>65 years (N=63) OR 2.0 (95% CI 0. 8-5.3) ; high dose melphalan with autologous stem cell transplant <12 months (N=7) OR 1.2 (95% CI 0. 2-7.4) , IgG<650 mg/dL (N=42) OR=1.2 (95% CI 0.4-3.1). In the entire series of 127 patients with plasma cell disorders, hypertension was significantly associated with the combined end-point (OR 3.4, 95% CI 1.5-8.1).
Although multiple myeloma patients have a compromised immune system due to both the disease and therapy; in this largest disease specific cohort to date of patients with multiple myeloma and COVID-19, compared to the general population, we found risk factors for adverse outcome to be shared and mortality rates to be within the higher range of officially reported mortality rates.
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has become a global health crisis since it was first reported in Wuhan, China, in December 2019. 1 has so far caused over 400,000 deaths globally and has spread to the majority of countries around the world. 2 New York City is a global epicenter for the SARS-CoV-2 outbreak and a significant number of individuals have been infected by the virus, including both patients with underlying health conditions as well as healthy individuals. 3 Clinical symptoms of COVID-19 include fever, cough, fatigue, diarrhea, headaches, and shortness of breath. 1 They range from mild symptoms to severe disease characterized by pneumonia, hypoxia, respiratory failure, acute respiratory disease syndrome (ARDS), immune dysregulation, cytokine storm, thromboembolic events, and multiorgan failure. 1 Reported risk factors for severe COVID-19 disease are male gender, advanced age, smoking, and certain comorbidities such as hypertension. 1, 4 Five studies of varying size have suggested that patients with cancer on active therapy or recent surgery had a higher risk of a more severe COVID-19 disease course. [5] [6] [7] [8] [9] Additionally, recent immunotherapy treatment with checkpoint inhibitors was associated with a poorer outcome. 7 Patients with multiple myeloma have an inherently compromised humoral and cellular immunity from the malignant plasma cell disorder itself and its associated hypogammaglobulinemia. 10 The immunosuppression seen at presentation can be exacerbated by the standard combination anti-myeloma therapies currently in use. 11 Among the conventional treatment options for multiple myeloma, the use of high-dose melphalan chemotherapy followed by autologous stem cell transplant . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint is particularly associated with acute and sustained hypogammaglobulinemia and T-cell suppression. 12 Here, we report on the largest experience to date from a cohort of multiple myeloma patients with COVID-19 from five large academic centers in New York City.
Consecutive patients with multiple myeloma and related precursor diseases, were included in this cohort study.
We obtained data on patient characteristics, comorbidities, laboratory findings, treatments, and outcomes. In addition to descriptive statistics, logistic regression was used to estimate risk factors associated with adverse outcomes. Taking this approach, we estimated odds ratios (ORs) with 95% confidence intervals (CIs). The primary composite end-point was admission to an intensive care unit (ICU), need for mechanical ventilation, or death. Hypogammaglobulinemia was defined as immunoglobulin G (IgG) levels <650 mg/dL (lower limit of normal), and severe hypogammaglobulinemia was . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint defined as IgG levels <400 mg/dL. Separate analyses were performed for patients with multiple myeloma (N=100) and for all patients with plasma cell disorders (N=127).
We identified a total of 100 patients with multiple myeloma and COVID-19. Median age at the time of COVID-19 infection was 68 years (range 41-91 years). Fifty-eight (58%) of the patients were male and 24 were current or former smokers ( Table 1) Table 1) .
Of the 100 patients with multiple myeloma, 28 patients (28%) had newly diagnosed multiple myeloma; 26 were being treated with induction therapy, one had not yet started induction and one had chosen not to start therapy. There were 35 (35%) patients with stable disease (i.e. non-active disease); 23 of these were on lenalidomide maintenance, 5 were on other forms of maintenance including ixazomib/dexamethasone and daratumumab/dexamethasone and 7 patients with stable disease were monitored off therapy. Thirty-five (35%) patients had relapse/refractory multiple myeloma of which 31 were on various treatments for relapsed/refractory multiple myeloma; the majority daratumumab-or carfilzomib-based. The remaining 4 relapse/refractory patients were not on active anti-myeloma therapy due to advance disease stage (hospice) or other . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint more pressing comorbidities. Information on treatment status was missing for two patients, these were both classified as newly diagnosed multiple myeloma.( Table 2) Overall, a total of 39 patients had undergone high-dose melphalan followed by autologous stem cell transplant; 7 patients within the 12 months prior to contracting COVID-19. Two patients had a prior allogeneic stem cell transplant several years before the COVID-19 diagnosis. ( Table 2 ) Forty-two patients (42%) had hypogammaglobulinemia (IgG <650 mg/dL) and 18 patients (18%) had severe hypogammaglobulinemia (IgG <400 mg/dL).
