Anti-RBD IgG antibodies and neutralizing antibody levels after the second BNT162b2 dose in patients with plasma cell disorders.

Patients with plasma cell disorders (PCD) are at an increased risk for severe morbidity and mortality due to COVID-19. Recent data have suggested that patients with hematological malignancies, including those with PCD, have suboptimal antibody response to COVID-19 vaccination. We compared the antibody titers of 213 patients with PCD to those of 213 immunocompetent healthcare workers after the second vaccine dose of the BNT162b2 mRNA vaccine. Blood samples were taken 2-4 weeks after the second vaccination and analyzed for anti-receptor binding-domain immunoglobulin G (RBD-IgG) antibodies and neutralizing antibodies (NA). At a median of 20 days after the second vaccine dose, 172 patients (80.8%) developed anti-RBD-IgG antibodies with a geometric mean titer (GMT) of 2.7 (95% confidence interval [CI], 2.4-3.1). In the control group 210 (98.9%) developed anti-RBD-IgG antibodies after a median of 21 days, with a GMT of 5.17 (95%CI, 4.8-5.6), p<0.0001. NA were observed in 151 patients with MM (70.9%) and in 210 controls (98.9%). The GMT of NA in patients with MM and controls was 84.4 (95% CI, 59.0-120.6), and 420.2 (95% CI, 341.4-517.1), respectively (p<0.0001). Multivariable logistic regression revealed that the number of prior therapy lines and age were significant predictors of poor humoral response among patients with MM. Injection site reaction, headache and fatigue were the most common adverse events after vaccination. Adverse events were less common in patients with MM than in controls. In conclusion, a significant percentage of patients with MM developed protecting NA to the BNT162b2 mRNA vaccine, which appears to be safe in this patient population.

Humoral and cellular immune response to second and third severe acute respiratory syndrome coronavirus 2 mRNA vaccine in patients with plasma cell dyscrasia.

BACKGROUND: The recently developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD). METHODS: We retrospectively measured serum SARS-CoV-2 antibodies against the spike protein (S-IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S-IgG titers ≥300 antibody units/mL). RESULTS: Although active anti-myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B-cell maturation antigen-targeted therapy. Dose 3 (booster vaccination) led to significantly higher S-IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine-induced cellular immune response in patients using T-spot Discovery SARS-CoV-2 kit, revealed an enhanced cellular immune response after Dose 3. CONCLUSIONS: This study highlighted the significance of booster SARS-CoV-2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine-induced humoral immune response.

Successful use of lenalidomide to treat refractory acquired von Willebrand disease associated with monoclonal gammopathy.

Acquired von Willebrand syndrome (AVWS) is a rare hematologic disorder characterized by quantitative or qualitative defects of von Willebrand factor (vWF), a protein crucial for normal hemostasis. AVWS has been described in association with several pathologic entities with varied mechanisms. Among these, lymphoproliferative disorders are the most common, with monoclonal gammopathy of undetermined significance (MGUS) being the most frequently reported. AVWS in this setting is commonly associated with the development of bleeding that is clinically challenging to manage due to accelerated clearance of vWF, limiting the utility of many conventional treatment modalities such as DDAVP or vWF/FVIII. We report a case of a 43-year-old male who was sent to our institution for new-onset easy bruising and laboratories concerning for von Willebrand disease (vWD). Further diagnostic workup revealed evidence of an IgG monoclonal gammopathy and findings suggestive of vWF inhibition. Ultimately, he was found to have monoclonal gammopathy of clinical significance (MGCS)-associated AVWS refractory to conventional treatment but responsive to lenalidomide and dexamethasone. This case suggests that lenalidomide may be suitable for patients with AVWS secondary to MGCS.

[Warm autoimmune hemolytic anemia and IgM-monoclonal gammopathy following BNT162b2 COVID-19 vaccine in a patient with splenic marginal zone lymphoma].

There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient's symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient's serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.

