccine policies followed in different countries.Notwithstanding, our data indicates that a combination of complete vaccination programs and an appropriate general management, possibly along with the emergence of more transmissible, but less aggressive VOC, have significantly improved OS of MM patients infected by SARS-CoV-2 during the pandemic waves that have occurred over time.However, despite these improvements and the recent declaration of the end of pandemic by WHO (5 May 2023), it should be remembered that MM patients remain at risk of breakthrough infections and severe related complications.It is, therefore, Demographic and clinical features of 1221 patients with multiple myeloma at the time of SARS-CoV-2 infection diagnosis.

overall survival (OS) after the introduction of vaccines and the progressive appearance of new viral variants of concern (VOC).
T A B L E 1 (Continued) and herd immunity in MM patients could have also played a role.Survival probability by COVID-19 waves (variants of concern).Overall mortality predictors in patients with multiple myeloma and SARS-CoV-2 infection.