Rates of hospital admission and mortality in patients with MGUS and COVID-19 infection

It was established early in the COVID-19 (SARS-CoV- 2) pandemic that patients with cancer, in particular haematological malignancy, have worse outcomes than non-cancer patients. Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition, which may be linked with immune dysregulation, raising the possibility that patients with MGUS could also have worse outcomes from COVID-19 infection. Our aim was to identify all local patients with MGUS who had contracted COVID-19 since the start of the pandemic. 120 cases of COVID-19 infection in 114 MGUS patients were identified. Pillar 1 (patients with clinical needs and healthcare workers, n = 35) and pillar 2 (wider population, n = 85) test results were compared to our patient database to identify cases. Patients were subdivided based on the time period when they acquired COVID-19: wave 1 (February 2020-June 2020, n = 2), wave 2 (July 2020-May 2021, n = 31) and wave 3 (June 2021-current [data to end April 2022], n = 87). No subgroup analysis was carried out for the wave 1 data due to small numbers. Our outcomes were hospital admission and 4-week mortality. We compared our patient outcomes to regional, age-matched, population data for the same time periods. For rates of hospital admission, we looked at patients aged 65+ years. When looking at all MGUS patients from waves 2 and 3, the rate of hospital admission was not significantly different to the regional population (30.1% vs. 24.1%, p = 0.11). In wave 3, the hospital admission rate fell in both groups but was significantly higher in the MGUS patients compared to the regional population (26.9% vs. 16.4%, p = 0.02). For patient mortality, we looked at patients aged 50+ years. The overall 4 -week mortality rate for MGUS patients was higher than the age-matched regional population (5.4% vs. 2.4%, p = 0.02). A higher mortality rate was seen in waves 2 and 3 of the pandemic, with wave 3 also showing a statistically significant difference (3.7% vs. 1.2%, p = 0.02). Comparing MGUS patient outcomes from wave 2 to wave 3, there was a modest reduction in hospital admission over this time period (38.1% to 26.9%), with a more notable reduction in COVID-related mortality (9.7% to 3.7%). In conclusion, patients with MGUS and COVID-19 seem to have higher rates of mortality, and possibly also hospital admission, compared to the age-matched regional population.

Altered immune response to vaccination in patients with plasma cell premalignancy

Introduction Patients with hematological malignancies, including multiple myeloma (MM), experience suboptimal responses to SARS-CoV-2 vaccination. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) are precursors to MM and exhibit altered immune cell composition and function. The SARS-CoV-2 pandemic and the subsequent population-wide vaccination represent an opportunity to study the real-life immune response to a common antigen. Here, we present updated results from the IMPACT study, a study we launched in November 2020 to characterize the effect of plasma cell premalignancy on response to SARS-CoV2 vaccination (vx). Methods We performed: (i) ELISA for SARS-CoV-2-specific antibodies on 1,887 peripheral blood (PB) samples (237 healthy donors (HD), and 550 MGUS, 947 SMM, and 153 MM patients) drawn preand post-vx;(ii) single-cell RNA, T cell receptor (TCR), and B cell receptor (BCR) sequencing (10x Genomics) on 224 PB samples (26 HD, and 20 MGUS, 48 SMM, and 24 MM patients) drawn preand post-vx;(iii) plasma cytokine profiling (Olink) on 106 PB samples (32 HD, and 38 MGUS and 36 SMM patients) drawn pre- and post-vx;and (iv) bulk TCR sequencing (Adaptive Biotechnologies) on 8 PB samples from 4 patients (2 MGUS, 2 SMM) drawn pre- and post-vx. Results Patients with MGUS and SMM achieved comparable antibody titers to HD two months post-vx. However, patient titers waned significantly faster, and 4 months post-vx we observed significantly lower titers in both MGUS (Wilcoxon rank-sum, p=0.030) and SMM (p=0.010). These results indicate impaired humoral immune response in patients with MGUS and SMM.At baseline, the TCR repertoire was significantly less diverse in patients with SMM compared to HD (Wilcoxon rank-sum, p=0.039), while no significant difference was observed in the BCR repertoire (p=0.095). Interestingly, a significant increase in TCR repertoire diversity was observed post-vx in patients with SMM (paired t-test, p=0.014), indicating rare T cell clone recruitment in response to vaccination. In both HD and patients, recruited clones showed upregulation of genes associated with CD4+ naive and memory T cells, suggesting preservation of the T cell response in SMM, which was confirmed by bulk TCR-sequencing in 4 patients.Lastly, by cytokine profiling, we observed a defect in IL-1beta and IL-18 induction post-vx in patients with SMM compared to HD (Wilcoxon rank-sum, p=0.047 and p=0.015, respectively), two key monocyte-derived mediators of acute inflammation, suggesting an altered innate immune response as well. Conclusion Taken together, our findings highlight that despite the absence of clinical manifestations, plasma cell premalignancy is associated with defects in both innate and adaptive immune responses. Therefore, patients with plasma cell premalignancy may require adjusted vaccination strategies for optimal immunization.

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.

Accuracy and Reliability of German Websites for Information on Monoclonal Gammopathy of Undetermined Significance

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a clonal, premalignant plasma cell or B-cell disorder. MGUS patients often seek disease-related information online. However, the quality of online resources available for MGUS is questionable. Method(s): The quality of 900 German websites from Google, Bing, and Yahoo was evaluated. Result(s): The websites did not differ regarding their search rank or between the search engines. The 83 unique websites showed a medium to poor general quality (median JAMA score 3 of maximum 4 points, only 4% websites with a valid HON certificate). The patient- (user-) focused quality was poor (median sum DISCERN score 24 of maximum 80 points). The reading level was very difficult (29 of maximum 100 points according to the Flesch Reading Ease score). The content level was very low (11 of maximum 50 points). 23% of websites contained misleading/wrong facts. Websites provided by scientific/governmental organizations had a higher content level compared to websites provided by foundation/advocacy or news/media. Discussion(s): Similar previously published analyses often focus on otorhinolaryngology- related topics, idiopathic pulmonary fibrosis, SARSCoV- 2 or neurological disorders. Precancerous conditions and cancer entities were rarely in the focus of such evaluations. This study was performed in a reproducible and objective score-based manner, applying a set of well-established scores covering the aspects of general, patient- (user-) focused quality, and MGUS-related content. Conclusion(s): MGUS-relevant online sources showed low general and patient-focused quality and poor content. Information is provided on a high reading level. Incorporation of quality indices and regular review of content is warranted.

