ABSTRACT
There is increased infection risk at the time of autologous stem cell transplantation (ASCT) including for patients with plasma cell disorders (PCD), therefore preventing infection with COVID-19 vaccination in this vulnerable group is key. However, patients with PCD have been shown to mount suboptimal responses to COVID-19 vaccination. A clinical audit of serological response to COVID-19 vaccination before and after ASCT was undertaken, to observe how antibody titres change during this period. Antibodies to the SARS-CoV-2 spike protein were measured using the Elecsys Anti-SARS-CoV-2S assay (Roche diagnostics) in 88 patients who underwent ASCT for PCD at the University College London Hospital NHS Foundation Trust between December 2020 and September 2021. Pre-ASCT antibody titres were measured following first or second vaccine and following ASCT. The majority ( n = 76) had no prior history of COVID-19 infection, and four of this cohort declined vaccination. In those who received one vaccine pre-ASCT ( n = 21), 76% seroconverted with a median titre of 11.3 3 U/ml (IQR 1.5-62.6). In those who received two doses pre-ASCT ( n = 51), 97% seroconverted with a median titre of 494 U/ml (IQR 190.5-1681). In those who received two doses pre-ASCT, anti-S antibodies were detected in the immediate post-ASCT setting, with titres of 373 U/ml (median, IQR 40.6-2326) measured less than or equal to 28 days (median 15 [6-25]) post-ASCT, and 170 U/ml (IQR 55-604) at more than 28 days (median 85 [32-125]) post-ASCT. Patients who received one dose pre-ASCT had lower median titres of 36.5 U/ml (IQR 12.6-1310) measured less than or equal to 28 days (median 15 [12-22] post-ASCT and 7.7 U/ml (IQR 2.9-23.8) at more than 28 days (median 85 [40-104] post-ASCT. Antibody levels declined over time, but patients who had received two vaccines pre-ASCT maintained higher titres post-ASCT compared to those who had received one dose, emphasising the importance of COVID-19 vaccination prior to ASCT. Our patients are advised to be re-vaccinated against COVID-19 3 months after ASCT, and antibody response following re-vaccination was measured in a subgroup ( n = 14). Those who were previously un-vaccinated did not seroconvert following one dose. However, antibody titres in those who had received either one or two vaccines ( n = 12) prior to ASCT increased from 32.4 U/ml (median, IQR 13.4-1082) post-ASCT to 431 U/ml (median, IQR 15.33-2500) following re-vaccination. Those who had received two vaccines pre-ASCT ( n = 2) achieved higher titres than those who had received a single dose. In conclusion, we demonstrated how protective titres fall during the patient's journey through ASCT and our repeated interactions with them. Despite this, patients vaccinated prior to ASCT maintain some level of measurable antibody immediately post-ASCT, which is encouraging as patients are considered most vulnerable to infection during this period. Titres were also boosted effectively after one dose of re-vaccination, compared to those never vaccinated. Current guidance is for adult patients who have undergone ASCT to be considered 'never vaccinated' against COVID-19, in line with pre-COVID-19 re-vaccination practice, and to receive a three-dose primary course followed by a booster vaccination post-ASCT. We must facilitate and encourage our patients to be vaccinated prior and after ASCT in this rapidly changing landscape, especially in context of the spread and evolution of a potentially more transmissible virus. (Table Presented).
ABSTRACT
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).
