key: cord-0782385-5pwa6i3d
authors: Jethava, Dr. Yogesh S
title: COVID-19 and Multiple Myeloma
date: 2020-06-13
journal: Leuk Res Rep
DOI: 10.1016/j.lrr.2020.100212
sha: f695b09ec57c62c3eaa135b029bf33b5d93eceb9
doc_id: 782385
cord_uid: 5pwa6i3d

At the end of 2019, a novel coronavirus was identified as the cause of pneumonia cases in Wuhan, a city in the Hubei Province of China. On January 30, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a public health emergency of international concern and, in March 2020, began to characterize it as a pandemic. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) In February 2020, the World Health Organization designated the disease COVID-19, which stands for coronavirus disease 2019.

The incubation period for COVID-19 is approximately 14 days following exposure, with most cases occurring approximately four to five days after exposure. In a study of 1099 patients with confirmed symptomatic COVID-19, the median incubation period was four days [3] [4] [5] . The spectrum of symptomatic infection ranges from mild to critical; most infections are not severe [5] [6] [7] . The mild disease causes no symptoms or symptoms of mild pneumonia. Severe disease is associated with the symptoms of dyspnea, hypoxia, or >50 percent lung involvement on imaging within 24 to 48 hours. Critically ill patients present with respiratory failure, shock, or multiorgan dysfunction. In a report from the Chinese Center for Disease Control and Prevention, that included approximately 44,500 confirmed COVID 19 infections [8] ; mild was reported in 81 percent, severe disease was reported in 14 percent and critical disease was reported in 5 percent.

The overall case fatality rate was 2.3 percent; no deaths were reported among noncritical cases.

Severe illness can occur in healthy individuals of any age, but it predominantly seen with advance age [8] [9] [10] , cardiovascular disease, diabetes mellitus, hypertension, chronic lung disease, recent cancer chemotherapy, chronic kidney disease, immunocompromising conditions, and severe obesity (body mass index ≥40. Laboratory findings, such as; lymphopenia, liver dysfunction, elevated D-dimer and elevated prothrombin time (PT), elevated troponin, elevated creatine phosphokinase (CPK) and acute kidney injury [4, 9] , are associated with poor outcomes.

In the United States, the CDC recommends collection of a nasopharyngeal swab specimen to test for SARS-CoV-2 [40] . Oropharyngeal swab can be collected but is not considered essential for the diagnosis. Similarly, expectorated sputum should be collected from patients with productive cough; induction of sputum is not recommended. A lower respiratory tract aspirate or bronchoalveolar lavage should be collected from patients who are intubated. SARS-CoV-2 RNA is detected by reverse-transcription polymerase chain reaction (RT-PCR) [24] . If initial testing is negative but there is strong suspicion, the test should be repeated [41] .

Serologic tests, as soon as generally available and adequately evaluated, should be able to identify patients who have either current or previous infection but a negative PCR test. In one study that included 58 patients with clinical, radiographic, and epidemiologic features suspicious for COVID-19 but with negative SARS-CoV-2 PCR testing, an IgM enzyme-linked immunosorbent assay (ELISA) was positive in 93 percent (and was negative when tested separately on plasma specimens that predated the COVID-19 outbreak) [25] .

For safety reasons, specimens from a patient with suspected or documented COVID-19 should not be submitted for viral culture.

There is not much data available in cancer patients with COVID-19 infection. Current information is based on Chinese and Italian data. In a report from Italy, 20 percent of the deaths from COVID-19 in the entire country were in patients with active cancer [9] . In a small series of 28 patients with COVID-19 from Wuhan, China, the median age was 65 years, 17 percent were male and most frequent cancer type was lung cancer (25 percent) [26] . In this patient population, the most frequent clinical presentation was, fever dry cough and dyspnea. The clinical course varied, but more than 50 percent of the patients had severe disease 6 patients required admission to the intensive care unit (ICU). There were more severe events among the seven patients who had received chemotherapy, radiotherapy, targeted therapy, or immunotherapy within the last 14 days, relative to those who had not received treatment with the last 14 days.

In a prospective cohort of 1600 patients with laboratory-confirmed COVID-19 acute respiratory disease, 18 patients had cancer [27] . Among these 18 patients, 7 patients had higher risk of severe events as compared to only 124 of 1572 patients had serious adverse events in non-cancer group. [28] . Patients >60 years with NSCLC had a higher incidence of COVID-19 than did younger individuals. Although there is no myeloma specific data available,

At this time, neither a diagnosis of MM nor active anti-MM treatment are indications for coronavirus testing in asymptomatic patients. CDC and The American Society of Clinical Oncology (ASCO) emphasizes on following recommendations:  Patients should be informed regarding the symptoms of COVID-19, and trained in proper handwashing, hygiene, and minimizing exposure to sick contacts and large crowds.  At this time, no specific evidence or guidance on mask use for patients with MM has been published. There is no guidance or evidence to suggest that N95 masks are required in MM patients receiving active treatment.

There is no "one size fits all" approach to delivering MM care during the COVID-19 pandemic. The consideration should be given to conceptual approach of the decision making in MM patients during COVID-19 pandemic, which will help in balancing the risk of progression with delay of cancer care versus the risk for significant morbidity from COVID-19 [29] .

