Clinical characteristics and outcome of multiple myeloma patients with concomitant COVID-19 at Comprehensive Cancer Centers in Germany.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered in Wuhan in December 2019 where it quickly led to a severe outbreak. In just a few weeks it evolved into a pandemic, with >3 million confirmed cases and >220,000 deaths attributed to COVID-19. Around 15% of infected people develop severe symptoms requiring hospitalization, and 3-10% of patients subsequently succumb to COVID-19, often due to acute respiratory distress syndrome (ARDS). Currently, neither specific treatment for COVID-19 nor a vaccine against SARS-CoV-2 is available, while trials evaluating pharmacological interventions are ongoing and specific risk groups are being defined. Whether cancer in general and hematological malignancies in particular bear substantial risks, is of eminent interest, as these patients receive immune-modulatory treatment. Of additional concern is the risk for severe COVID-19 disease in hematological malignancies given cytotoxic chemotherapy, including novel agents such as immunomodulatory drugs (IMiD) and immunotherapies (i.e., monoclonal antibodies such as daratumumab, elotuzumab and others). It is also unclear, whether the immunosuppressant state of cancer patients predisposes them to a severe COVID-19 disease or, if a diminished host immune response may decrease the risk of multiorgan complications. Early reports from China and others indicate that cancer patients with COVID-19 may have a higher risk of a severe disease course and less favorable outcome compared to non-cancer patients, albeit not shared by others and if diligently compared with non-cancer cohorts. Most of these studies are, as yet, hampered by sample sizes, and patient cohorts consist mainly of patients with solid tumors. Other risk factors associated with adverse outcome seem to be nearly the same as for non-cancerpatients: advanced age, male sex, presence of substantial comorbidities (neurological: advanced Alzheimer, Parkinson, cardiovascular disease, diabetes mellitus, respiratory disease, chronic kidney disease, liver disease and immunosuppression). In this German Multiple Myeloma (MM) Study Group Consortium (DSMM and GMMG), we aimed to characterize a population of MM patients registered from 10 institutions who developed COVID-19 at hotspot areas in Germany. All MM patients with concomitant SARSCoV-2 infection were treated at secondary and tertiary Comprehensive Cancer Centers (CCC). Our goal was to determine whether COVID-19 in MM patients resulted in a greater morbidity and mortality compared to prior COVID-19 reports in cancer and specifically in MM patients. We performed a retrospective multicenter DSMM/GMMG cohort study involving 10 secondary and tertiary CCC in German pandemic epicenters. From March 1 to May 31, 2020, all MM inand outpatients with concomitant SARS-CoV-2 infection were included (registered via DSMM/GMMG-performed incentive). SARS-CoV-2 infection was confirmed by reverse-transcriptase-PCR (RT-PCR) assay (Table 1A-B). Laboratory findings and radiological data were retrieved from the electronic medical records of each center. Comparative analysis of prior reports in cancer and MM patients was additionally performed as summarized in Table 2. The study was conducted in accordance and in compliance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. The data cutoff date was May 31, 2020. Descriptive data with median and ranges are presented. Our cohort of 21 MM patients encompassed 81% males and a median age of 59 years (range: 46-83). Most were Caucasians (Table 1A-B). Their median Karnofsky Performance Status (KPS) was 80% and the median number of comorbidities was 1 (0-3), the most prevalent being cardiovascular (hypertension), renal impairment and others (polyneuropathy [PNP], diabetes; Table 1A). Smokers versus non-smokers comprised 4 (19%) versus 17 (81%) of patients, respectively. In line with the patients' KPS and comorbidities, the median revised myeloma comorbidity index (R-MCI) and International Myeloma Working Group (IMWG)frailty scores were 3 (=fit) and 1 (=intermediate-fit), respectively. Nonetheless, 48% (via R-MCI) and 62% (via IMWG-frailty score) were in the intermediate-fit/frail group (Table 1A). The median time from MM diagnosis to SARS-CoV-2 infection was 20 months (0-142). MM patients had a median of 1 (0-4) prior line of therapy. Fifteen (71%) patients had a prior autologous stem cell transplantation (ASCT). Preceding anti-myeloma treatments were proteasome inhibitors (PI) in 19 of 21 (90%; in all except both patients with newly diagnosed [IDMM]), IMiD in 12 of 21 (57%) and antibodies (daratumumab, elotuzumab, isatuximab) in 10 of 21 (48%) patients (Table 1A). The most common MM subtype was IgG (67%), followed by IgA (24%) and light-chain (LC)-only MM in 9% of the patients. High-risk cytogenetics (del17p, t(4;14), t(14;16)) were present in six (29%) patients. Seven (33%), 19 (48%) and four (19%) patients had an international staging system (ISS) of 1, 2 and 3, respectively. A median of two CRAB criteria had led to anti-myeloma treatment, in line with prior reports in MM without SARS-CoV-2 infection. The disease status at the time of SARS-CoV-2 infection included six patients in complete remission (CR), three in very good partial remission (VGPR), 10 in partial remission (PR) and two patients with IDMM. At the time of SARS-CoV-2 infection, 12 (57%) were being treated, either with daratumumab (5), elotuzumab (1), VCd (2), KRd (1) or lenalidomide-maintenance (3). Nine patients were not on active anti-MM therapy. At the time of SARS-CoV-2 infection, anti-MM treatment was transiently stopped for ~4 weeks in all of them (Table 1A). The most common reported symptoms among all patients were a cough (81%) and fever (76%). Notably, two patients were almost asymptomatic. Seventeen (81%) patients were admitted to the hospital for inpatient care. The median time between self-reported symptom onset and admission was 3 days. Three patients required intensive care unit (ICU) support, all were treated with high-flow oxygen, and two were eventually intubated. These two developed ARDS, with one already fully recovered. The median time to recovery in all patients from symptom onset was 17 days and from test positivity 14 days. There were no deaths in the total cohort. Pulmonary infiltrates via computer tomography (CT) scans were present in 18 (86%) patients. Blood counts at SARS-CoV-2 infection showed absolute neutrophil counts (ANC) of 2.9x10/L, whereas median absolute lymphocyte counts (ALC) were suppressed (0.8x10/L). On initial presentation, platelets, lactate dehydrogenase (LDH), creatinine, PTT and D-dimer were normal or less compromised, whereas C-reactive protein (CRP) and ferritin were elevated (Table 1B). The number of patients