Relapse of Monoclonal Gammopathy of Renal Significance after mRNA Covid-19 vaccination: a case report (preprint)

Introduction This case report represents, to our knowledge, the first suspected case of Light Chain Deposition Disease (LCDD) relapse associated with mRNA COVID-19 vaccination. It must be made clear that timing is the only link between the vaccination and the relapse of LCDD, and since millions of individuals received these vaccines, an event like this may be due to chance. At the same time, this case report may be an entry point into further explorations of the pathogenesis of LCDD, given the mechanism of action of the vaccine and the pathophysiology of the disease, as it is currently understood. Case presentation The 75-year-old female patient of Greek ethnicity was admitted into our clinic for the investigation of worsening renal function that was detected on routine lab examinations two weeks after she received the second dose of the moderna COVID vaccine (mRNA-1273). Rapidly progressive glomerulonephritis and anemia were the most notable findings upon admission. She had a history of Light Chain Deposition Disease (LCDD) which had remained stable under management for four years. Serum protein electrophoresis was performed and showed monoclonal kappa zones, while bone marrow biopsy revealed 5% plasma cell infiltration. All the above, along with other investigations, established the diagnosis of LCDD recurrence. She was started on chemotherapy, which improved her immunological profile but not her renal function. The patient has remained on hemodialysis since. Conclusions The association between mRNA vaccinations and LCDD relapse may be ground for investigations into the pathophysiology of MGRS, given the patient’s previous long-term remission. In this context, we want to stress once again the importance of following standardized routine mandates on COVID vaccination, especially in immunocompromised patients. This case report is not intended to directly inform changes in clinical practice.

Idiopathic systemic capillary leak syndrome, a unique complement and interferon mediated endotheliopathy syndrome: The role of the normal skin biopsy in establishing the diagnosis and elucidating pathogenetic mechanisms.

Idiopathic Systemic Capillary Leak Syndrome (ISCLS), also known as Clarkson's Syndrome, is due to primary fluid and protein leak across capillaries that leads to an accumulation of interstitial fluids and cardiovascular collapse from intravascular hypovolemia. Viral infections are a putative trigger of these episodes. ISCLS is typically associated with a monoclonal gammopathy. Here we present four patients with idiopathic systemic capillary leak syndrome. The cohort consists of three men and one woman who range in age from 55 to 72 years old. All of the patients had a monoclonal gammopathy. Two patients had viral triggers. Biopsies of normal skin were examined throughout all phases of the disease. During an acute attack, we identified perivascular mixed CD4+ and CD8+ T cell lymphocytic infiltrates in the superficial dermis. We observed significant microvascular deposits of C5b-9 and upregulation of type I interferon signaling in endothelium along with reduced serum levels of complement during very active disease. We also identified deposits of immunoglobulin along the dermal epidermal junction mirroring the monoclonal immunoglobulin isotype implicated in each patient. During a post treatment recovery or mild disease phase there was reduced inflammation and decreased amounts of C5b-9 and type I interferon expression. Sudden onset capillary leak syndrome reflects enhanced endothelial cell permeability as a unique form of endothelial injury mediated by the combined effects of complement pathway activation and upregulation of type I interferon signaling on endothelium.

Antibody and T-cell responses by ultra-deep T-cell receptor immunosequencing after COVID-19 vaccination in patients with plasma cell dyscrasias.

We investigated antibody and coronavirus disease 2019 (COVID-19)-specific T-cell mediated responses via ultra-deep immunosequencing of the T-cell receptor (TCR) repertoire in patients with plasma cell dyscrasias (PCD). We identified 364 patients with PCD who underwent spike antibody testing using commercially available spike-receptor binding domain immunoglobulin G antibodies ≥2 weeks after completion of the initial two doses of mRNA vaccines or one dose of JNJ-78436735. A total of 56 patients underwent TCR immunosequencing after vaccination. Overall, 86% tested within 6 months of vaccination had detectable spike antibodies. Increasing age, use of anti-CD38 or anti-B-cell maturation antigen therapy, and receipt of BNT162b2 (vs. mRNA-1273) were associated with lower antibody titres. We observed an increased proportion of TCRs associated with surface glycoprotein regions of the COVID-19 genome after vaccination, consistent with spike-specific T-cell responses. The median spike-specific T-cell breadth was 3.11 × 10^-5 , comparable to those in healthy populations after vaccination. Although spike-specific T-cell breadth correlated with antibody titres, patients without antibody responses also demonstrated spike-specific T-cell responses. Patients receiving mRNA-1273 had higher median spike-specific T-cell breadth than those receiving BNT162b2 (p = 0.01). Although patients with PCD are often immunocompromised due to underlying disease and treatments, COVID-19 vaccination can still elicit humoral and T-cell responses and remain an important intervention in this patient population.