We suggest that existing patients should be divided into 3 categories: A) Patients who need immediate treatment B) Patients whose treatment can be delayed for 2-4 weeks C) Patients whose treatment can be delayed for more than 4 weeks A) Patients who need immediate treatment: Presentation of MM can be dramatic, with onset of hypercalcemia (28 percent), elevated creatinine (48 percent) or symptomatic spinal cord compression [30] . There is no evidence that COVID-19 infection interferes with or has an effect on the diagnosis and staging of MM. In a patient with severe symptoms, it will be imperative to perform standard of care investigations such as diagnostic bone marrow, functional imaging (PET, MRI or DWIBS) and appropriate laboratory investigations. In such situations, treatment can't be delayed. It is important to ask direct questions pertaining to COVID-19 to these patients and masks should be provided to these patients. There should be low threshold for COVID-19 testing in these patients. Lymphopenia is one of the adverse prognostic factors and hence, low dose dexamethasone can be considered in the beginning. Wherever possible, oral regimen consisting of proteasome inhibitors, immunomodulatory agents and low dose steroid would be more appropriate regimen. However, approximately 50 percent of the MM patients will have slowly progressive symptoms such as anemia, bony pains, weight loss or spontaneous fractures, at the time of diagnosis. CDC recommends that, during COVID-19 pandemic, any clinic visits that can be postponed without risk to the patient should be postponed Similarly, relapsed refractory MM patient population poses a unique challenge. Occasionally clinical trials remain the only option available for this patient population. The clinical trials aspect is discussed below. B) Patients whose treatment can be delayed for 2-4 weeks: The treatment can be delayed in certain group of patients. Patients who are waiting to start autologous stem cell transplant (ASCT) process and post-ASCT patients, waiting to start extended maintenance therapy, can wait up to 4 weeks. The planned stem cell collection cn be delayed and patient can continue induction therapy. Post-ASCT patients' restaging and maintenance treatment can also be delayed. Patients with stable disease and coming for routine visits, can be delayed. C) Patients whose treatment can be delayed for more than 4 weeks: The asymptomatic stages and routine follow up of smoldering myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS) patients can be postponed. Patients, who are in complete remission and on maintenance treatment can certainly be delayed for more than 4 weeks. However it is important to acknowledge that the risk of infections in MGUS is increased ~2-fold as compared to healthy controls, with an increased susceptibility to bacterial infections and viral infections such as influenza and herpes zoster infections [31] . Depressed antibody titers to a number of common infectious pathogens have been found in several conditions associated with presence of an M-protein [32] . Hence it is imperative that in MGUS and SMM patients with fever and respiratory symptoms, COVID-19 is ruled out. Although data regarding COVID-19 in MGUS and SMM patients is not available, it is possible that this group of patients might have delayed immune reconstitution and therefore, more likely to shed virus for prolong time period. This can put immediate family members and healthcare workers at higher risk. Although not the best analogy, their situation can be similar to "Typhoid Mary", symptomatic but potential to infect others.

When patients must receive in-person care for imaging, procedures, surgeries, radiation therapy, or infusions, minimizing time in waiting rooms, rearranging patient contact areas to maximize social distancing, augmenting early discharge planning efforts, executing prompt and safe discharge events, minimizing visitors, instituting pharmacy deliveries, and anticipating/avoiding the possibility of urgent care/emergency department visits (eg, consider more delayed removal of drains/catheters based on risk benefit profile) are all necessary steps in creating a safe experience.

MM patients are immunosuppressed from the time of diagnosis. The median age of MM patient population is 65 years and many patients have significant comorbidities such as diabetes, heart disease, underlying renal insufficiency etc and hence, such patients should be considered higher risk, and therefore aggressive work up should be done in suspected symptomatic cases. The important thing to acknowledge is that, absence of symptoms is not associated with a predictably low viral load. If the patient tests positive for COVID-19, the CDC, recommends that all treatment should be held until symptoms from COVID-19 have resolved for at least 72 hours, irrespective of a cancer diagnosis [38] . There is presently no vaccine or specific anti-viral drug regime for the critically ill patients. The management of patients mainly focuses on the provision of supportive care, e.g., oxygenation, ventilation, and fluid management. Combination treatment of low-dose systematic corticosteroids and anti-virals and atomization inhalation of interferon have been encouraged as part of critical COVID-19 management. There is a case report of one MM patient with COVID-19 infection successfully treated with tocilizumab. The symptoms are driven by excessive pro-inflammatory milieu and hence anti-IL6 strategy might be worth exploring [37] .

If a patient with relapsed MM, on active treatment, acquire COVID-19 and requires mechanical ventilation, the prognosis is likely to be dismal. It is imperative for clinicians to have proactive discussions with patients about goals of care and advance care planning, especially for those with advanced cancer who may become infected with COVID-19. Depending on state regulations, patients should be offered the option of completing a Physician Order for Life-Sustaining Treatment (POLST) form, especially if they would not want to receive cardiopulmonary resuscitation (CPR) or mechanical ventilation. The reinfection rates of COVID-19 are unknown and hence, restarting immunosuppressive treatment should be carefully considered on case by case basis. For patients who are SARS-CoV-2 negative, other possible etiological factors responsible for respiratory symptoms needs to be ruled out and appropriate care needs to instituted.

Clinical trials can be the only option available for a relapsed or refractory MM patient. The phase 1 studies are heavy on correlative studies, need repeated lab draws for pharmacokinetic studies and require multiple clinic visits for the patients. Such trials can be put on hold. This will help reducing exposure to the patient as well as trial staff. Important issues, such as trial drug shipment, audit monitoring visits and appropriate utilization of trial unit staff will have to be considered. We suggest that trial staff should be cohorted to reduce exposure. One cohort can work from home and another cohort can be onsite. In the patients on immune checkpoint inhibitor therapy trials, treatment-related pneumonitis is a concern, which may increase the risk of serious complications if the patient develops concurrent COVID-19 infection. For those with a known coronavirus exposure, it is recommended to hold immune check point inhibitor therapy trials, until it is clear that the patient did not develop COVID-19.

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