ABSTRACT
Introduction: Daratumumab in combination with bortezomib and dexamethasone (DVd) demonstrated a superior overall response rates (ORR) and progression free survival (PFS) compared to Vd in the CASTOR phase 3 trial for patients with RRMM. On this basis, DVd was recommended in March 2019 for UK patients with RRMM that had 1 prior line (PL). Discrepancies in outcomes between patients treated in clinical trials compared to routine practice is well recognised due to a combination of patient, disease and treatment-related factors. In addition, bortezomib is often administered once-weekly in routine practice to minimise neuropathy, while CASTOR used bi-weekly bortezomib dosing. As a result, the real-world outcomes of patients treated with DVd are yet to be determined. The primary aims of this analysis was to assess the ORR and PFS for patients with RRMM with 1PL treated with DVd in routine practice. Secondary aims were to assess OS, time to next treatment (TTNT), and efficacy in different sub-groups (high risk cytogenetics, previous proteasome inhibitor (PI) exposure, refractoriness of prior therapies, bi-weekly vs weekly bortezomib schedule, and previous treatment free interval (TFI)). Methods: This was a retrospective analysis from 14 centres (academic and community hospitals;7 within the West Midlands Research Consortium (WMRC)) treated with DVd between March 2019 and June 2021. Patients received daratumumab (IV and then SC from June 2020) weekly in cycles 1-3, on day 1 of a 3-week cycle during cycles 4-8, and then monthly from cycle 9 to progression. SC Bortezomib was predominantly given weekly for cycles 1-8 although 5 centres used bi-weekly dosing for selected patients with aggressive disease. Adverse events were graded as per CTCAE criteria. Results: 288 patients were included, with a median age of 69 years (range 20-88) (Table 1). Patients received a median of 1 PL (range 1-2) with 93% (269) 1PL, 7% (18) 2 PL (due to COVID-19 measures). The majority had an ECOG performance status of 0-2 (98%) and most received weekly bortezomib (n=201). This population differed from those with 1PL treated on CASTOR in being older, more were ISS 3 (31% vs 19%, p=0.0145), and more had prior bortezomib exposure (71% vs 51%, p=0.0003), 4% were PI refractory, 9% had a GFR of <30ml/min (<20ml/min was an exclusion from CASTOR), and 2% had an ECOG performance status of ≥3. The ORR was 76%, with >VGPR in 54% (Table 2), with no significant difference in response between patients receiving biweekly vs weekly bortezomib (85% vs 83%;p=0.71). The median time to response was 1.6m. With a median follow up of 15m, the median PFS was 14m (95% CI 11.6-16). High cytogenetic risk patients had inferior outcomes: median PFS 10m (95% CI 6-14) for high risk vs not reached for standard risk (p=0.043);as did those with advanced ISS: median PFS was not reached, 15 and 12m for stage I, II and III respectively (p=0.05). For 15 patients with extramedullary disease (EMD), the median PFS was 3m (95% CI 1-5). Median PFS for patients who were PI refractory was shorter (10m vs 15m for PI sensitive patients (p=0.006)). There was no difference in median PFS for patients with prior PI exposure vs no prior PI (15 vs 13m;p=0.75), or according to weekly or bi-weekly bortezomib schedule (11 vs 15m;p=0.14). The median TTNT was 21m (95% CI 17-25). Overall, the median duration of treatment was 8m and 25 patients (9%) stopped treatment to receive a second autologous stem cell transplant. Those that had a prior TFI of >12m had a longer median PFS of 21m vs 10m (p=0.0004). The median OS has not been reached, with an estimated 2-year OS of 74%. For patients with high risk cytogenetics the median OS was 16m (95% CI 9-23;vs not reached for standard risk;p=0.0006), with estimated 2-year OS in the high risk group of 36%. There was no difference in OS for patients treated with biweekly vs weekly bortezomib (not reached for either;p=0.38). DVd was generally well tolerated with 6% stopping due to adverse events (CASTOR 9.5%). Grade 3 or 4 toxicity occurred in 62 (22%) most comm nly neutropenia and thrombocytopenia, with any grade infusion reactions reported in 27 (9%). Conclusions: These real-world data of DVd at 1 st relapse demonstrated good tolerability and high response rates with a weekly bortezomib schedule despite a more heterogenous population. However, high risk patients by cytogenetics, ISS or EMD had inferior outcomes as did those treated within 12 months from first line treatment. [Formula presented] Disclosures: Cook: Karyopharm: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding;BMS: Consultancy, Honoraria, Research Funding;Oncopeptides: Consultancy, Honoraria;Roche: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Research Funding. Pratt: Binding Site: Consultancy;BMS/Celgene: Consultancy;Gilead: Consultancy;Janssen: Consultancy;Takeda: Consultancy;Amgen: Consultancy. Kishore: Celgene: Other: Attending fees;Jannsen: Other: Attending fees;Sanofi: Other: Attending fees;Takeda: Other: Attending fees. Yong: Amgen: Honoraria;Autolus: Research Funding;BMS: Research Funding;Janssen: Honoraria, Research Funding;Sanofi: Honoraria, Research Funding;GSK: Honoraria;Takeda: Honoraria. Popat: Abbvie, Takeda, Janssen, and Celgene: Consultancy;Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES;GlaxoSmithKline: Consultancy, Honoraria, Research Funding;AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria;Janssen and BMS: Other: travel expenses.
