key: cord-273618-klj6asdz
authors: Jain, Ankur; Ramasamy, Karthik
title: Potential ‘significance’ of monoclonal gammopathy of ‘undetermined significance’ during COVID-19 pandemic
date: 2020-07-24
journal: Blood Cells Mol Dis
DOI: 10.1016/j.bcmd.2020.102481
sha: 
doc_id: 273618
cord_uid: klj6asdz

nan

cases. 4 Importantly, presence of MGUS further impairs the already senescent immune system of the elderly population.

In the epidemiological studies, people with MGUS were shown to have a 2-fold increased risk of developing bacterial, and viral infections, and an excess mortality risk due to bacterial infections as compared to the healthy controls (HC). Pathogen-specific IgG antibodies against varicella, mumps, and rubella were significantly reduced in people with MGUS as compared to HC. 2,4 Therefore, presence of MGUS could possibly increase the susceptibility, and severity of COVID-19, and might account for an increased mortality (15%) due to COVID-19 observed in the elderly population. 5 In a recent case series of seven COVID-19 positive MGUS patients, 71%

were hospitalized. There were no intensive care unit (ICU) admissions or deaths. One patient had acute kidney injury (AKI) which recovered after hemodialysis. 6 Two New York (NY)-based studies, 7, 8 and one UK-based study evaluated the impact of COVID-19 in multiple myeloma (MM) patients. 9 Hospitalization rates of COVID-19 positive MM patients were higher as compared with the respective general COVID-19 populations (62-74% vs 25.8% in NY studies, 7, 8, 10 and 96% vs 14.7% in the UK study). 9, 11 In the NY studies, ICU admission rates of COVID-19 positive MM patients were higher as compared to the general COVID-19 population (24-30% vs 14.2%). 7, 8, 10 Mortality rates in COVID-19 positive MM patients from NY were similar to the general COVID-19 NY population (18-24% vs 21%), 7, 8, 10 whereas mortality rate was significantly higher in the UK study as compared to the general UK COVID-19 mortality (54.6% vs 14%). 9, 11 As compared to the general COVID-19 population, COVID-19 positive MM patients mounted a delayed antibody response (2-3 weeks vs 32 days), 8, 12 and had delayed virus clearance (median 9.5 days vs median 43 days). 8, 13 Baseline hypogammaglobulinemia was significantly associated with increased mortality, and predicted for lower anti-COVID-19 antibody titers in one study. 8 Above studies are limited by small sample size, lack of comparison with age/sex-matched HC, and incomplete assessment of immunoparesis. Nevertheless, this data indicates the potential severity, and delayed Diagnosis of MGCS requires tissue demonstration of monoclonal immunoglobulin deposits in the setting of organ dysfunction. 3 Certain MGRS entities could have a systemic presentation. Cardio-renal involvement is most characteristic for immunoglobulin light-chain (AL) amyloidosis, and monoclonal immunoglobulin deposition disease (MIDD). 18 Although, COVID-19 is predominantly a respiratory illness, involvement of cardiac, gastrointestinal, kidneys, central nervous system (CNS), skin, and hemato-immune systems have been recognised. 19 COVID-19-related myocarditis may cause elevation of biomarkers of cardiac injury like troponins, and N-terminal pro-brain natriuretic peptide (NT-Pro-BNP). AKI has been reported in about 0.5%-25% COVID-19 patients, and about 43.9% of such cases may have proteinuria. 19 Such a multisystem involvement in COVID-19 could pose several diagnostic, and therapeutic challenges for patients with MGCS. (1) Diagnosis of MGRS, particularly AL amyloidosis may be overlooked in patients with COVID-19-related myocarditis, or AKI resulting in diagnostic delays. Evaluation for an alternate cause for elevated cardiac biomarkers, or renal impairment should be pursued when either of these derangements are disproportionate to the clinical severity of COVID-19, or if they persist despite recovery from COVID-19. Due to its potential organ threatening nature, diagnostic work-up for MGRS as recommended even during COVID-19 pandemic. 18 Organ-directed biopsy may be compromised during the COVID-19 pandemic due to limited availability of health-care resources for performing the invasive procedures, or reluctance of the patients to seek medical attention due to the fear of COVID-19. 19 Lesser invasive sites of tissue sampling like abdominal fat pad, or gingival biopsies may be considered for AL amyloidosis, although a negative result from these sites does not necessarily exclude the diagnosis. 18 For other MGRS entities, kidney biopsy is essential, and efforts must be made to obtain tissue $ Addition of Rituximab to the chemotherapy backbone has been shown to improve overall response rates, and PFS for patients with Bcell lymphoma. 36 Therefore, patients with LPL/B-cell-associated MGCS must be treated with Rituximab combinations, albeit with some modifications of chemotherapy backbone $$ In one RCT, BR was shown to have PFS advantage, but no overall survival (OS) benefit over R-CVP. 37 $$$ Use of maintenance Rituximab for low-grade B-cell lymphoma was shown to improve PFS, but not OS in an RCT. 38 @ Patients with severe renal impairment (estimated glomerular filtration rate <30 ml/minutes/1.73m 2 , on hemodialysis, or peritoneal dialysis) were excluded from the recent Remdesivir trials 33 Review of the nation-wide hospital data of COVID-19 cases to identify patients with concurrent MGUS, and comparison of disease severity, outcomes, and differences in the immunological indices between MGUS, and non-MGUS groups.