TIME TO EXPAND THE USE OF CASIRIVIMAB/IMDEVIMAB MONOCLONAL ANTIBODY THERAPY? A CASE OF COMPASSIONATE USE IN SEVERE COVID-19 PNEUMONIA

SESSION TITLE: COVID-19 Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: The FDA limits REGEN-COV (Casirivimab/Imdevimab) use to asymptomatic adults at high risk for progression to severe COVID-19 pneumonia or post-exposure prophylaxis. Here, we present a case of compassionate use of REGEN-COV in severe COVID-19 pneumonia. CASE PRESENTATION: A 76-year-old male with a medical history significant for COPD, Rheumatoid arthritis (treated with hydroxychloroquine and low dose steroids), and monoclonal gammopathy of undetermined significance (MGUS) presented with one week of fever, cough, and fatigue. He was febrile to 103 F, with normal oxygen saturation on admission. SARS-CoV-2 rapid molecular PCR was positive. He was started on Levofloxacin, but he did not meet the criteria for administration of dexamethasone, remdesivir, or monoclonal antibody (mAb) therapy. On day one of admission, he became hypoxemic and was subsequently started on dexamethasone and remdesivir. He was given convalescent plasma to address inadequate antibody response to COVID-19 immunization secondary to his chronic immunosuppressed/immunodeficient state. His hypoxemia continued to worsen, requiring high-flow nasal cannula oxygen (HFNC). A regimen of tocilizumab was also initiated. CT chest angiography ruled out pulmonary embolism but revealed diffuse bilateral patchy opacities. His oxygen requirements continued to increase with decreasing ROX index and hence was transferred to the Intensive Care Unit. Repeat PCR for SARS-COV-2 was significant for a high viral load. Approval for compassionate use of REGEN-COV was obtained and administered to the patient. Following administration, his symptoms improved significantly with the transition from HFNC to simple nasal cannula oxygen. Repeat PCR for SARS-CoV-2 also showed a remarkable decline of the viral load. He was transferred back to the medical floors and later to the skilled nursing facility once he was clinically more stable. DISCUSSION: In the United States, REGEN-COV (Casirivimab/Imdevimab) treatment has been approved for emergency use since November 2020. The combination of these two neutralizing immunoglobulin gamma 1 (IgG1) mAb attacks the spike protein of the SARS-CoV-2 virus and has been shown to effectively prevent the progression of symptomatic COVID-19 pneumonia and decrease the high viral load of SARS-CoV-2. It also reduces COVID-19 related hospitalization or death, especially in immunosuppressed patients. Our patient received dexamethasone, remdesivir, tocilizumab, and convalescent plasma as part of conventional COVID-19 treatment with continued worsening of COVID-19 pneumonia. However, the compassionate use of REGEN-COV led to rapid clinical improvement of the patient's symptoms and reduced the SARS-CoV-2 viral load. CONCLUSIONS: Hence, physicians and FDA should consider expanding the use of REGEN-COV mAB therapy to immunosuppressed patients with rapidly worsening COVID-19 pneumonia in adjunct to conventional COVID-19 treatment. Reference #1: Stein D, Oviedo-Orta E, Kampman WA, McGinniss J, Betts G, McDermott M, Holly B, Lancaster JM, Braunstein N, Yancopoulos GD, Weinreich DM. Compassionate Use of REGEN-COV ® in Patients with COVID-19 and Immunodeficiency-Associated Antibody Disorders. Clin Infect Dis. 2021 Dec 31:ciab1059. doi: 10.1093/cid/ciab1059. Epub ahead of print. PMID: 34971385;PMCID: PMC8755381. Reference #2: O'Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan KC, Sarkar N, Bar KJ, Barnabas RV, Barouch DH, Cohen MS, Hurt CB, Burwen DR, Marovich MA, Hou P, Heirman I, Davis JD, Turner KC, Ramesh D, Mahmood A, Hooper AT, Hamilton JD, Kim Y, Purcell LA, Baum A, Kyratsous CA, Krainson J, Perez-Perez R, Mohseni R, Kowal B, DiCioccio AT, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD, Weinreich DM;Covid-19 Phase 3 Prevention Trial Team. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. N Engl J Med. 2021 Sep 23;385(13):1184-1195. doi: 10.1056/NEJMoa2109682. Epub 2021 Aug 4. PMID: 34347950;PMCI : PMC8362593. Reference #3: Weinreich DM, Sivapalasingam S, Norton T, Ali S, Gao H, Bhore R, Xiao J, Hooper AT, Hamilton JD, Musser BJ, Rofail D, Hussein M, Im J, Atmodjo DY, Perry C, Pan C, Mahmood A, Hosain R, Davis JD, Turner KC, Baum A, Kyratsous CA, Kim Y, Cook A, Kampman W, Roque-Guerrero L, Acloque G, Aazami H, Cannon K, Simón-Campos JA, Bocchini JA, Kowal B, DiCioccio AT, Soo Y, Geba GP, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD;Trial Investigators. REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. N Engl J Med. 2021 Dec 2;385(23):e81. doi: 10.1056/NEJMoa2108163. Epub 2021 Sep 29. PMID: 34587383;PMCID: PMC8522800. DISCLOSURES: No relevant relationships by Mubashir Ayaz Ahmed No relevant relationships by Shayet Hossain Eshan No relevant relationships by Sami Hussein No relevant relationships by Khalid Hussein No relevant relationships by Kamalnath Sankaran Rajagopalan No relevant relationships by Chenyu Sun

UPDATE AND FOLLOW-UP OF NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM) WITH HIGH-RISK CYTOGENETIC (HRC)