The laboratory findings in this multiple myeloma cohort revealed lymphopenia and elevated C-reactive protein, ferritin, D-dimer, and IL-6 levels. (Table 3 Table 4 ) Nine patients received treatment with IL-6 inhibitors, tocilixumab or sarilumab, and one patient was treated with the IL-1 inhibitor anakinra and the TNF-alpha inhibitor infliximab. Other treatments included high . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint dose steroids, broad-spectrum antibiotics, and investigational anti-viral therapies such as lopinavir-ritonavir and remdesivir. Two patients were treated with convalescent plasma. Eighteen of the multiple myeloma patients, thus 24% of those admitted, expired during the follow-up time.
Twenty-seven patients (27%) of the 100 multiple myeloma patients met the combined adverse end-point (ICU-admission, mechanical ventilation, or death) and the risk was highest for patients with hypertension. None of the studied risk factors were significantly associated (P>0.05) with adverse outcomes, including hypertension, OR 2.3 (95% CI 0.9-5.9); diabetes, OR 1.1 (95% CI 0.3-3.2); age >65 years, OR 2.0 (95% CI 0.8-5.3), or male gender, OR 0.9 (95% CI 0.4-2.1). Based on small numbers (N=7), patients who received high-dose melphalan chemotherapy followed with autologous stem cell transplant within 12 months prior to COVID-19 diagnosis were not significantly associated with the adverse combined endpoint, OR 1.2 (95% CI 0.2-7.4). Also, we did not observe any statistical association between the adverse combined endpoint and hypogammaglobulinemia (IgG <650 mg/dL); OR 0.9 (95% CI 0.3-2.5) or severe hypogammaglobulinemia (IgG <400 mg/dL); and 1.2 (95% CI 0.4-4.2), respectively.
In the entire case series of 127 patients with plasma cell disorders, the OR of severe outcome (ICU-admission, mechanical ventilation, or death) was significantly elevated for those with hypertension (OR 3.4, 95% 1.5-8.1) while diabetes, male gender, age >65
. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint years, or chronic obstructive pulmonary disease/asthma were not significantly associated with the adverse combined end-point.
COVID-19 is a disease caused by the SARS-CoV-2 virus where, in the general population, the most severe outcomes are observed among elderly patients and patients with cardiovascular comorbidities. 3, 13 There is limited data on outcomes in patients with cancers particularly patients with hematological malignancies. Here, we present the first large case series of COVID-19 in patients with multiple myeloma, a plasma cell malignancy associated with a compromised immune system, due to both disease biology and anti-myeloma therapies. Consecutive patients with multiple myeloma and related precursor diseases with confirmed presence of SARS-CoV-2 between March 1 st and April 30 th , 2020 from five large academic centers in New York City were included in this study. In the general population, the probability of dying from COVID-19 has been reported to be between 0.5-3% including all COVID-19 positive patients, and between 6-30% for hospitalized patients due to the virus. 1, 3, [13] [14] [15] [16] Here, we show that among 74 multiple myeloma patients admitted due to COVID-19, the mortality rate was 24% which thus is in the higher range of what has been reported in the general population.
We were motivated to better understand risk factors associated with severe outcomes from COVID-19 positive multiple myeloma patients. Specifically, we studied host characteristics as well as available variables related to the disease and treatment.
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The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint Similar to reports from the general population, we found more men than women diagnosed with COVID-19 in this series, and there was a tendency towards a higher OR for adverse outcome (ICU-admission, mechanical ventilation, or death) in patients with hypertension. In the analysis of the entire series of COVID-19 positive patients with multiple myeloma and related plasma cell disorders (N=127), similar to the general population, cardiovascular risk factors were significantly associated with adverse outcome. 3 Independent of COVID-19, typically, patients with multiple myeloma are at an increased risk of infections due to both disease and treatment associated immunosuppression. 17 Examples of these associations are the immunomodulatory and conventional chemotherapy drugs which cause myelosuppression, the targeted monoclonal antibodies such as anti-CD-38 associated with suppression of the humoral immune system. [18] [19] [20] [21] [22] In the current series, we did not identify an association between hypogammaglobulinemia and adverse outcome; however, due to the lack of detailed biomarker data, we were unable to rule out associations involving other immunological mechanisms (such as T-cell suppression) that are important in the immune response towards viral and other infections. In multiple myeloma patients undergoing high-dose melphalan chemotherapy followed by autologous stem cell transplant, it is well-known that there are severe acute as well as sustained long-term immunosuppression including broad aspects of the immune system. 23, 24 In this study, 39 of the 100 multiple myeloma patients included had been treated with autologous stem cell transplant, 7 within the 12 months prior to contracting SARS-CoV-2. Based on small numbers (N=7), the OR for the adverse combined end-point was not significantly elevated in patients who had high-dose melphalan chemotherapy followed by autologous stem cell . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint transplant within 12 months prior to contracting COVID-19. Despite not seeing an increased mortality associated with high-dose melphalan chemotherapy followed by autologous stem cell transplant, we note the concerns of the American Society of Hematology as well as the International Myeloma Society whose recommendations state that for transplant-eligible patients, high-dose melphalan chemotherapy followed with autologous stem cell transplant should be postponed, if possible, until the pandemic abates. 25, 26 Given that it is unknown whether there could be additional seasonal outbreaks in upcoming winter of 2020 as well as following years, it is good clinical practice to have this discussion with every patient. When a safe and efficacious SARS-CoV-2 vaccine becomes available, it should be recommended to multiple myeloma patients and should be added to re-immunization programs for melphalaninduced inactivation of prior vaccines.