Do people with MGUS have a suboptimal response to COVID-19 vaccine?

1. Pre-vaccination measurement of serum immunoglobulin levels, or lymphocyte subset analysis to predict post-vaccine immune response. 40 2. In-vitro studies based on lymphocyte-stimulation by SARS-CoV-2 antigens to assess the immune-responsiveness of people with MGUS to COVID-19 vaccines. 41 4

Does MGUS add to the hypercoagulable milieu of COVID-19?

Screening the admitted COVID-19 patients for the presence of MGUS may provide some clue to the excess thrombotic risk, and/or different pattern of coagulopathy conferred by MGUS to COVID-19 patients MGUS: monoclonal gammopathy of undetermined significance; COVID-19: coronavirus disease 2019; SARS-CoV-2: severe acute respiratory distress syndrome coronavirus 2 * Antibody-based assays have a relatively high false-negative rate as compared to conventional polymerase chain reaction (PCR)-based assays, and are therefore, not routinely recommended for COVID-19 diagnosis during the acute stage. However, antibody-based tests may represent a reasonably acceptable, and cost-effective strategy to screen for asymptomatic COVID-19 cases for an epidemiological survey. 39 ** Since people with MGUS may have an impaired anti-viral antibody response, 4 a lower SARS-CoV-2-specific IgG in the MGUS population as compared to the HC in the serology-based epidemiological studies would suggest an increased susceptibility of people with MGUS to COVID-19 

Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy

A Case Series of MGUS and COVID-19

COVID-19 infections and outcomes in patients with multiple myeloma in New York City: a cohort study from five academic centers

A tertiary center experience of multiple myeloma patients with COVID-19: lessons learned and the path forward

Real-world assessment of the clinical impact of symptomatic infection with severe acute respiratory syndrome coronavirus (COVID-19 disease) in patients with multiple myeloma receiving systemic anti-cancer therapy

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area

Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study

COVID-19 and Postinfection Immunity: Limited Evidence, Many Remaining Questions

Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients

Coagulation abnormalities and thrombosis in patients with COVID-19

Hemostatic dysfunction in paraproteinemias and amyloidosis

Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism

Anticoagulation with Argatroban in patients with acute antithrombin deficiency in severe COVID -19

Pathophysiology and management of monoclonal gammopathy of renal significance

Challenges in the Management of patients with systemic light chain (AL) amyloidosis during the COVID-19 pandemic

1. Uncertain benefit of HCQ and macrolides both for primary as well as post-exposure prophylaxis 25 2. HCQ and macrolides are potentially cardiotoxic ** 3. HCQ is renally excreted 19 1. Use of HCQ/macrolide prophylaxis for MGCS patients must follow national guidelines, but in general should be restricted. 2. Use of HCQ in patients with MGRS could be further detrimental to cardiac and renal functions, and therefore, must be avoided.

1. Use of antigen-based SARS-CoV-2 vaccines in MGCS could be safe. 2. Underlying 'MGUS', and clone-directed therapies could compromise vaccine efficacy Apart from the routine seasonal influenza, and pneumococcal vaccines, vaccination against SARS-CoV-2 when available, must be considered for patients with MGCS *** Bortezomib reduced the post-vaccine protective antibody titer by  30% in patients with SLE 26Consider usual SARS-CoV-2 vaccination in MGCS patients on a PI *** DARA did not affect the antibody response to seasonal influenza vaccine in patients with heavily pre-treated MM 27Consider usual SARS-CoV-2 vaccination for patients with MGCS on DARA.Rituximab causes profound B-cell depletion, and complete B-cell recovery could take 6-12 months after the last dose ****28Consider SARS-CoV-2 vaccination either prior to, or atleast 6-months after the last dose of Rituximab in MGCS patients IMiDs were shown to augment the vaccine response 29 Consider usual SARS- General measures of hand hygiene and sanitisation are mandatory for all MGCS patients. **QT prolongation ***subsequent vaccine dose may be considered for MGCS patients based upon the SARS-CoV-2-specifc IgG titer measured after the first dose **** Although Rituximab does not affect the pre-existing PC, it reduces the genesis of new long-lived PC. Likewise, administration of multiple courses of Rituximab could cause hypogammaglobulinemia, and impair the vaccination response. 28 + It would be interesting to evaluate the role of IMiDs as an adjuvant to the SARS-CoV-2 vaccine. ++ Given the rarity of MGCS, different regimens have not been tested in randomized controlled trials (RCT). However, bortezomib-based regimens have been used most commonly, and are renal-safe. +++ For patients with complete organ response, or complete haematological response with stable organ function # No data is available for the use of Ixazomib, an oral PI in MGRS entities other than AL amyloidosis ## Although Ixazomib is not approved for the frontline use in AL amyloidosis, preliminary clinical data indicates rapid and deep haematological response (HR) rates with upfront Ixazomib and low-dose dexamethasone combination (Id). 34 In a phase-I/II study, Ixazomib showed impressive HR (52%) and organ response (OR) (56%) rates in patients with relapsed/refractory (RR) AL amyloidosis. 35 ### Phase-II clinical trial evaluating Ixazomib maintenance for AL amyloidosis is currently ongoing (NCT03618537)