Background: Despite therapeutic strategies improvement, there is still a subgroup of NDMM patients (pts) that pose a clinical challenge, whose represents a <20%, we refer to HRC. HRC Pts are associated with a poor prognosis and aggressive course, although, recent studies propose different clinical evolution according to the cytogenetic alteration (CA). IMWG identified a 4-year progression free survival (PFS) of 12% and OS of 35%. Aims: Describe our clinical experience and therapeutic management, also the clinical-biochemical alterations at diagnosis in a heterogeneous NDMM HRC's cohort. Evaluate survival curves according to HRC. Methods: Descriptive and retrospective analysis, using clinical and analytical NDMM HRC patient's data from 2009 to 2022 at Guadalajara University Hospital. 61/201 pts were selected in the MM treatment (tto) protocols. FISH results were not found in <30% NDMM, due to lack of metaphases or no request. Pts with t(4;14), t(14;16), gain 1q, t(14;20), plasmablastic leukemia and/or del(17p13) were classified as HRC. Survival data and Pearson (P) correlation were used. P value <0.05 was considered significant. Results: Total HRC NDMM 61 pts were analyzed. 21 of 61 pts (35%) were diagnosed with stage monoclonal gammopathy of undetermined significance (MGUS) prior to HRC NDMM, with a mean 4 years (y) (IR 2-10 y), greater % representation of MGUS were del17p (38), gain 1q (48), t (14;16) (4,5) and del17p + gain1q (9,5). Clinical characteristics data at diagnosis according to HRC are shown in Table 1. Pts receiving 1st line were 100% (61), 90,2% of the pts received bortezomib (V) - based induction, of them 29% (n=16) were treated with alkylating agents, 49,1% (n=27) received IMIDs and 18,2% (n=10) V with dexamethasone (d), plus two of these pts received regimens composed of 3xVCd + 3xVPd and the other dara-VRd. 25 pts (40,98%) were transplant eligible (TPH). 2nd line, 32 pts (52,5%), (n=3) VTD-PACE, (n=6) daratumumab (n=1 alone, 3 R, 1 V, 1 K), (n=1) Kdexa, (n=1) Pocydex and (n=9) V plus 3 IMIDs, 2 alkylating, 2 P or 2 alone and (n=12) IMIDs and alkylatings in combination. 5 pts (8,2) were TPH (1 alogenic). 3rd line, 16 pts (26,2), just 3 pts were TPH. 4th line, 7 pts (11,4), 1 pts were TPH. 5th line, 4 pts (6,5). 6th line, 2pts (3,3). In the last lines, the use of triplets with pomalidomide, karfilzomib or intensive chemotherapy prevail. After a median follow-up of 3 y (IR 1,6-6,2) from diagnosis, pts had relapsed at least one time (60,6%) and more than 3 times (11,5%), and 25 had died (40,9%), 16 of them due to infections (14 bacteremia, 2 COVID), 5 cardiorespiratory arrest and 3 due to progression. (Image 1) represents PFS y OS for only 5 CA, as data were no representative in other CA. Correlation between ISS and ISS-R data were only able to execute in HRC gain1q, due to lack of sample in other CA. We found a P coefficient of 0.568399 or 56.83% (p- <0.00578, CI 95%). Summary/Conclusion: Our case series continues with a longer survival curve compared to those commented in other studies. As cytogenetic abnormalities (t(4;14), t(14;16), t(14;20) and gain1q), similar % of representation are described as Kumar. Nat Rev Clin Oncol. 2018, except for del(17p), 23% vs 10%. From the second line, the probability of receiving a new line, the duration of tto and the interval without tto decreased with each line of tto. As treatment lines progress, therapeutic combinations are more heterogeneous and less concordant. A further longer follow-up and higher HRC NDMM pts's recruitment will be necessary to clarify the response to tto regimens based on individual cytogenetic groups.

Retrospective analysis of vaccine antibody titers in patients with different stages of monoclonal plasma cell disorders

Background: Infections occur with up to twofold increased risk in patients with monoclonal gammopathy of undetermined significance (MGUS) and tenfold increased risk in multiple myeloma (MM). To reduce risk, revaccination following autologous hematopoietic cell transplantation (AHCT) is recommended to restore humoral immunity. We have previously shown that vaccine titers after AHCT have prognostic significance. In the COVID era, reliable clinical data about antibody titers is relevant yet scarce. We investigated the significance of different vaccine titers in newly diagnosed patients in different stages of the disease. Methods: The study population comprised of 77 patients with MGUS, smoldering multiple myeloma (SMM) and MM who were seen at a tertiary cancer center from 2018- 2022. All patients had antibody titers (B. pertussis, Diptheria, H. Influenzae B, Hepatitis, Influenza, Meningitis, Mumps, Rubeola, Rubella, Poliovirus, S. pneumoniae, Varicella Zoster and Tetanus) tested at the time of diagnosis, prior to start of treatment if indicated. Titers were interpreted in accordance with the manufacturers' recommendations. Patient characteristics were compared using the Kruskal- Wallis and Fisher's exact tests. Associations with % titer positivity were evaluated using the Kruskal- Wallis test. Results: There was significant difference in antibody titer positivity between the different patient groups (51.4% in MGUS, 40.5% in SMM and 34.2% in MM) (p < 0.001). There was no difference in antibody titer positivity depending on age, sex or race. Among individual pathogens, there was a significant difference between the three groups in regards to titers for Diphtheria, Mumps, Poliovirus 3, Strep pneumoniae 19, Strep pneumoniae 56 and Varicella Zoster. Conclusions: Antibody titers for vaccine preventable diseases are significantly different between patients with MGUS, SMM and MM at the time of diagnosis, with MGUS having the highest and MM having the lowest positivity. Patient related factors such as age, sex or race were not associated with antibody titer positivity. Current guidelines for revaccination are not extended to patients with MGUS and SMM and can be considered in prospective trials.

