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Clinical Infection & Immunity

Case Report

Volume 5, Number 3, September 2020, pages 77-81

Fatal Outcome of COVID-19 Reactivation in a Patient With Multiple Myeloma After Reintroduction of Myeloma Therapy

In December 2019, Wuhan City in China experienced an outbreak of a novel coronavirus disease designated by the World Health Organization (WHO) as coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has subsequently spread rapidly, with over five million cases confirmed globally and more than 300,000 deaths reported so far [1, 2].

The risk factors for developing COVID-19 among hematological cancer patients are uncertain. Some studies suggest that patients with cancer have more severe COVID-19 symptoms than the non-oncological population, and a substantially greater risk of death [3, 4]. In multiple myeloma (MM), recurrent infections are a major cause of morbimortality due to the immune dysfunction resulted from the patient characteristics, underlying disease and the anti-tumor therapies, especially when the MM is active in the first months of therapy [5, 6].

There is a lack of information regarding COVID-19 in patients treated with chemoimmunotherapy. In our center, a third-level hospital in Madrid, Spain, we have treated more than 3,000 patients with COVID-19, including 50 with hematological malignancies and 12 with actively treated MM.

We report a case of COVID-19 reactivation in a patient with MM with a previously resolved COVID-19 infection who received a salvage regimen of carfilzomib, daratumumab and dexamethasone [7].

In this report, we reviewed the medical records of a 52-year-old man with a diagnosis of MM of immunoglobulin G (IgG) kappa subtype, ISS III. We report the clinical and epidemiological characteristics, laboratory findings, chest X-ray and computed tomography (CT) imaging, treatment approach, and clinical outcome.

Our patient was diagnosed with MM in 2018. He travelled from Venezuela, his home country, to continue treatment in our center. He was refractory to multiple first-line treatment regimens including lenalidomide, bortezomib, doxorubicin and cyclophosphamide.

In March 2020 a re-evaluation of the disease showed clear data of progression, with an increase in the monoclonal component and the levels of kappa free light chains, massive bone marrow infiltration by plasma cells in bone marrow biopsy and generalized lytic bone lesions in positron emission tomography-CT. Thus, the patient was refereed for a novel salvage treatment including carfilzomib, daratumumab and dexamethasone on compassionate use [7]. On April 7, 2020, he received the first dose of carfilzomib (20 mg/m²) and dexamethasone (40 mg).

On April 10, he was admitted to the hospital with COVID-19 infection. He presented with fever, diarrhea, dry cough and dyspnea, and a chest X-ray showed bilateral pneumonia suggestive of SARS-CoV-2 infection (Fig. 1), which was confirmed by real-time polymerase chain reaction (RT-PCR) on a nasopharyngeal sample.

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Figure 1. Radiological images. Red arrows point to the most affected areas. (a) Chest X-ray upon admission (day 1) showed bilateral infiltrates. (b) Chest X-ray 1 week after tocilizumab administration (day 18) showed persistence of bilateral infiltrates. (c) Chest X-ray upon second admission (day 23) showed worsening and increased extension of pulmonary infiltrates. (d) Chest X-ray on ICU admittance (day 26). (e-h) Chest CT images on day 24 showed bilateral infiltrates and multiple ground-glass opacities and absence of pulmonary embolism. CT: computed tomography; ICU: intensive care unit.

On admission, analytical findings revealed an elevation of inflammatory parameters (C-reactive protein (CRP) 2.15 mg/dL, fibrinogen 672 mg/dL, D-dimer 1,434 ng/mL, lactate dehydrogenase (LDH) 297 U/L) and severe lymphopenia (lymphocytes 0.5 × 1,000/µL; natural killer (NK) cells 0.19 × 1,000/µL) (Table 1). The patient was treated with oral hydroxychloroquine, oral ritonavir/lopinavir, low-molecular-weight heparin and ceftriaxone, according to hospital protocols. In the following days the high fever persisted and there was a worsening of inflammatory parameters (CRP 8.94 mg/dL, fibrinogen 873 mg/dL, D-dimer 2,083 ng/mL, interleukin-6 48 pg/mL, LDH 387 U/L) (Table 1), and he required oxygen supplementation delivered by nasal canula (2 L/min). We elected to add a high dose of oral corticosteroids (dexamethasone, 40 mg daily during 4 days) and a single dose of tocilizumab [8]. We also started treatment with remdesivir within the clinical trial GS-US-540-5773 (a phase III, randomized clinical trial to compare the antiviral activity and safety of remdesivir in patients with severe COVID-19) [9]. Subsequently, the patient showed a satisfactory clinical evolution with resolution of the symptoms and normalization of analytical parameters, and he was discharged at day 13 after admission.

