Introduction: Lenalidomide (Len) is increasingly used at earlier lines of treatment for patients with multiple myeloma (MM) and is usually continued until disease progression. Subsequent treatment choices are based on prior treatment, response, cytogenetics and overall performance status. The natural history of patients treated with Len is not fully captured by clinical trials due to limitations with long-term follow-up. It is also apparent that those treated in the real world have different outcomes to those treated within clinical trials. Whilst clinical trial data is emerging for Len refractory treatments, real world data for this group is limited. We therefore examined a dataset of patients treated with Len that were followed up for subsequent treatments and outcomes. Methods: This was a retrospective cohort review from 2 UK myeloma centres of patients with relapsed MM who received Len between 2006 and 2017. Data were collected for demographics, Len treatment (T0), subsequent treatments after Len (T1, T2, T3 etc) and enrollment into clinical trials. Response was assessed by IMWG criteria and measures of survival determined by Kaplan-Meier analysis. Differences between survival were assessed by log rank test, comparison of variables between patients was performed using student t-test, Mann Whitney U or Fisher's exact test. Results: 461 patients were identified between August 2006 and September 2017 of whom 263 were excluded due to incomplete data or a non-myeloma diagnosis. 198 patients (median age 66 years (35-88)) were evaluable who commenced Len a median of 41 months (0.5-210m) from diagnosis. Patients had a median of 2 prior lines (1-3); 73% had received proteasome inhibitor (PI) and thalidomide. Toxicity stopped Len use in 11 patients. There were 114 patients (72% of 158 evaluable) refractory to Len after initial response. Of these 90 (57%) had biochemical evidence of disease progression (PD) but continued on Len for a median of 3.45m (0-20.1m); 24 (26%) continued on Len for >6 months. 41 (20.7%) patients did not have PD, of whom 31 (15.7%) were alive and 10 (5%) died (Figure 1). Numbers of patients receiving subsequent treatments after Len were as follows: T1 113 (57%); T2 61 (31%); T3 24 (12%); T4 10 (5%); T5 2 (1%); T6 1 (0.5%). The mortality during each treatment line was: T1 37 (33%); T2 22 (36%); T3 9 (38%); T4 5 (50%). The most common treatment immediately after Len was pomalidomide-dexamethasone. Response rates by each subsequent treatment are shown in Table 1. Proportions of stable disease increased with subsequent lines. After a median follow-up of 33.8m from Len, the PFS for each subsequent treatment was: T0 11.1m; T1 5.7m; T2 6.6m; T3 6.7m; T4 3.6m. As the majority of patients were refractory to Len at the start of next treatment, PFS2 from Len was assessed to determine optimal salvage treatment. The median PFS2 was similar irrespective of treatment (pomalidomide (n=28) 23m, bortezomib and panobinostat (n=12) 24m, bendamustine (n=16) 25m, clinical trials (n=9) 19m, other (n=48) 25m (p=ns)). The median OS from diagnosis was 87.4m and the median OS from Len PD or change of therapy (if without PD) was 14.7m. Overall 37 (33%) enrolled into a clinical trial at any time after Len. Those treated in a clinical trial had a superior OS to those that did not (median OS 30.0m vs 8.8m, p=0.0002; HR: 2.49, Figure 2). There was a high early mortality in the non-trial group with a 6 month OS after Len PD of 63.2% (trial) vs 91.9% (non-trial) (p=0.0017, HR 3.2, 95% CI 1.5-6.7). Trial patients also had a higher median eGFR (77.5 vs 61 ml/min (p=0.02)) and better performance status (p=0.016) than those not enrolled suggesting this was a better biological population. Conclusion: The outcomes for patients with relapsed MM following Len are poor with an OS of 14.7m and 15.7% dying before receiving further treatment. Decreasing numbers of patients receive subsequent treatments, with few able to get 5 or 6 further lines after Len. These outcomes are likely to change as Len moves to front line and immunotherapies are incorporated in routine practice. This data-set therefore serves as a baseline with which to compare such advances. The superior outcomes for those in clinical trials may in part reflect the potential of novel treatments with different modes of action in Len and PI exposed patients. However, the differences in performance status and renal function provide evidence of the disparity between trial and real world data-sets. Disclosures Lee: Autolus Therapeutics: Equity Ownership, Research Funding. Parrish:AbbVie: Consultancy, Honoraria; JAZZ: Honoraria; JAZZ: Honoraria; Takeda: Honoraria, Other: Financial support to attend scientific meetings; Takeda: Honoraria, Other: Financial support to attend scientific meetings; Celgene: Other: Financial support to attend scientific meetings; Janssen: Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Other: Financial support to attend scientific meetings; Janssen: Honoraria. Yong:Amgen: Research Funding, Speakers Bureau; Autolus: Consultancy; Janssen: Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau. Popat:Takeda: Honoraria, Other: travel, accommodations, expenses; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria.
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. References: 1. University of Birmingham. About the OCTAVE Trial 2021 [Available from: https://www.birmingham.ac.uk/research/crctu/trials/octave/patients-and-public/about-octave.aspx. Accessed 1 st August 2021. 2. Avivi I, Balaban R, Shragai T, Sheffer G, Morales M, Aharon A, et al. Humoral response rate and predictors of response to BNT162b2 mRNA COVID19 vaccine in patients with multiple myeloma. Br J Haematol. 2021. Figure 1 Figure 1. Disclosures Wechalekar: Amgen: Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy; Caelum Biosciences: Other: Clinical Trial Funding; Janssen: Consultancy; Takeda: Honoraria; Celgene: Honoraria. Popat: AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Janssen and BMS: Other: travel expenses. Rabin: BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings; Takeda: Consultancy, Honoraria, Other: Travel support for meetings; Janssen: Consultancy, Honoraria, Other: Travel support for meetings. Yong: BMS: Research Funding; Amgen: Honoraria; GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Autolus: Research Funding.
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