FEVER OF UNKNOWN ORIGIN: ATYPICAL CLINICAL PRESENTATION OF MURINE TYPHUS

CASE: 66yo woman with a past medical history of hypertension and monoclonal gammopathy of undetermined significance was sent from clinic in winter for 4 days of worsening fevers and sinus congestion unrelieved by over-the- counter medications. COVID and flu negative. Patient has had no sick contacts or recent travel and has pet cats but no recent scratches. Initial chest x-ray showed no acute processes, but patient was continuing to have fevers up to 103 with mild dyspnea and chills so a CT chest was completed which showed ground glass opacities in the right middle lobe. Blood and sputum cultures were obtained, and patient was started on ceftriaxone and azithromycin for community acquired pneumonia. Urine strep and legionella antigens were also acquired, both negative. Over the next two days, she continued to have high fevers and chills at nights with leukocytosis, thrombocytopenia, hyponatremia, and notable worsening of mild elevation of liver enzymes on admission. Cultures were negative and patient had no other indication of an infection aside from the cyclical fevers therefore empiric doxycycline was added for coverage of atypical infections. Over the next two days, she continued to have nightly fevers up to 103 so ID was consulted for fever of unknown origin. On repeat exposure assessment, patient revealed that she lived with multiple animals including cats, dogs, parakeets, chickens, geese and a pony. Patient was continued on doxycycline while additional lab tests were sent for atypical infections including Rickettsia typhi, Coxiella brunetti (Q fever), and Brucella spp given patient's history of exposure to multiple animals at home. Patient was discharged on doxycycline after being afebrile for 48hrs with declining white count and liver enzymes. Lab results confirmed the diagnosis with high titers for Rickettsia typhi IgG and IgM. IMPACT/DISCUSSION: This case illustrates an atypical presentation of murine typhus with pneumonia in winter. There are several key teaching points in this case: 1. Ricketssia typhi infections have largely nonspecific symptoms therefore it should should be included in differential diagnoses of febrile illnesses with thrombocytopenia and elevated liver enzymes 2. Although a complete history is acquired on admission, it is important to revisit and review information again when a clinical diagnosis has not been established 3. Defeverscence after starting doxycycline can take anywhere from 4 to 66hrs so fevers during this timeframe is not an indication of failure of therapy CONCLUSION: Murine typhus presents with non-specific symptoms so it should be included in the differential diagnosis of patients with fevers of unknown origin with potential exposure to flea-bearing animals. The optimal therapy is doxycycline 100mg twice a day for seven days. Patients should also be advised to treat their animals for fleas to prevent recurrent infections.

Humoral SARS-CoV-2 response in asymptomatic precursor plasma cell dyscrasia patients: IMPACT study results

Introduction: Patients with hematologic malignancies, including multiple myeloma (MM), experience worse SARS-CoV-2 infection outcomes and sub-optimal vaccine responses. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) precede MM and affect ∼5% of individuals age >=50. We previously showed that individuals with MGUS and SMM exhibit immune dysregulation. Here, we investigate the immune response to SARS-CoV-2 vaccination in these asymptomatic but potentially immunocompromised individuals. Methods: The IMPACT study (IRB #20-332) is a prospective study at Dana-Farber Cancer Institute in collaboration with MMRF, which enrolled individuals nationwide with a diagnosed plasma cell dyscrasia and healthy individuals. As of October 2021, 3,005 individuals completed a questionnaire regarding prior infection or vaccination. We obtained 1,350 blood samples from 628 participants and analyzed anti-SARS-CoV-2 IgG antibody titer by ELISA. Results: 2,771 (92%) participants were fully vaccinated (2 doses BNT162b2 or mRNA-1273;1 dose Ad26.COV2.s), 269 (9%) had received a 3rd mRNA vaccine dose, and 234 (8%) were unvaccinated. 1,387 (46%) and 1,093 (36%) participants received mRNA vaccines (BNT162b2 and mRNA-1273), and 139 (5%) participants received an adenovirus vector vaccine (Ad26.COV2.S). 34 (1%) individuals reported SARS-CoV-2 infection after full vaccination. We measured antibody titers in 201 MGUS, 223 SMM, 40 smoldering Waldenstrom macroglobulinemia (SWM), 64 MM, and 100 healthy controls. Multiple linear regression model estimated the association between various clinical variables and post-vaccination antibody titers. As previously reported, having MM was associated with low antibody titer (p < 0.001). Of note, having SMM, regardless of risk stratification by 2/20/20 criteria, was also associated with low antibody titers, indicating that even low-risk SMM patients have a poor response to vaccination. MGUS and SWM diagnoses were not significantly associated with antibody titers. Additionally, male sex (p < 0.010), elapsed time after vaccination (p < 0.001), and BNT162b2 vaccine (p < 0.001) were associated with low antibody titers. SARS-CoV-2 infection prior to vaccination was associated with high antibody titers. We identified 25 patients (6 MGUS, 10 SMM, 2 SWM, 7 MM) who submitted blood samples after both the 2nd and 3rd dose. In these patients we observed a significant increase in antibody titer after a 3rd dose (p = 0.002). We also observed that antibody titers of patients after a 3rd dose (13 MGUS, 12 SMM, 2 SWM, 31 MM) were comparable to that of healthy individuals after a 2nd dose (p = 0.833). Conclusion: Our data indicates that suboptimal response to SARS-CoV-2 does not only occur with MM and cancer patients receiving therapy but also in precursor asymptomatic patients including low-risk SMM.

Single-cell RNA-sequencing for immune profiling of SARS-CoV2 vaccine response in healthy individuals and patients with precursor plasma cell malignancies

