key: cord-0999599-pwxprzha authors: Hungria, Vania; Garnica, Marcia; de Queiroz Crusoé, Edvan; de Magalhaes Filho, Roberto Jose Pessoa; Martinez, Gracia; Bittencourt, Rosane; de Farias, Danielle Leão Cordeiro; Braga, Walter Moises; Neto, Jorge Vaz Pinto; Ribeiro, Glaciano Nogueira; Maiolino, Angelo title: Managing Patients with Multiple Myeloma during the COVID-19 Pandemic: Recommendations from an Expert Panel – ABHH Monoclonal Gammopathies Committe date: 2020-05-13 journal: Hematol Transfus Cell Ther DOI: 10.1016/j.htct.2020.05.001 sha: aed0f7c87bba77cd89343c6865156830aa49d499 doc_id: 999599 cord_uid: pwxprzha Abstract Since the World has been facing the COVID-19 pandemic, special attention has been taken concerning cancer patients; related to their immunosuppression status, adding risk for more aggressive COVID-19 and mortality, but also concerns about the access and the quality of care in cancer therapy. The COVID-19 pandemic impacts the number of infected, its related mortality, as well as the care of cancer patients. Multiple myeloma patients are a particular group with several important aspects to be considered during pandemic times. In essence, they are immunosuppressed in different intensities during their treatment. Most of them are elderly and all of them require long-term therapy, with prolonged contact with the health care system, possibly including a stem cell transplant during the treatment. A panel of experts in multiple myeloma and infectious diseases discusses pieces of evidence and the lack of the same in the scenario of COVID-19 in myeloma patients, while also exposing what is expected for the next phases of the COVID-19 pandemic. The world is facing a challenge. Cancer care in this scenario is particularly challenging. New cases demanding urgent intervention, patients that are already under cancer treatment, intense therapies, such as stem cell transplant, and several other issues have to be discussed and planned to ensure that the quality of patient care is maintained, with minimal impact on their prognosis. (2) In this manuscript, a panel of Experts discusses multiple myeloma and the challenges of diagnosis and therapy during the COVID-19 pandemic. Multiple myeloma and other plasma cell disorders have a close association with immune system disorders. Dysfunction in humoral response against virus and bacterial agents, concerning immune senescence, can be noted in newly diagnosed patients and during all treatment phases of the disease. (3) Anti-myeloma therapies, mostly resulting from a combination of different classes of agents, also contribute to intensifying the immune damage. Corticosteroid, a backbone agent in several protocols, proteasome inhibitors and monoclonal antibodies decrease T-cell response. Immunomodulatory agents impact the immune response and, in some settings, can also induce myelotoxicity and neutropenia. In addition, myeloma patients are frequently elderly, or present comorbidities. All these characteristics negatively impact infection events, not only increasing the risk of infection acquisition, but also worsening the outcomes. Cohort data from 9,000 Swedish patients demonstrated that J o u r n a l P r e -p r o o f myeloma was associated with a 10-fold increased risk of viral infections, and mortality related to infection increases from 2% to 12%, compared to healthy controls. (4) Vaccine response is another important issue in myeloma patients. Low rates of seroconversion have already been documented in Influenza and pneumococcal vaccination. (5) Although international oncohematological societies are considering multiple myeloma alone a risk factor for COVID-19, few data were published addressing incidence and outcomes of COVID-19 in myeloma patients. There are some data from the International Myeloma Foundation, (6) The SARS-CoV 2 is a novel coronavirus that was first documented in China. It is a betacoronavirus, closely resembling the SARS-CoV, the coronavirus related to SARS, in the years of 2002 and 2003. The SARS-CoV 2 has a very efficient mechanism of entry in host cells by angiotensin-converting-enzyme 2 (ACE 2) receptors, and it has RNAdependent RNA polymerase and proteases. In the majority of cases, it causes asymptomatic or oligosymptomatic respiratory diseases. These characteristics have been essential to the great and fast spread of the virus, as it spreads person to person J o u r n a l P r e -p r o o f through respiratory droplets. After a median incubation period of 4 to 5 days, symptomatic patients can experience one or more symptoms, such as fever, cough, sore throat, gastrointestinal symptoms, anosmia and ageusia. (7, 8) Patients can develop worsening of the respiratory disease, with shortness of breath, hypoxemia, or other signs of multiorgan involvement. The COVID-19 has been described as a disease with two different phases. (9) The first phase presents symptoms and signs related to viral infection and the late phase is related to severe inflammatory disease with a high rate of necessity for intensive supportive care, such as mechanical ventilation, with a high mortality rate. (10) Fortunately, most of the cases do not experience the inflammatory phase, but special groups of patients, so-called high-risk groups, have shown worse outcomes. The elderly individuals suffering from comorbidities and obesity and other subgroups have