To minimize the risk for exposure, management of multiple myeloma including the use of infusions, injections and oral drugs has been adjusted to favor fewer visits, fewer injections/infusions and a preference for oral drugs. 25 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint cases (>200,000), and the large catchment area covered by the five included hospital centers.
In prior reports from the general population, the immune response in patients with severe COVID-19 show a unique pattern with high IL-6, low HLA-DR expression, and dysregulation of lymphocytes characterized by CD4 lymphopenia and subsequently Bcell lymphopenia. 34 In the current series of multiple myeloma patients, we found high levels of IL-6, elevated ferritin, and low absolute lymphocyte levels. Furthermore, previous studies have reported that COVID-19 infection can lead to a hypercoagulable state and patients with severe COVID-19 have an increased risk of venous thromboembolism and stroke. 4, 35 In this series, D-dimer levels were found to be elevated and one patient had a cerebrovascular event leading to significant neurological sequelae. The biological underpinnings of these observations remain to be further explained in functional studies.
No treatment has so far shown an unequivocal beneficial effect for treatment of COVID-19. Hydroxychloroquine in combination with azithromycin was initially suggested to be an effective treatment combination; however, validation trials have been unable to confirm beneficial effects. Importantly, the World Health Organization recently expressed concern over cardiac arrhythmias and other potentially serious effects with the hydroxychloroquine-azithromycin combination and several of the initial publications have now been retracted. [36] [37] [38] [39] A few patients in our series were treated with lopinavirritonavir; however, clinical trials have not shown a clinical benefit of these anti-retroviral . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint drugs. 40 Recent reports on remdesivir as well as treatment with convalescent plasma therapy have showed promising results and there are case reports on successful treatment of COVID-19 with IL-6 blockade. [41] [42] [43] [44] [45] [46] Additionally, there are indications that the Bruton tyrosine kinase inhibitor acalabrutinib can reduce the excessive inflammatory response in patients with severe COVID- 19. 47 Limitations of this study includes it being a case-series from tertiary cancer centers with a selected patient population in which patients who were treated at local hospitals in the outpatient setting were less likely to be included. There was missing data for certain laboratory results for some of the patients, primarily those who were treated as outpatients where not all tested for C-reactive protein, ferritin, D-dimer, or IL-6 levels.
In summary, we present data on a large case-series of COVID-19 positive patients with multiple myeloma and related precursor diseases showing case fatality rates in the higher range of reports from the general population. We comprehensively investigated the role of other comorbidities and found that the strongest risk factors for severe outcome were similar to those in the general population. The molecular and immunological mechanisms responsible for this finding remain unclear; however, given that patients with multiple myeloma are at an increased risk of various other infections due to both disease and treatment associated immunosuppression 17 , current recommendation by American Society of Hematology and the International Myeloma Society state that high-dose melphalan chemotherapy followed with autologous stem cell transplant should be postponed, if possible, until the pandemic levels off. 25, 26 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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Ongoing larger studies with a wide range of hematological malignancies will provide additional information on geographical variations of risk factors in these patients. Going forward, until there is a vaccine or effective treatment for COVID-19, clinical management and treatment of patients with multiple myeloma have to be carefully considered and adjusted to reduce the risk of exposure and minimize immunesuppression, while still aiming to achieve deep remissions in the era of COVID-19.
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The copyright holder for this preprint this version posted June 11, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted June 11, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint Bortezomib-including regimen 20
Ixazomib-including regimen 6
Other treatments* 10
Prior allogeneic transplant 2
Missing information regarding treatment status 2 MEL/ASC=high dose melphalan and autologous stem cell transplantation *Other treatments included DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin), low dose melphalan, panabinostat, iberomid, chlarithromycin, venetoclax, selinexor, and AMG-701.
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The copyright holder for this preprint this version posted June 11, 2020. Adverse combined end-point=ICU-admission, mechanical ventilation, or death ANC=Absolute neutrophil count, ALC=absolute lymphocyte count, NA=Not available, ND=Not done . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 11, 2020. . https://doi.org/10.1101/2020.06.09.20126516 doi: medRxiv preprint Hydroxychloroquine 52
Azithromycin 52
Combination hydroxychloroquine and azithromycin 40
Lopinavir-ritonavir 4
Remdisivir 1 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
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