Introduction: Patients with hematological malignancies exhibit inferior response to SARS-CoV2 vaccination, compared to healthy individuals, however little is known about patients with precursor hematological malignancies and the cellular underpinnings of vaccination response. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Myeloma (SMM) are plasma cell premalignancies that precede Multiple Myeloma (MM) and exhibit signs of immune dysregulation;they affect approximately 5% of the population over 50 years of age, who remain largely undiagnosed, due to lack of screening. In November 2019, we launched the IMPACT study to characterize the immune response to SARS-CoV2 vaccination in patients with plasma cell dyscrasias and healthy individuals. Methods: We performed single-cell RNA-sequencing on 224 peripheral blood mononuclear cell samples drawn from 118 IMPACT (IRB #20-332) participants with MGUS (n=20), SMM (n=48), or MM (n=24), as well as healthy individuals (n=26). Samples were collected before vaccination and after 2 doses of BNT162b2 (Pfizer-BioNtech) (n=123), mRNA-1273 (Moderna) (n=83) or 1 dose of Ad26.COV2.S (Janssen) (n=14). Results: Overall, we sequenced 2,025,611 cells from 224 samples of 118 patients with MGUS, SMM, MM and healthy individuals pre- and post-vaccination for SARS-CoV2, and profiled 553,082 T-cells, 95,392 B-cells, 74,394 NK cells, 195,371 Monocytes, and 35,236 Dendritic cells (DC). We identified activated clusters of B-cells, NK cells and DCs expressing genes such as CD83, CD69, CXCR4, and genes related to the NF-kB and AP-1 pathways. We compared cell type abundances pre- and post-vaccination within each participant population and found that activated CD83+ cells significantly increased post-vaccination in healthy individuals and patients with MGUS (paired t-test, q < 0.1), but not in patients with SMM or overt MM. At baseline, patients with SMM and MM had significantly fewer memory B-cells and significantly more cytotoxic T-cells and NK cells, compared to healthy individuals (Wilcoxon, q < 0.1), which could partly explain the differences observed post-vaccination. Patients with MM also had significantly higher levels of tolerogenic IL-10-expressing DCs (DC10) at baseline (Wilcoxon, q < 0.1), which could be dampening antigen-specific T-cell responses. Conclusion: We identified a significant expansion of activated B-cell, NK cell and DC subpopulations expressing CD83, CD69 and CXCR4, following vaccination in healthy individuals and patients with MGUS, but less so in patients with SMM and overt MM. Our results provide insight into the cellular mechanisms of immune response to SARS-CoV2 vaccination in healthy individuals and patients with precursor plasma cell malignancies and suggest that asymptomatic individuals with SMM may exhibit inferior response to vaccination.

Severe Anemia Due to Cold Agglutinin Syndrome in a COVID-19 Patient with IgM Monoclonal Gammopathy of Undetermined Significance Successfully Treated with Corticosteroids.

Secondary cold agglutinin syndrome (CAS) is autoimmune hemolytic anemia secondary to infections and lymphoid disorder. We here report the first Asian case of CAS secondary to novel coronavirus disease 2019 (COVID-19). A 72-year-old Japanese woman presented with a 2-week history of dyspnea and cough, and laboratory data revealed severe hemolytic anemia with a hemoglobin level of 4.7 g/dL. She was diagnosed with COVID-19, CAS, and monoclonal gammopathy of undetermined significance (MGUS). The anemia responded to corticosteroids administered for COVID-19 and required maintenance therapy. Although corticosteroids are not a standard therapy for CAS, they might be effective for CAS secondary to COVID-19 complicated with MGUS.

EFFECTS OF VACCINATION ON INCIDENCE AND OUTCOME OF SARS-COV-2 INFECTION IN PATIENTS WITH MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)

We recently investigated incidence of SARS-CoV-2 infection and COVID-19 outcomes in MGUS patients during the early waves of pandemic, when vaccines were still not available (Sgherza N. et al Haematologica. 2022). In that study, we found that these subjects neither have an increased risk of contracting SARS-CoV-2, nor show poorer COVID-19 outcomes with respect to controls. Aiming to specifically address the clinical effects of vaccines, we compared incidence and outcome of SARS-CoV-2 infection of 1,454 previously described, not vaccinated MGUS patients (91 of whom were SARS-CoV-2 positive), with those observed in a similar population during the national vaccination campaign. So far, we have obtained retrospective information from 41 individuals found to be SARS-CoV-2 positive among 763 MGUS patients analyzed after at least two doses of anti-SARS-CoV-2 vaccine received between April 2021, and January, 2022. The mean age of this group was 64.1 +/-14.1 years (range 31-90);16 patients were female (39%), and 25 were male (61%). About MGUS-subtypes, the most frequent one was IgG-lambda (n=20;48.8%), followed by IgG-kappa (n=14;34.1%), IgA-kappa (n=3;7.3%), IgA-lambda (n=2;4.9%) and IgM-kappa (n=2;4.9%). Most of patients (39/41, 95%) were at low or low-intermediate risk, according to Mayo Clinic prognostic model. Twenty-one (51.2%) patients developed SARS-CoV-2 infection after two doses (5, 15 and 1 patients receiving ChAdOx1-S, BNT162b2 mRNA and mRNA-1273 vaccines, respectively), twenty (48.8%) after three doses (BNT162b2 mRNA or mRNA-1273 as 'booster' dose, repectively). The mean number of days between last dose of vaccine and SARS-CoV-2 infection was 98.8 +/-77.8 (range 2-240). The two populations of SARS-CoV2 positive MGUS patients (before and after vaccination) were comparable for age, sex and presence of co-morbidities (data not shown). Overall, rates of symptoms (59.3% vs 31.8%), hospitalization (20.9% vs 0%), and hospitalization in Intensive Care Unit (11% vs 0%) were significantly higher in still not vaccinated MGUS patients than in those who had received vaccines (Table 1). A strong trend toward a higher rate of deaths (8,8% vs 0%) was also observed in not vaccinated patients, although it did not reach statistical significance, probably due to the small number of evaluated patients. Interestingly, incidence of SARS-CoV-2 detection in vaccinated patients was not significally different from that of patients analyzed before vaccination (5.4% vs 6.2%, respectively) (p=0.402). Our data indicate that the possibility to be infected by SARS-CoV-2 is probably not significantly reduced by vaccination (even after three doses), likely also because of the higher diffusion capacity of the recently recognized Omicron viral variants. However, as observed in normal population and in other hematological contexts, the clinical outcome of COVID- 19 may be significantly improved after vaccination in MGUS patients, with less of one third of patients who were symptomatic and no case of hospitalization or death in our series. These observation reinforces the need to proceed with an active vaccination program in these patients. .