been described as having a worse prognosis. (11) Patients under specific drugs, such as corticoids, are also considered at high risk for COVID-19 complications. (12) Few studies have reported the incidence and outcomes of COVID-19 in cancer patients suggesting a worse prognosis, but they have had a limited design regarding control groups. The diagnosis of COVID-19 is based on clinical-epidemiological data confirmed by laboratory tests. There are tests to detect the virus, using polymerase chain reaction (PCR) or rapid antigen identification, and tests to detect immunoglobulin against the virus, expressing a late exposition to the agent. Other drugs, such as heparin and defibrotide have been tested, targeting prothrombotic status and endotheliitis (16, 17) . Regarding a vaccine, research is ongoing, and no preliminary data have been published to date. (18) Few reliable measures to control the COVID-19 pandemic are available, but one is categorical. Social distancing is necessary to reduce the spread of transmission and to prevent a health care system collapse. (19) There is another significant issue in regard to the health care staff. High rates of infection have been reported all over the world, including in-hospital transmission and dissemination. This has been causing a reduction in the staff taking care of patients, as if the ASCT is considered a priority. The virologic cure is also mandatory before ASCT in these cases. For ultra-high-risk cases, some authors suggest that a minimum of 14 days can be a safety period to reduce Covid-19 complications risks. It is important to note that all these recommendations were based on viral kinetic data and they have not been validated by clinical studies. Patients with respiratory symptoms without COVID-19 lab J o u r n a l P r e -p r o o f confirmation and those who report contact with COVID-19 patients should be asymptomatic and wait at least 14 days to start ASCT procedures. (28) Patients who benefit from maintenance should continue treatment if adverse side effects are not a problem. If steroids are part of the regimen, a progressive reduction in the dose should be considered. The main issue is the time to consider the initiation of subsequent-line treatment. For clinical and more aggressive relapses, subsequent treatment cannot be postponed. Nevertheless, for standard-risk patients, experiencing biochemical relapses without symptoms, we recommend postponing the initiation of active treatment, if possible. As mentioned for first-line therapy, we also do not favor any specific regimen for the relapse setting because until the present there is no available specific data on myeloma drugs. In addition to vaccination against other viruses, such as Influenzae, family members must improve measures to decrease the risk of the myeloma patient being exposed to SARS-CoV2. Family members and all communities should follow the WHO and National Health Ministry recommendations. Restricting the contact of the myeloma patient solely to close relatives is prudent, as asymptomatic or pre-symptomatic individuals are an essential key in the transmission of COVID-19. All families should be informed of the importance of reporting respiratory symptoms or exposure to a symptomatic person before having any contact with the myeloma patient or close relatives. J o u r n a l P r e -p r o o f The COVID-19 must be classified as a mild, moderate, or severe disease to decide between hospitalization or home monitoring. Close monitoring and ensured access to the health care system are crucial to the safety of home-monitoring cases, as clinical deterioration may occur at the end of the first week. Regarding myeloma patients, some considerations should be addressed: antineoplastic therapy should be discontinued during the infection and reintroduced only after convalescence, ensuring safety. The rationale for this recommendation is the same as for other types of severe infections. New data supports that there is an increasing risk of thrombosis and endotheliitis during the COVID-19 infection. (17) Multiple myeloma patients are already at increased risk for thrombosis, especially in the initial months of treatment or during thalidomide treatment. (32) Clinicians must be aware of this to decide on the prophylactic or therapeutic use of antithrombotic drugs. Until now, no clinical trials of therapy against the SARS-CoV2 or COVID-19 inflammatory phase have been published, let alone shown an advance. Although most data regarding COVID therapy are from cohorts and small or uncontrolled trials, there are several ongoing trials and we hope new and good options J o u r n a l P r e -p r o o f will soon be available. Great attention should be paid regarding safety issues and drug interactions, especially if the therapy is provided out of a clinical trial. The COVID-19 is challenging for all and the treatment of chronic diseases, such as multiple myeloma, requires attention, organization and compromises on the part of patients, clinical staff, health care institutions and families. In this manuscript, a panel of experts in multiple myeloma and infectious diseases provided recommendations to help manage myeloma patients from the diagnosis to the relapse, striving to ensure that the myeloma prognosis would not be affected by the current pandemic. 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