Patients with multiple myeloma lacking an antibody response to COVID-19 vaccination may also fail to mount a T-cell response, researchers from the Icahn School of Medicine at Mount Sinai have reported. This scenario seemed to be most common among patients actively treated with anti-CD38 and anti-BCMA (B-cell maturation antigen) bispecific antibodies.
Their discoveries were recently published in two issues of Cancer Cell.1,2 The studies aimed to explore the kinetics of the vaccine responses in patients with myeloma and the impact of antimyeloma treatments on these responses. According to the authors, this is the first study to analyze patients with myeloma and compare their B-cell and T-cell responses to COVID-19 proteins with those of healthy controls.
The vulnerability of individuals with multiple myeloma has recently received attention because of the death of General Colin Powell, who had the disease and contracted COVID-19.
“Our findings indicate a high degree of variability in SARS–CoV-2–specific B-cell and T-cell responses in patients with multiple myeloma. The unexpected lack of T-cell responses, coupled with the absence of anti-S antibodies following SARS–CoV-2 vaccination—particularly in patients actively receiving anti-CD38 and anti-BCMA antibody-based therapies—is of concern and emphasizes the need for serological testing post vaccination to identify this specific subgroup,” said lead investigator Samir Parekh, MD. Dr. Parekh is Director of Translational Research in Multiple Myeloma at The Tisch Cancer Institute at Mount Sinai and Professor of Medicine (Hematology and Medical Oncology) and Oncological Sciences at Icahn School of Medicine at Mount Sinai.
The good news, he added, is that a third “booster” vaccine may make a dramatic difference. “Before we had boosters, all we could tell our patients was to mask and get their family and friends vaccinated to create a protective bubble. We have boosted most of our patients and are seeing very promising results,” Dr. Parekh told The ASCO Post. “We have to get the message out: Boosters are very effective in patients with myeloma, and they need to get them.”
In the Mount Sinai study of 44 patients, whose first author was Adolfo Aleman, PhD candidate, T-cell responses were observed in 96% of those who did have detectable antibodies against the spike protein (comparable to healthy controls). However, T-cell responses were seen but in just 35% of patients who did not mount an antibody response.
The Mount Sinai study contradicts some others showing that although patients with hematologic malignancies may have weak antibody responses, their T-cell responses are adequate—a finding that had provided some reassurance as to their protection. One such study, the CAPTURE trial from the United Kingdom, was presented recently during the Presidential Session of the European Society for Medical Oncology (ESMO) Congress 2021.3
Heterogeneous Antibody Responses
In their first publication,1 whose first author was Oliver Van Oekelen, MD, Dr. Parekh and his team evaluated SARS–CoV-2 spike-binding IgG antibody levels in 260 patients with myeloma who received COVID-19 vaccination (almost all with mRNA vaccines), measured 10 or more days after the second dose. Antibodies were detected in 84% of patients and varied by three orders of magnitude (median, 149 AU/mL; range 5–7,882 AU/mL); 16% had values below the level of detection.
In a control group of 67 individuals, levels were more homogeneous, and none were below the level of detection. Notably, antibody levels in the 38 fully vaccinated patients with prior infections were 10 times higher than those in infection-naive patients. Patients actively receiving treatment for myeloma had significantly lower antibody levels than those not on active treatment: median, 70 AU/mL vs 183 AU/mL (P = .004).
Antimyeloma Treatment Matters
Of note, 16% of patients with myeloma failed to develop any antibodies after two doses; 58% of nonresponders were on anti-CD38 antibody treatment at the time of vaccination, 32% were on anti-BCMA bispecific antibodies, and 10% had undergone anti-BCMA chimeric antigen receptor (CAR) T-cell therapy more than 3 months prior. In a multivariate analysis, the odds ratios for not developing detectable antibodies were 4.2 for treatment with anti-CD38 antibodies (P = .005) and 10.3 for treatment with anti-BCMA bispecific antibodies (P < .001).
“These patients were particularly prone to having no serologic reaction to the vaccination. They remain vulnerable to COVID-19 infection,” Dr. Parekh commented. A total of 10 of these patients had “breakthrough” infections; 4 required hospitalization and 1 (with no detectable antibodies) died. He said this “drives home” the clinical relevance of the study’s findings.
Asked why these antimyeloma treatments seem to create more vulnerability, Dr. Parekh noted that they are depleting the immune-fighting plasma cells. “These drugs kill normal B cells as well as myeloma cells, destroying the antibody-producing factory,” he said. “But while there are not enough cells left to respond to a stimulus, the ones left behind do seroconvert if given appropriate boosting. We have seen that more than two-thirds of our patients with no antibodies after two doses actually convert after the booster [unpublished data].”
B-Cell and T-Cell Responses Often Lacking
It is well established that in persons with prior SARS–CoV-2 infection and in immunocompromised persons without cancer, T-cell responses are often detected in the absence of antispike IgG antibodies. It is also known that persons with hematologic malignancies may have inadequate antibody responses, but less is known about their T-cell responses, which are also important components of the immune response. The aim of their second study was to determine whether patients with myeloma lacking detectable antispike IgG antibodies could nevertheless have detectable B-cell and T-cell responses, which might potentially protect them from severe disease in the absence of those antibodies.
B-cell and T-cell responses were profiled in 44 patients with myeloma (17 without antibody responses [seronegative] and 27 with antibody responses [seropositive]) as well as 12 healthy participants at least 2 weeks after their second mRNA vaccine dose (predominantly Pfizer-BioNTech). SARS–CoV-2–specific IgG antibodies were measured in these cohorts using the COVID-SeroKlir Kantaro Semi-Quantitative SARS–CoV-2 IgG Antibody Kit.
Spike-reactive B cells were found in the peripheral blood mononuclear cells of all but one seropositive patient (96%) as well as all the healthy individuals but in just 40% of the seronegative patients. Seronegative patients also had lower B-cell numbers than seropositive patients (P < .0015) and significantly reduced total CD4-positive T-cell counts (P = .0065).
As for T cells, seropositive patients had interferon-gamma–, tumor necrosis factor-alpha–, interleukin-2–, or granulocyte-macrophage colony-stimulating factor–expressing CD4-positive T cells at similar levels as age-matched healthy controls. The CD4-positive T-cell responses of seronegative patients, on the other hand, were significantly reduced as compared with healthy controls and seropositive patients (P < .005). Altogether, 96% of seropositive patients had a CD4-positive T-cell response compared with 35% of seronegative patients. The percent of patients with CD38-positive T-cell responses was 50% among seropositive patients and healthy controls and 28% among seronegative patients.
By treatment, CD4-positive T-cell responses were observed in 33% of patients given anti-BCMA bispecific antibodies and 68% of those given anti-CD38 antibodies, compared with 90% of patients who received other antimyeloma drugs and 89% of those who underwent anti-BCMA CAR T-cell therapy.
Dr. Parekh says Mount Sinai is working with Regeneron to study the prophylactic use of the monoclonal antibodies casirivimab and imdevimab in vulnerable patients. “We need those studies to open quickly, to protect our patients who are mounting suboptimal responses,” he said.