COVID-19 AND MYELOMA

The disease- and treatment-induced immunosuppression in MM accounts for a two-fold higher risk for infection with the SARS-CoV-2 virus, an increased risk for a prolonged, severe symptomatic disease, and an increased mortality. Most pts are aware of these risks and show a higher compliance with vaccination recommendations compared to the general population. Several studies revealed differences in the humoral and cellular immune response between pts with MGUS, SMM, and MM, with normal median antibody titers in MGUS, moderately impaired response in SMM, and significantly reduced antibody response in MM, albeit with a wide variation in titers between individual pts. Pts with active, poorly controlled disease and those exposed to CD38 and BCMA-targeting treatments frequently show no or reduced SARS-CoV-2 antibody responses. The EMN issued a consensus that MM pts should ideally be vaccinated before onset of active disease and/or during periods of well controlled disease. A third dose should be administered after an interval of approximately 6 months, and early data in immunocompromised pts show a vaccination response in several previously poorly responding pts after a forth dose. An open question pertains to the role of the interrelationship between the innate, humoral and cellular immune system. Neutralizing antibodies provide the best proxy for protection, although specific thresholds associated with protection against infection are unlikely to be established given the many factors associated with infection control. Antibody titers decline with time from vaccination and more so in vaccinated pts compared to those who have been infected and vaccinated, mandating booster shots in time intervals that need to be established. Pts may present without measurable antibody titers but with detectable cellular immunity or vice versa, although in most reports, correlations between antibody and cellular response were noted. Data suggest that SARSCoV- 2 specific memory B and T cells persist for prolonged periods. One of the threads to patient protection is the substantial mutational activity of the SARS-CoV-2 virus with reduced neutralizing capacity of vaccine induced antibodies against recent variants of concern, particularly the omicron variant, posing vaccinated pts at risk for breakthrough infections. Recent research efforts resulted in new prophylactic treatments for pts with high risk for severe COVID-19 disease (Table 1) that have been shown to reduce the incidence of severe complications. .

Are we looking for Monoclonal Gammopathy of Renal Significance ( MGRS )? An audit of investigations in current clinical practice

Monoclonal gammopathy of unknown significance (MGUS) is a premalignant condition defined as the presence of a monoclonal protein with no evidence of plasma cell/B-cell-related malignancy. The risk of progression from MGUS to a related malignancy is approximately 1% per year. MGUS patients are closely monitored for signs of progression allowing for rapid initiation of treatment. In 2012, the International Kidney and Monoclonal Gammopathy Research Group (IKMG) introduced the term Monoclonal Gammopathy of Renal Significance (MGRS). MGRS is the clonal proliferation of a nephrotoxic monoclonal protein without meeting the criteria for any other plasma cell/B-cell malignancy. The diagnosis of MGRS allows for the initiation of urgent treatment required to prevent further deterioration in renal function. Updated diagnostic criteria from the IKMG made renal biopsy essential for diagnosis of MGRS. Consequently, the IKMG set out an algorithm to guide clinicians on when to consider a renal biopsy. The parameters measured to evaluate the need for a renal biopsy include urine albumin creatinine ratio (ACR). This audit was conducted in the Clatterbridge Cancer Centre Liverpool (CCC-L) a leading cancer centre in the Northwest of England. Urine ACR was chosen as the parameter to audit as it is a cheap, non-invasive, quantitative investigation. The primary outcome of this audit is to assess the number of MGUS patients who had an ACR measured at diagnosis in the Myeloma clinic from January 2014 to December 2020. Data were collected retrospectively from electronic clinic letters and notes. The date of diagnosis was defined as the date of clinic letter in which diagnosis was first confirmed. Patients were considered to have had an ACR performed at diagnosis if ACR was measured between 28 days prior to and post the date of diagnosis. ACR performed during disease was defined as any ACR measured from 28 days prior to date of diagnosis and date of death/data collection. Data from 503 patients (249 females, 254 males) were analysed. The median age at diagnosis was 73. Table 1 shows data for patients who had an ACR measurement performed at diagnosis and during disease. There is a trend towards greater compliance to measuring ACR at diagnosis in successive years from 2014 to 2019 (Table 1). This trend reverses in 2020 when only 40.0% of patients had an ACR measured at diagnosis. For all patients where ACR was performed during disease;56.8% ( n = 179) had the highest ACR measurement of <3.0 mg/mmol with only 14.0% ( n = 44) having the highest ACR measurement of >30.0 mg/mmol. If ACR was performed at diagnosis it was more commonly repeated if the value was higher;the frequencies with which ACR was repeated were 85.7% ( n = 12), 65.1% ( n = 28) and 28.4% ( n = 31) when ACR value at diagnosis was >30.0 mg/mmol, 3.0-30.0 mg/mmol and <3.0 mg/mmol respectively. This audit has shown an increased recognition for the importance of ACR measurement with increased compliance year on year. A likely hypothesis for the reduced measurements in 2020 is the need for remote clinic appointments during the Coronavirus 2019 (Covid-19) pandemic. Following IKMG guidelines 14.0% ( n = 44) of patients would be advised to have a renal biopsy due to their ACR measurement of >30.0 mg/ mmol. Further evaluation of this patient cohort is required to audit compliance with other parameters suggested by the IKMG. A diagnostic pathway to be used at the earliest opportunity for MGUS patients may then be developed..

Serological response to the BNT162B2 mRNA or ChAdOx-nCOV-19 COVID-19 vaccine after first and second doses in plasma cell disorder patients: Influence of host and disease factors