Efficacy of SARS-CoV-2 vaccination in patients with monoclonal gammopathies: A cross sectional study.

SARS-CoV-2 vaccination is the most effective strategy to protect individuals with haematologic malignancies against severe COVID-19, while eliciting limited vaccine responses. We characterized the humoral responses following 3 mo after mRNA-based vaccines in individuals at different plasma-cell disease stages: monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma on first-line therapy (MM), compared with a healthy population. Plasma samples from uninfected MM patients showed lower SARS-CoV-2-specific antibody levels and neutralization capacity compared with MGUS, SMM, and healthy individuals. Importantly, COVID-19 recovered MM individuals presented significantly higher plasma neutralization capacity compared with their uninfected counterparts, highlighting that hybrid immunity elicit stronger immunity even in this immunocompromised population. No differences in the vaccine-induced humoral responses were observed between uninfected MGUS, SMM and healthy individuals. In conclusion, MGUS and SMM patients could be SARS-CoV-2 vaccinated following the vaccine recommendations for the general population, whereas a tailored monitoring of the vaccine-induced immune responses should be considered in uninfected MM patients.

Reduced Immune Response and Neutralizing Antibody Activity to the SARS-CoV-2 Vaccination in Patients with a History of Solid Organ Transplant.

OBJECTIVE: Three SARS-CoV-2 vaccinations and boosters are available. We determined whether solid organ transplant patients mounted an immune response to the vaccinations and whether the antibodies had neutralizing activity compared to healthcare worker controls and monoclonal gammopathy patients. METHODS: Remnant plasma was obtained from vaccinated solid organ transplant, allogeneic stem cell transplant, monoclonal gammopathy patients, and healthcare worker controls. Samples positive on a SARS-CoV-2 IgG assay (detects spike protein and nucleocapsid) were run on a SARS-CoV-2 in vitro neutralizing antibody assay and a nucleocapsid-specific SARS-CoV-2 IgG assay. RESULTS: Only 25% of solid organ transplant patients produced antibodies to SARS-CoV-2 vaccination. Of these, 90% had neutralizing activity against wild type virus, but reduced activity to the variants compared to monoclonal gammopathy patients and healthcare worker controls, particularly the delta variant, for which only 50% had neutralizing antibody activity. CONCLUSION: Solid organ transplant patients should consider protecting themselves against future SARS-CoV-2 infection.

Adequate Antibody Response to COVID-19 Vaccine in Patients with Monoclonal Gammopathies and Light Chain Amyloidosis.

OBJECTIVE: Determine the COVID-19 seroconversion rate for patients with multiple myeloma receiving a COVID-19 vaccine. MATERIALS AND METHODS: After 45 patients received their second COVID-19 vaccine dose, their serum IgG antibodies were measured: 22 with monoclonal gammopathy (MG) of unknown significance, 3 with smoldering myeloma, 2 with light chain amyloidosis, and 18 with MG (9 in remission, 6 out of remission, and 3 with free light-chain gammopathy alone). A second serum specimen was retained for 16 patients with MG. Their antibody levels were compared to those of 78 uninfected healthy vaccinated control patients. RESULTS: Three patients with MG had low antibody levels on blood collected 98, 100, and 113 days after the initial vaccine dose (2 with MG of unknown significance and 1 with hypogammaglobulemia). The other 40 patients with MG (seroconversion rate 93%) and both patients with amyloidosis produced antibodies. Relative to days after vaccination, patients with MG had lower antibody levels than control patients. CONCLUSION: After receiving a COVID-19 vaccine, most patients with MG produce anti-SARS-CoV-2 antibodies comparable to levels in uninfected vaccinated healthy control patients.