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Table 1. Laboratory Parameters

On April 27, the SARS-CoV-2 RT-PCR test was negative, the patient was asymptomatic and analytical parameters were significantly improved (CRP 0.15 mg/dL, D-dimer 281 ng/mL, LDH 310 U/L, lymphocytes 1.1 × 1,000/µL). Chest X-ray showed persistence of bilateral infiltrates, but the patient had adequate oxygen saturation and no tachypnea. At this point, we prioritized the MM treatment due to the high risk of progression. On April 28, he received the second dose of carfilzomib and the first dose of daratumumab (16 mg/kg intravenously). Immediately after daratumumab administration, he presented with high fever and shivering and was treated with an oral quinolone antibiotic.

On May 3, he was re-admitted to the hospital with persistent high fever despite the antibiotic treatment, dyspnea and desaturation requiring oxygen supplementation (4 L/min). Blood analysis revealed an increase in inflammatory parameters (CRP 9.27 mg/dL, fibrinogen 950 mg/dL, and LDH 663 U/L), severe lymphopenia (lymphocytes 0.2 × 1,000/µL; NK cells 0.03 × 1,000/µL), and elevation of the myocardial damage enzyme troponin T (75.6 ng/L) (Table 1). CT angiography revealed bilateral parenchymal consolidations and no signs of thromboembolism (Fig. 1). The RT-PCR for SARS-CoV-2 was positive, confirming the reactivation of COVID-19. A second dose of tocilizumab [8] was administered, as well as hyperimmune plasma as compassionate use [10]. Two days later, he presented clinical worsening requiring admission to the intensive care unit for orotracheal intubation and vasoactive medication, leading to a fatal outcome (Fig. 2).

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Figure 2. Evolution of analytical parameters and treatment after admission.

Based on the clinical evolution of the disease, we suggest that the reintroduction of treatment with carfilzomid and daratumumab could be related to the reactivation of COVID-19 in our patient. We have considered other factors that may have played an important role in COVID-19 reactivation, such as the evolution of the hematological disease.

To our knowledge, this is the first case regarding COVID-19 reactivation after any treatment. Daratumumab treatment, an anti-CD38 IgG1 monoclonal antibody, results in a rapid depletion of NK cells, as they express CD38 on their surface, and a decrease in the number of non-malignant plasma cells and other innate immune cell populations, which overall leads to a higher susceptibility to recurrent infections [11-14]. Carfilzomib, second-in-class inhibitor of the proteasome, selectively inhibits the γ5 subunit of the constitutive proteasome (c20S) and LMP7 of the immunoproteasome (i20S). Inhibition of all proteasome subunits leads to cytotoxic effects in hematologic tumor cells, but also to peripheral blood mononuclear cells [15]. Accordingly, viral infections such as virus herpes zoster are more frequent in patients treated with both drugs [13, 14].

The immunomodulatory and cytotoxic effect of daratumumab and carfilzomib, in combination with the immune dysfunction conditioned by the hematological disease, may have resulted in COVID-19 reactivation. However, we cannot be sure whether the depletion of NK cells is due to myeloma treatment or to the lymphopenia associated with COVID-19 infection.

Interestingly, cancer patients are more likely to be diagnosed with viral infections, including COVID-19, and they have more severe symptoms than the non-oncological population. In this scenario, hematologists need to carefully weigh the risks and benefits before planning chemotherapy treatments. In the setting of COVID-19 in a patient with MM and active disease with features of high-risk MM, the need for MM treatment should be carefully evaluated, and it may be prudent to delay treatment until effective treatment for COVID-19 is available. More studies are needed in MM populations with COVID-19 infection to elaborate strong recommendations for MM management in the context of this pandemic.

Acknowledgments

The authors acknowledge all the medical staff members involved in treating this patient.

Financial Disclosure

This work was partially supported by CRIS Foundation for cancer research.

Conflict of Interest

JML declares honoraria for lectures and membership on advisory boards with Janssen, BMS, Sanofi, Novartis, Incyte, Roche and Amgen and boards of directors of Hosea and Altum sequencing. The rest of the authors declare that they have no conflict of interest.

Informed Consent

Not applicable.

Author Contributions

CCPA designed the study, interpreted the data and wrote the paper. JML designed the study and interpreted the data. IZ performed and designed the figures and table of the paper. MTC performed the cytometry analysis. Evaluation and edits were performed by all the authors.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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Clinical Infection and Immunity is published by Elmer Press Inc.