Background Plasma cell disorders (PCD) are at risk of inadequate immune responses to COVID-19 vaccines due to recognised humoral and cellular immune dysfunction which is multi-factorial and related to host and disease factors. With an estimated risk of 33% mortality from contracting COVID-19 in this population, protection with an anti-SARS-CoV-2 vaccination is critical. Initial extension to vaccination intervals in the United Kingdom to 12 weeks in December 2020 led to concerns that PCD patients would be left vulnerable for an extended period. Methods A clinical audit was performed on measured serological responses in PCD patients after first and second doses of the BNT162b2 and ChAdOx-1 nCoV-19 vaccines. Antibody levels were measured using Elecsys Anti-SARS-CoV-2S assay (Roche) for quantitative detection of IgG Abs, specific for the SARS-CoV-2 spike-protein. Positive cut-off of 0.80 U/mL defined serological response. Testing was performed at (or closest to) 4 and 8-weeks post-dose. Baseline nucleocapsid Ab results were available from previous screening in a subset of patients. All patients on CIT underwent 4-weekly swabs. Clinical information was retrieved from medical records. Results 188 PCD patients (155 multiple myeloma, 18 amyloid, 10 SMM/MGUS, other 5 PCD), median age 64 (range 32-84), had serological assessment after both vaccine doses. Fourteen with previous COVID-19 infection were excluded. Of 174 patients, 112 were tested after first dose. 88% (153) were on chemo-immunotherapy treatment (CIT). Seropositive rate after first dose was 63% (71/112);of those with available negative baseline antibody test, 62% (31/50) seroconverted. After second dose, 89% (154/174) were seropositive;of those with negative baseline antibody, 90% (61/68) seroconverted. Expectedly, paired median titres after second dose were significantly higher than post first dose (n=112, 3.245 U/mL (IQR 0.4-25.55) vs 518 U/mL (IQR 29.40-2187) p<0.0001) (Figure 1A). Of 41 patients seronegative after first dose, 25 (61%) seroconverted after second, though with lower titres than those only requiring one dose (Figure 1B). Active CIT, disease response less than PR, >=4 lines therapy, light-chain disease, male gender and not responding to first dose were significant factors for not responding to two vaccine doses. We explored <400 U/mL as sub-optimal response (in keeping with upcoming booster study eligibility, OCTAVE-DUO(1), also encompassing the lower quartile of reported healthy controls(2)), which included 43% (75/174) patients. Age 70 years, male gender, >=4 lines of treatment were independent predictors of less-than-optimal response (anti-CD38 CIT of borderline significance). Importantly, vaccine dosing intervals classified as =<42 vs >42 days (Figure 1C) or 28 +/- 14 days vs 84 +/- 14 days (excluding n=66 in neither) (Figure 1D) did not show difference in both definitions of response, neither did vaccine type. Fourteen with previous COVID-19 infection responded to one vaccine dose, median titres 2121 U/mL (IQR 23.48- 2500)) rising to median 2500 U/mL (IQR 2500-2500) after second dose (Figure 1E), significantly higher than those without previous infection. Conclusion Serological response to COVID-19 vaccine is lower in PCD patients than reported healthy controls at 63% after first dose, rising to 89% after second dose, despite extended dosing intervals. PCD patients should be prioritised for shorter intervals, as we show that patients seronegative after first dose, respond after second dose. Further work in PCD is needed to understand how Ab levels correlate to neutralisation capability, cellular responses, protection from infection and how long seroconversion lasts to better define correlates of protection. A booster vaccination or prophylactic passive antibody strategy may be required for those identified at risk, shown not to have responded to two vaccine doses or to have less-than-optimal response. Results from these trials will be eagerly awaited. (Figure Presented).

Clinical Profile and Outcome of COVID Positive Hematology Patients during the COVID-19 Pandemic - an Analytical Cross Sectional Study from a Tertiary Care Centre in India

Introduction: The COVID-19 pandemic is a global public health challenge that has affected more than 30 million people and taken more than 4 lakh lives in India. The first and second COVID waves have greatly impacted the lives of a vast majority and vaccination of the masses remains a struggle. Although SARS -CoV-2 infections in patients with hematological diseases are expected to have an adverse outcomes, only limited reports are available from India. Hence, our study aims to identify the outcome in terms of severity and mortality in this group and the risk factors involved in developing severe COVID-19 and death. Methodology: This is a cross sectional analytical study done in a tertiary care hospital in Southern India for a period of 11 months. All hematological patients irrespective of age, who were infected with SARS-CoV-2 during the first wave (June -December 2020) and second wave (March - June 2021) were consecutively enrolled for the study after IRB approval. The patients were then categorized as neoplastic (acute and chronic leukemia, lymphoma, myeloma, MPN and MDS ) and non-neoplastic (ITP, aplastic anemia, hemolytic anemia, MGUS and TTP ) diseases. The clinical data was collected retrospectively from the electronic medical records and by direct telephonic contact. Patients were categorized as having mild (spO2 > 94 % symptomatic /asymptomatic), moderate (spO2 90 - 94 %) and severe (spO2 < 90 %) disease based on their severity of infection, each category of patients received appropriate clinical management. Treatment details, mortality and other outcomes were recorded for 30 days. The continuous variables were represented as mean (± SD)/median (IQR) and categorical variables as frequency and percentage. The association of the outcome variable with selected variables were calculated using Chi-square tests and kaplan meier survival analysis. The data sets were analyzed (SPSS version 21) and a p value of < 0.05 was considered statistically significant. Results: The study was conducted with 70 patients (n=70). Demographic details of patients are summarized in Table 1.Seventeen (24.3%) out of 49 (70%) hospitalized patients required ICU care. There were 13 (18.6%)deaths. in the patients who survived, prolonged antigen positivity of COVID on testing after 21 days was seen in 9 patients (16.1%). In 35 patients (50%)hematological treatment was restarted with a mean delay of 9.2 +/- 10.72 days. Predictors of severity of the disease is summarized in Table 2. Age more than 50 years (P=0.002)(Figure 1a), severe COVID (P=<0.001) and D dimer value of >2 times normal (P=0.047) were associated with a 30-day mortality. Additionally, patients on active treatment for hematological disease were at greater risk of severe COVID (P=0.012). There was no significant difference in severity (P=0.197) or mortality (P=0.556)in patients with neoplastic vs. non-neoplastic disorders Conclusion: COVID-19 patients with malignant and non-malignant hematological diseases showed an increased mortality. Age > 50 years and high D dimer values (>2N) were identified as predictors of mortality. Active treatment for haematological disease predisposed to severe disease.The study needs to be validated further on a larger cohort of patients. Preventive strategies including vaccination is warranted in patients with hematological disorders. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Severity of Covid-19 Clinical Outcomes and Mortality in Multiple Myeloma Patients over Year 1 of the Pandemic

