Mortality risk and clinical outcomes in patients with MM admitted to hospital with SARS-CoV-2/COVID-19 infection

In a multi-center case series, Joaquin Martinez-Lopez and colleagues presented data from 167 patients with multiple myeloma (MM) admitted to hospitals in Spain with COVID-19 between March and April 2020 to explore clinical outcomes and risk factors for mortality within this population. Their results have recently been published in Blood Cancer Journal¹ and have been summarized here.

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) first became evident in 2019 and have since developed into a World Health Organization (WHO)-classified pandemic. Respiratory symptoms can be variable, but severe pneumonia, increasing oxygen requirements, and respiratory distress syndrome lead to admission to intensive care for invasive ventilation in up to 5% of patients.² Several demographic and clinical groups have been identified at an increased risk of death, including those with immunosuppression and immunocompromised of any cause, such as cancer.² Different approaches have been taken to reduce this risk, including switches from intravenous therapies to oral therapies to minimize hospital/clinic attendance and promote self-isolation, reduced-intensity chemotherapy regimens, delays in treatment cycles, and interim treatment protocols in national guidelines.

It is established that in some patients with hematological malignancies, higher degrees of immune suppression are expected, especially relative to patients with solid tumors.² This is reflected in the increased use of growth colony-stimulating factors to aid count recovery between cycles, and prolonged admissions to hospital seen with high-intensity treatment protocols (e.g., for acute myeloid leukemia), to reduce the risk of life-threatening sepsis. Alongside this, targeted therapies such as monoclonal antibodies have found increasing prevalence in hematological malignancies. These novel agents are effective but affect both humoral and cell-mediated immunity and lead to increased susceptibility to viral infections. However, these factors' impact on the propensity to infection and death from COVID-19 is so far not clearly understood.²

A previous large, multi-center, registry-based study was undertaken in Spain between March 13 and May 25, 2020, to establish the impact of hematological malignancy and type of therapy on the severity and mortality of patients admitted to hospital and diagnosed with COVID-19. Across 26 public hospitals and six private hospitals, 833 consecutive patients were reported over the 10-week period, with statistical analysis performed on 697. The main findings of the study were that patients ≥ 60 years of age, with more than two comorbidities, acute myeloid leukemia, and treatment with monoclonal antibodies were associated with increased mortality.²

Focusing on multiple myeloma

MM has seen improvements in prognosis following the introduction of novel monoclonal antibodies such as elotuzumab and daratumumab, especially in the treatment of relapsed/refractory disease. However, in the series described above, patients with MM were not identified as being at increased risk of mortality from COVID-19 (p = 0.8), whilst accounting for 20% of all the patients included in the analysis. Since the start of the COVID-19 pandemic, limited information has been available on the characteristics, prognostic factors, and clinical outcomes of patients with multiple myeloma admitted to hospital with a diagnosis of COVID-19. Here, we summarize the latest report on clinical characteristics and risk factors for inpatient mortality and adverse outcomes of patients with multiple myeloma admitted to hospital with COVID-19.¹

Study design

Multi-center, retrospective case-matched series (not case-controlled).

• Coordinated through the Spanish Myeloma Collaborative Group (PETHEMA/GEM) national cancer network
• All patients admitted between March 1 and April 30, 2020

Case population

Inclusion criteria:

• Diagnosis of active MM
• Positive nasopharyngeal and oropharyngeal swab PCR test for SARS-CoV-2

Exclusion criteria:

• Patients attending hospital but not admitted (19 of 216)
• Non-MM plasma cell malignancy (30 of 216)

Comparison population

Non-oncologic patients were chosen randomly from six centers to match core demographic, clinical, and COVID-19 data.

Data collection

A core dataset for both cases and the matched cohort was collected (Table 1).

Table 1. Core data collected¹

Demographic data	Age, sex
COVID-19 data	Severity (mild to critical), need for respiratory support (ranging from no supplementary oxygen required to non-invasive ventilation)
Comorbidities	Hypertension, diabetes, or any cardiac, pulmonary, or renal conditions
Hematological parameters	Absolute neutrophil count, lymphocyte count, platelets, D-dimer, and ferritin
COVID-19 therapy	Including hydroxychloroquine, antibiotics, antiretrovirals (monotherapy or combinations of treatment options), steroids, anti-interleukin (IL)-6 therapy, heparin, or any of these treatments in combination
Outcome	Ongoing admission, death, discharge

MM-specific data for case analysis were collected using a study-specific questionnaire, adapted from an International Myeloma Society (IMS) advocated version, with data including:

• Monoclonal immunoglobulin component of patients’ MM
• Disease stage at diagnosis
• Cytogenetic risk categorization
• Presence of bone or renal disease at diagnosis
• Time since diagnosis
• Previous treatment history, including prior stem-cell transplant and systemic treatment (number of lines of treatment and therapy class)
• MM status at admission (active, progressive, partial response, or complete response)

Statistical analysis

Logistical regression was used to estimate crude and adjusted odds ratios (ORs) for COVID-19 poor prognostic factors accepted from non-cancer populations (e.g. age, comorbidities).

Results

Prognostic factors with an increased risk of death if present at the time patients were admitted to hospital with COVID-19 infection, relative to the comparison group, were:

• Age > 65 years (OR, 3; p = 0.006)
• Renal disease (OR, 4.6; p < 0.001)
• Male gender (OR, 3.8; p = 0.001)
• Active or progressive disease (OR, 2.7; p = 0.017)

No other MM-specific demographic, comorbidity, or treatment variables were shown to affect either treatment or survival. Differences in the treatment, supportive management, and clinical outcomes of patients with MM relative to non-oncologic patients are described in Table 2. There was no discernible pattern to antiviral and/or antimicrobial treatment choices between the MM or non-oncologic groups – for either monotherapy, dual therapy, or triple therapy (no analysis for statistical significance).

Table 2. COVID-19 treatment and outcomes differences between MM and non-oncologic patients¹

	Patients with MM	Non-oncologic patients
Moderate–severe COVID-19	77%	89%
Critical COVID-19	8%	4%
Requirement for non-invasive ventilation	21%	8%
Requirement for invasive ventilation	9%	6%
Death	34%	23%

Conclusion

It is established that increasing age and concurrent comorbidities such as heart and renal disease are associated with a higher degree of mortality in all patients who contract SARS-CoV-2/COVID-19. This paper affirms that these risk factors are also true for patients with a diagnosis of MM.

The study is limited in several ways. MM patients were randomly matched to non-oncologic patients, meaning the study cannot be considered either a cohort- or case-controlled study. Furthermore, there is both sample and data bias in that the 167 'cases' are from 73 study centers, while the 'comparison' group of 167 were assessed in only six hospitals. Subsequently, potentially significant differences could exist in clinical assessment and treatment decisions between centers, with further discrepancies in clinical and research data collection. Finally, diagnosis of COVID-19 was dependent on RT-PCR, but was undertaken in multiple, undisclosed laboratories within the network, with potential variance in assays and technologies used, quality assurance procedures, and parameters such as false positives and negatives.

To summarise, patients admitted to hospital with COVID-19 who have MM have a higher risk of mortality than patients with no history of cancer. MM patients who are male, > 65 years of age, have comorbid renal conditions, or have an active or progressive disease are at an even greater risk of death. Treatment decisions and advice on clinical management must consider these parameters in the ongoing care of patients during the COVID-19 pandemic to minimize the risk of mortality through hospital admission. Larger, case-controlled studies are required to replicate these findings and inform the clinical management of patients with MM through the COVID-19 pandemic.