key: cord-0766339-mkuc0w2s authors: Ludwig, Heinz; San‐Miguel, Jesús; Munshi, Nikhil; Sonneveld, Pieter; Mateos, María‐Victoria; Moreau, Philippe; Terpos, Evangelos title: COVID‐19 vaccination in patients with multiple myeloma: Focus on immune response date: 2021-05-31 journal: Am J Hematol DOI: 10.1002/ajh.26263 sha: 913cc7382620895dea16e862c1fa34fa25fc79e7 doc_id: 766339 cord_uid: mkuc0w2s nan Patients with multiple myeloma (MM) are at increased risk for severe clinical symptoms and mortality due to SARS-CoV-2 infection. To protect against these complications, the International Myeloma Society recommends vaccinating all patients with monoclonal gammopathy of undetermined significance (MGUS), monoclonal gammopathies of clinical significance, smoldering MM (SMM), and MM 1 . Protective immunity against SARS-CoV2 in those patients is partially relevant given their increased risk for infections, which may cause significant morbidity and represent the second most frequent cause of mortality 2 . The extent of the immune impairment in MM largely depends on the disease-inherent immune suppression exerted by the malignant clone that can affect all immune effector mechanism including B-, T-, NK-, and dendritic cells, and the complement system 3, 4 . The myelomainduced immune deficiency can resolve completely during periods of deep response, such as minimal residual disease negativity, but deep responses are achieved in a proportion of patients only, and several of those eventually relapse and become immune suppressed again and/or suffer from other causes of reduced immune competence. Many patients present at older age with comorbidities and immunosenescence 5 with an impaired defense against infections and compromised development of long-term immune memory, which is aimed at by vaccination. Myeloma therapy including proteasome inhibitors, dexamethasone, high dose melphalan, monoclonal antibodies, antibody-drug conjugates, BiTEs and cellular therapies, such as CAR-T cells, result in specific and cumulative immune suppression, and after extensive therapy in T cell exhaustion 6 . Hence, myeloma and myeloma treatmentinduced immunosuppression and other above mentioned factors frequently impose critical hurdles for an effective vaccination response in many patients and emerging data seem to underpin these concerns 7 . A recent study in 48 elderly patients with MM (median age 83 years) reported a significantly lower proportion of MM patients with a neutralizing antibody response on day 22 after the first dose of the BNT162b2 vaccine compared to controls of the same age category (20.6% versus 32.5%, respectively). Virus neutralizing antibody titers of ≥ 50% deemed to be clinically relevant, were noted in 4 (8.3%) of 48 patients and in 21 of 104 (20.2%) controls only; all these four patients were in remission without any therapy 8 . Only 1 of the 9 patients with SMM had neutralizing antibody titers. This poor response did not improve substantially with the second dose 9 . Part of the observed low response rate could be due to the high age of the study participants as specific antibody production in response to vaccination declines with older age 10, 11 . Similar results were noted in 93 patients (median age 67 years) after one dose of the BNT162b2 or ChAdOx1-S vaccine 12 . After a median time from first dose to Accepted Article This article is protected by copyright. All rights reserved. antibody testing of 33 days, SARS-CoV-2 IgG antibodies were noted in 55.9% of patients, with no difference between both vaccines. These results compare with a positivity rate of 98.8% observed in hospital staff. When testing was expanded for IgA and IgM antibodies in 40 of the IgG antibody negative patients, a positive result was obtained in further 13 patients, adding up to a total antibody response in 65/93 patients (69.9%). Factors associated with antibody response were depth of response (CR-PR), absence of Immunoparesis, and fewer lines of therapy, while being on therapy was associated with poor antibody response. Another presently unpublished study included seven patients with MM within a group of 38 patients with hematological cancers, which showed an IgG antibody response to the SARS-Co-2 spike protein in only 13% of them, compared to 97% in healthy controls after one dose of the BNT162b2 vaccine 13 . Furthermore, half of the patients with haematologic malignancies tested had an impaired T cell response, and 8 of the 9 who showed a cellular immune response were serological non-responders. Similarly, a discordance between cellular and IgG antibody response was noted in previously COVID-19 infected health care workers; during follow up a T-cell response, but no antibody formation was observed