Introduction In the first weeks of the Covid-19 pandemic when healthcare systems in many areas were overstretched, we documented that hospital mortality in multiple myeloma (MM) patients infected by Sars-Cov-2 was 50% higher than in age matched Covid-19 patients without cancer. In the following months, the pressure on healthcare systems in Spain continued although it did not reach the extreme levels of the first weeks of the pandemic. In this study, we proposed to determine if the severity of Covid-19 outcomes in MM patients has changed over the first year of the pandemic. Patients and methods The Spanish MM Collaborative Group (Pethema-GEM) conducted a survey at national level on plasma cell disorder patients infected by SARS-Cov-2 between March 2020 and February 2021. Sixty-six (69%) out of 96 contacted healthcare centers, from all 17 regions in Spain, reported 502 patients. Data on Covid-19 acute and post-acute phase outcomes (hospitalization, oxygen requirements, severity of symptoms and mortality) were reported first in May 2020 (Martinez-Lopez et al, BCJ 2021) and updated in February 2021. In this study, we compared outcome occurrence between two study periods: P1, a period of extreme stress for the healthcare system in Spain, from March to mid-June 2020;and a second period, P2, up to mid-February 2021 with a sustained but lower burden on the national health care system. Results Among the 451 patients with plasma cell disorders and a Sars-Cov-2 infection documented with an rRT-PCR positive test, 377 (84%) were MM patients, 15 SMM (3%), 40 MGUS (9%) and 19 amyloidosis (4%). The number of MM weekly reported cases was 57% (95%CI, 48-65) lower in P2 (188 cases in 35 weeks) compared to P1 (189 cases in 15 weeks), p<0.001. The mean (SD) age and the proportion of men did not differ between P1 and P2, respectively 69.8 (10.9) vs 68.6 (11.0) years, p=0.6, and 53.3% vs 59.6%, p=0.2. MM patients with active or progressive disease at time of Covid-19 diagnosis were 24% in P1 and 34% in P2, p=0.05;patients on active treatment were more frequent in P1, 89%, than in P2, 79%, p=0.01. MM treatment was withheld in 78% and 82% of patients, p=0.4. Covid-19 treatment changed over time: MM inpatients received more remdesivir and corticoids in the second period (3% vs 31% p<0.001, and 49% vs 73%, p<0.001, respectively). In P1, 90% of the reported MM patients were hospitalized compared to 71% in P2, p<0.001. Thirty-one and 41% of patients did not require oxygen support during P1 and P2, respectively;non-invasive ventilation in 19% and 14%, and mechanical ventilation in 7% and 8%, p=0.12. Overall, acute clinical Covid-19 severity was reduced from P1 to P2: 75% to 51%, p<0.001: moderate/severe pneumonia was reduced from 68% to 36%, p<0.001 but severe distress syndrome increased from 7% to 15%, p=0.03. However, mortality in all reported patients was 30.7% in P1 vs 26.1% in P2, p=0.3;and no differences in mortality were observed in hospitalized patients, 32.2% in P1 and 35.3% in P2, p=0.6. We performed a multivariable adjustment with the predictors identified in our previous study (BCJ 2021) and confirmed that inpatient mortality was similar in both study periods, odds ratio (OR) 0.99 (95%CI 0.59-1.66). Independently of the study period, an increased mortality was observed in men (OR 1.81, 1.08-3.05), patients over 65 (OR 2.40, 1.33-4.36), and patients with active or progressive disease (OR 2.12, 1.24-3.62). The severity of Covid-19 clinical outcomes -besides mortality, was associated with increased age but not with active or progressive disease. Conclusions Although COVID-19 clinical severity has decreased over the first year of the pandemic in multiple myeloma patients, mortality remains high with no change between the initial weeks of the pandemic and the following months. Prevention and vaccination strategies should be strengthened in this vulnerable population, particularly in patients with active or progressive disease at time of Covid-19 diagnosis. Disclosures: Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfi er: Consultancy;Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Mateos: Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees;Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVie: Honoraria;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Bluebird bio: Honoraria;GSK: Honoraria;Oncopeptides: Honoraria. López-Muñoz: Amgen: Consultancy. Sureda: GSK: Consultancy, Honoraria, Speakers Bureau;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Other: Support for attending meetings and/or travel;Mundipharma: Consultancy;Bluebird: Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;MSD: Consultancy, Honoraria, Speakers Bureau;BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. Lahuerta: Celgene, Takeda, Amgen, Janssen and Sanofi: Consultancy;Celgene: Other: Travel accomodations and expenses. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board.

Monoclonal Gammopathy of Undetermined Significance Clinic during the Coronavirus Disease-19 Pandemic: Caring for the Vulnerable in an Academic Medical Center.

BACKGROUND: Patients with monoclonal gammopathy of undetermined significance (MGUS) have clinical features including older age, presence of medical comorbidities, susceptibility to infections, and thrombotic tendencies which are relevant when assessing their risk during the coronavirus disease (COVID-19) pandemic. OBJECTIVE: To study the vulnerability of patients with MGUS during the COVID-19 pandemic, we assessed the local management of MGUS patients and their clinical outcomes. METHODS: Retrospective chart reviews were performed for all patients with MGUS seen at a university medical center clinic (2014-2020). RESULTS: A total of 228 MGUS patients were included; 211 patients are alive, 7 patients died before the pandemic, and 10 patients died since the pandemic declaration. The mean age and the overall survival (OS) of the patients who died before versus during the pandemic were 83.0 versus 75.2 years, p = 0.4, and OS 40.6 versus 53.2 months, p = 0.3, respectively. One patient died of COVID-19. Nine patients had venous thromboembolisms (VTE), all of which occurred before the pandemic onset. CONCLUSIONS: There were no significant differences found in the mean age or OS of the MGUS patients who died before versus after the pandemic onset. An increase in VTE rates was not seen. Study results are limited by small patient numbers.

Case of Kikuchi-Fujimoto disease associated with multiple myeloma.

We present a 47-year-old, South-African origin, woman with a background of stable monoclonal gammopathy of unknown significance (MGUS) who attended A&E with a history of coryzal symptoms associated with persistent fever, lymphadenopathy and a new onset of rash, not responding to antibiotics and paracetamol. A trial of high-dose steroids resolved symptoms. Bone marrow biopsy confirmed a progression of MGUS into multiple myeloma and her axillary lymph node biopsy analysis supported a diagnosis of Kikuchi-Fujimoto disease (KFD). This is an unusual presentation where KFD has been noted alongside MGUS progression to multiple myeloma. Haematology follow-up is underway.