Impact of Omicron variant on the response to SARS-CoV-2 mRNA vaccination in multiple myeloma and monoclonal gammopathies (preprint)

Multiple myeloma (MM) patients may have a reduced response to vaccination due to immunodeficiency. The humoral and cellular response to SARS-CoV-2 mRNA full vaccination and booster dose as well as the impact of spike variants, including the emerging Omicron one, are still unclear and have been investigated in this study in a cohort of MM patients and those with pre-malignant monoclonal gammopathies. Firstly, we have shown that MM patients with relapsed-refractory disease (MMR) had a reduced spike-specific antibody levels and neutralizing titers after SARS-CoV-2 mRNA full vaccination. Interestingly, all the analyzed variants, remarkably Omicron, had a significant negative impact on the neutralizing ability of the vaccine-induced antibodies in all patients with MM and in smoldering MM too. Moreover, lower spike-specific IL-2-producing CD4+ T cells and reduced cytotoxic spike-specific IFN-{gamma} and TNF--producing-CD8+ T cells were found in MM patients as compared to MGUS. Finally, we found that booster immunization improved SARS-CoV-2 spike humoral and cellular responses in newly diagnosed MM (MMD) patients and in most, but not all, MMR patients. After the booster dose, a significant increase of the neutralizing antibody titers against almost all the analyzed variants was achieved in MMD. On the other hand, in MMR patients, Omicron retain a negative impact on neutralizing ability, suggesting these patients need to be considered still at risk of Omicron SARS-CoV-2 infection with a clinically relevant disease.

Depletion of CD38-positive regulatory T cells by anti-CD38 monoclonal antibodies induces a durable response to SARS-CoV-2 vaccination in patients with plasma cell dyscrasia.

This study reports the relationship between CD38+ regulatory T cells (Tregs) and messenger RNA coronavirus disease 2019 (mRNA-COVID-19) vaccination in 60 patients with plasma cell dyscrasia. Patients treated with anti-CD38 monoclonal antibodies (mAbs) had significantly lower CD38+ Tregs than those not treated (0.9 vs. 13.2/µl). Late-responders, whose antibody titres increased from weeks 4-12 after the second vaccination, had significantly lower CD38+ Treg counts than non-late-responders (2.5 vs. 10.3/µl). Antibody titres in patients with lower CD38+ Treg levels were maintained from weeks 4-12 but decreased in those with higher CD38+ Treg levels. Therefore, depletion of CD38+ Tregs by anti-CD38 mAbs may induce a durable response to mRNA-COVID-19 vaccination.

Cross-sectional study to assess the efficacy of SARS-CoV-2 vaccination in patients with monoclonal gammopathies (preprint)

SARS-CoV-2 vaccination is the most effective strategy to protect patients with haematologic malignancies against severe COVID-19, but primary vaccine responses are less effective in this population. Here, we characterized the humoral responses following 3 months after mRNA-based vaccines in patients at different stages of the same plasma cell diseases, including monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and multiple myeloma on first line therapy (MM), compared to a healthy control population matched by sex and age. We observed that plasmas from uninfected MM patients after 3 months post-vaccine have lower SARS-CoV-2 specific IgG and IgA antibodies and decreased neutralization capacity compared with MGUS and SMM individuals, and a group of healthy controls. Importantly, we detected significantly higher plasma neutralization capacity in MM individuals who recovered from COVID-19 compared to their uninfected counterparts, highlighting that hybrid immunity elicit stronger immune responses even in this immunocompromised population. In contrast to MM group, no differences in the vaccine-induced humoral response were observed between uninfected MGUS, SMM and healthy individuals. In conclusion, a booster vaccine dose is recommended in uninfected MM patients to develop an adequate and effective humoral response to SARS-CoV-2 vaccine.