ABSTRACT
Background: Plasma cell disorder (PCD) patients are extremely vulnerable to SARS-CoV-2 infection due to disease-related impaired humoral and cellular immunity as well as the receipt of immunosuppressive therapy. Reported mortality in a large cohort of patients with plasma cell disorders is 33%. The roll out of the COVID-19 vaccine is welcomed in this population, however there is concern of suboptimal antibody responses, from previous experience with the influenza vaccine. There is urgent need to understand the humoral response to SARSCoV- 2 infection in these patients, in the context of systemic anti-cancer therapy (SACT). Aims: We aimed to investigate the presence of SARS-CoV-2 antibodies in a cohort of PCD patients, the relationship with symptomatic infection, PCD characteristics and receipt of SACT. Methods: SARS-CoV-2 antibody screening with the Elecsys Anti-SARSCoV- 2 assay (Roche Diagnostics, Basel, Switzerland), a semi-quantitative assay of IgG and IgM against the nucleocapsid (N) antigen was introduced for PCD patients at our institution in July 2020. Clinical information was retrieved from the medical records. Patients with unexpected positive antibody tests were asked about possible past contacts and exposure to SARS-CoV-2. Results: We report on a six-month period of routine SARS-CoV-2 antibody screening. Two-hundred and forty-three PCD patients had one antibody test, 106 had serial samples. Total seroprevalence was 10.7% (26/243), of which 12 were patients with known PCR-swab positive COVID-19 disease. In a separate but overlapping cohort, 41 patients have had PCR confirmed COVID-19 disease;20 of these patients were tested, and 12 (60%) had seroconverted. Median time to testing from positive PCR test in the antibody positive patients was 86.5 days (range 22-256) and in antibody negative patients, 30.5 days (range 5-176 days). No PCD or COVID-19 disease factors were found to influence the likelihood of mounting an antibody response after PCR-confirmed COVID-19 disease in these 20 patients. In our screened cohort, 14 (6.3%) patients were unexpectedly antibody positive. Their clinical course is summarised in the included figure. The majority 85.7% (12/14) of patients described no COVID-19 symptoms. Seven (50%) patients were on SACT (including ixazomib, pomalidomide, lenalidomide and dexamethasone combinations) throughout the period from possible exposure to positive antibody test, with no interruption to their ongoing oral immunomodulatory treatment. Ten antibody positive patients had serial positive results at median 45 days (range 21-119) apart, demonstrating persistence, but some decline in titre over time. Summary/Conclusion: Our seroprevalence of 10.7% is lower but not dissimilar to that reported in the London population over a similar time period reflecting shielding behaviours in our patients but also the challenges of protecting them during high SARS-CoV-2 incidence in the community. Nevertheless, PCD patients retain the ability to seroconvert, even with asymptomatic COVID-19 disease and while on immunomodulatory therapy. Seroconversion rates following symptomatic infection appear lower however, with evidence of delay compared to the general population. These data support the advice for COVID-19 vaccination to be offered to all PCD patients although the suboptimal humoral response calls for close antibody monitoring of all vaccinated PCD patients and timely booster doses.