in 7 out of 70 individuals, while in 2 subjects weak antibody titers, but no cellular responses were detected 14 . These findings raise the question about the kind of humoral and cellular immune response which is required for protection against infection with SARS-CoV-2 virus, and which test systems provide most relevant information. Neutralizing antibodies have been shown to correlate with protection in rhesus macaques 15 , and may be more informative than assessing levels of antibodies against spike proteins, but data comparing their clinical relevance are not available as yet. For evaluation of cellular immunity, spike peptides are used for T-cell stimulation, but COVID-infected patients show reactivity against other peptides as well 16 . This shows that available evidence is insufficient for clear guidance, therefore more laboratory data need to be generated and linked with clinical outcome including asymptomatic and symptomatic infection rate, hospitalization and mortality. Another issue of importance is the duration of the protection in patients with a documented immune response. Will antibodies and T-cell reactivity vane with time, even in patients in complete remission, and how fast will protection be lost in patients with progressive or recurrent disease? Will it be worthwhile to add additional doses of the same vaccine to non-or lowresponders, or will a change of the vaccine for instance from an RNA to an adenovirus vector, peptide, protein, or inactivated virus vaccine, adjuvanted or not, or vaccines designed by a new molecular technology called NDV-HXP-S, which uses a specially designed spike called HexaPro and is much easier to manufacture, elicit the desired immune response? Figure 1 Accepted Article This article is protected by copyright. All rights reserved. considered. These treatments are presently not approved for prophylactic use, but may turn out to protect all those with insufficient immune response to COVID-19 vaccines, particularly when preparations with extended half-life will be introduced. But until this option will become available for clinical practice, creation of 'herd immunity' using a strategy of 'ring vaccination' around affected patients will be required. Those patients will also be obliged to strictly follow general recommendations for infection risk reduction. They will desperately hope for new effective anti-COVID treatments, and finally for an end of the pandemic. This article is protected by copyright. All rights reserved. Figure 1 . Platforms used for development of anti-SARS-CoV2 vaccines Table 1 . List of recent SARS-CoV-2 variants of concern, their clinical attributes and coverage by selected common vaccines. Recommendations for vaccination in multiple myeloma: a consensus of the European Myeloma Network Immunodeficiency and immunotherapy in multiple myeloma Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6 Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade T cells in multiple myeloma display features of exhaustion and senescence at the tumor site SARS-CoV-2 Vaccines in Patients With Multiple Myeloma Low Neutralizing Antibody Responses Against SARS-CoV-2 in Elderly Myeloma Patients After the First BNT162vb2 Vaccine Dose Age-related reduction of antibody response against the human endogenous retrovirus K envelope in women Age-dependent and genderdependent antibody responses against SARS-CoV-2 in health workers and octogenarians after vaccination with the BNT162b2 mRNA vaccine Interim results of the safety and immune-efficacy of 1 versus 2 doses of COVID-19 vaccine BNT162b2 for cancer patients in the context of the UK vaccine priority guidelines. medRxiv : the preprint server for health sciences Discordant neutralizing antibody and T cell responses in asymptomatic and mild SARS-CoV-2 infection DNA vaccine protection against SARS-CoV-2 in rhesus macaques Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine Emergence of genomic diversity and recurrent mutations in SARS-CoV-2. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. The New England journal of medicine Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil. medRxiv : the preprint server for health sciences Neutralizing Activity of BNT162b2-Elicited Serum. The New England journal of medicine NERVTAG: New and Emerging Respiratory Virus Threats Advisory Group, ECDC: European Center for Disease Prevention and Control , CDC: Center for Disease Control, COG-UK: COVID-19 Genomics UK Consortium All authors contributed equally to concept and writing of the manuscript. All authors approved the final version. Data sharing is not applicable to this article as no new data were created or analyzed in this study. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.