COVID-19 lessons learnt in patients with multiple myeloma

During the 18th International Myeloma Workshop, Evangelos Terpos provided a summary of what has been learnt with respect to patients with multiple myeloma (MM) and COVID-19 so far.¹

COVID-19 increases mortality in patients with myeloma

Infection is the main cause of death for patients with MM. The COVID-19 pandemic has, as a result, caused concern for doctors and patients alike. In a study by the International Myeloma Society, infection with SARS-CoV-2 was shown to increase mortality in patients with MM. Death rates following the development of COVID-19 were between 26% and 59%, recorded across different countries surveyed in this study. The probability of mortality increased with the age of the patient.

Other risk factors included:

• renal insufficiency;
• presence of active or progressive disease;
• one or more comorbidities;
• high International Staging System score; and
• high-risk disease.

A Czech registry study of 197 patients with MM confirmed the International Myeloma Society results. In this subset of patients, 20.8% died following SARS-CoV-2 infection and 34% experienced critically severe or severe disease.

Vaccination

Efficacy

Given the data on the severity and high risk of mortality for patients with MM who develop COVID-19, it is clear to see that vaccination is a necessary step. However, the effectiveness of vaccination can be variable in patients with hematologic malignancies. Out of a cohort of 213 patients with MM who had received a second dose of the Pfizer vaccine, 53.5% had ≥50% neutralizing antibodies at 4 weeks and 71% had ≥30%, which was significantly decreased when compared with healthy volunteers (p < 0.01).

When patients with monoclonal gammopathy of unknown significance were compared with patients with MM or smoldering myeloma, the former were shown to have increased titers at 4 weeks following full vaccination.

Treatment for MM

In addition to the effect of MM itself, antimyeloma therapy can also impact the effectiveness of vaccination. Patients who were treated with anti-B-cell maturation antigen (BCMA) or anti-CD38 antibodies showed significantly decreased inhibition at 4 weeks post-second vaccination compared with patients with MM who were not receiving treatment (p = 0.001) or those receiving other treatments (p = 0.005). Lymphopenia was also found to be a poor prognostic factor for the development of neutralizing antibodies in patients with MM.

A Mount Sinai study of anti-CD38 and anti-BCMA therapies investigated the impact of treatment further. In this study, 15.8% of patients with MM did not develop IgG antibodies to the spike proteins (Sp) of SARS-CoV-2. When this study investigated antimyeloma treatment, 41.9% of patients received anti-BCMA therapy, and 20.5% received anti-CD38 treatment. These patients showed significantly reduced production of IgG towards the Sp compared with patients with MM who were not actively being treated (p = 0.00027). This study also identified lymphopenia Grade ≥3 as a risk factor for a poor outcome following SARS-CoV-2 infection.

In addition, this study demonstrated significantly decreased SARS-CoV-2 specific CD4 T-cell responses in patients with MM that have undetectable anti-Sp levels.

A German study investigated B-cell responses in patients with MM (N = 82) following one dose of an mRNA or vector-based vaccine. Anti-Sp antibody levels were assessed at a median of 25 days (SD±, 11.8 days) after the first dose of vaccine. With a threshold value of ≥30 CD19⁺ B-cells/μl, patients with higher CD19⁺ B-cell levels showed significantly increased anti-Sp levels compared with patients with CD19⁺ B-cell levels below the cut-off (p < 0.0005). In line with previous findings, patients on anti-CD38 treatment were found to have significantly reduced anti-Sp antibodies.

Waldenström’s macroglobulinemia (WM)

Vaccine responses in patients with WM were assessed at Day 22 following the first vaccine dose. These patients had lower levels of neutralizing antibodies than controls and a median neutralizing antibody inhibition titer of 20.5% compared with 39.8% for the controls (p < 0.001). Overall, only 34% of patients with WM compared with 65% of the controls developed ≥30% neutralizing antibody titers by Day 22.

This trend continued following the second dose of vaccine, with WM patients continuing to show lower levels of neutralizing antibodies at Day 50. Out of the 74 patients with WM, 60.8% developed neutralizing antibody titers compared with 92.5% of the controls (p < 0.001).²

Booster doses

A recent study by Gavriatopoulou, et al. found that patients with myeloma who develop COVID-19 have improved antibody responses with a neutralizing antibody titer of 87.6% compared with patients who have received two doses of the BNT162b2 vaccine at only 58.7%. As a result, the authors recommend booster doses for patients with MM.³

Currently the European Medicines Agency (EMA) and the US Center for Disease Control (CDC) recommend booster doses for patients with severely weakened immune systems, at least 28 days after their second dose of vaccine.^4,5 This booster dose is distinct from the third vaccination that healthy individuals are due to receive around 6 months after the second dose.

Conclusion

As our experience with COVID-19 is still limited, questions remain about how best to treat these patients, especially those who do not respond to two doses of vaccine, although a booster dose may have some benefit. What we have learnt so far shows that SARS-CoV-2 infection in patients with MM leads to a high rate of morbidity and mortality. While vaccination remains a key weapon in our arsenal against COVID-19, patients with MM show reduced antibody titers against the virus. Antimyeloma therapy, in particular anti-BCMA or anti-CD38 therapy, reduce antibody responses to SARS-CoV-2 infection.

The Multiple Myeloma Hub will soon publish the latest recommendations from the European Myeloma Network on COVID-19 vaccination. Stay tuned!