ABSTRACT
Background: Systemic AL amyloidosis is an incurable relapsing plasma cell disorder. Despite therapeutic advances, there are no approved treatments for relapse disease. Treatment is often challenging due to underlying organ dysfunction. Belantamab mafodotin is an antibody-drug conjugate targeting B-cell maturation antigen with approval for relapsed refractory myeloma. In multiply pre-treated myeloma, the DREAMM-2 phase II trial showed an overall response rate of 32% for those with 2.5 mg/kg dose administered every three weeks with 2/3rd patients reporting keratopathy. A small case series of 6 patients with relapsed AL amyloidosis (Zhang et al , ASH 2021) was recently reported and a phase 2 trial is recruiting for patients with refractory amyloidosis (NCT04617925). Aims: We report our initial results using Belantamab monotherapy for the treatment of patients with AL amyloidosis with relapsed disease. Methods: Data for consecutive patients who were administered Belantamab at a specialist referral centre, National Amyloidosis Centre, University College London, was analysed. Results: Eleven patients were included 8 male, 3 female. Median age at Belantamab initiation was 65 (range 42-74) years. Eight patients had λ AL-type and three κ AL-type. At diagnosis, median involved free light-chain concentration was 534 (range 73-7181) mg/l. A median of two organs involved at baseline (range 1-3): 4 had cardiac involvement (half Mayo stage 2;half Mayo stage 3a) and 8 had renal involvement. The median prior lines of therapy was 3 (range 2-5) with all exposed to prior immunomodulatory drugs, proteasome inhibitors and 73% to anti-CD38 antibody treatments. Thirty-six percent had relapsed after melphalan-conditioned autologous stem cell transplantation. A median of 3 cycles of belantamab were delivered (range 1-8). The most frequent adverse event was ocular toxicity which was experienced in 8 patients (grade 1-3), necessitating dose modification of the three-weekly schedule. One patient developed transient grade 1 dyspnoea and liver dysfunction. No patients developed cytopenias, unlike previous reports (Zhang et al , 2021), nor infections beyond COVID (2 patients mild with no hospital admissions). The majority of the cohort required dose reduction either at initiation (patient 4, due to end stage renal failure;patient 11, post-renal transplant) or during therapy (n=5;three to 1.9mg/kg, two to 1.25mg/kg) due to ocular toxicity. Only one patient remained on the standard dose of 2.5mg/kg for >3 cycles. Ocular toxicity improved after treatment interruption (drug intervals 4-6 weeks) and no patients required complete treatment cessation. One patient is too early to assess response. Haematological responses (PR or better) were seen in 7 patients with 3 complete responses and two very good partial responses (VGPR) which are ongoing. Both renal patients (patients 4 and 11) commenced a dose of 1.25mg/kg and sustained a VGPR with no additional toxicity. Patient 3 had a 42% reduction in sFLC after two doses but then a prolonged gap due to keratopathy and has lost the response. There were no cardiac or renal toxicities observed. Summary/Conclusion: Belantamab mafodotin demonstrates significant activity in patients with heavily pre-treated AL amyloidosis with 70% achieving a ≥PR. Apart from keratopathy requiring dose modification, no other substantial toxicity was observed. Two patients with renal impairment (stage V CKD and ESRD) and one patient post-renal transplant tolerated treatment with no additional toxicity. Belantamab mafodotin shows promise in treatment of relapsed AL and needs further prospective trials.
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
Background: The role of upfront ASCT for NDTE MM remains under evaluation with high MRD rates following novel induction and consolidation (cons) strategies. K maintenance represents an alternative strategy to lenalidomide maintenance. The CARDAMON trial investigated K maintenance following KCd induction plus either ASCT or KCd cons. Methods: NDTE pts received 4 x KCd induction (K 20/56 mg/m2 biweekly, C 500 mg D 1,8,15, d 40mg weekly) before 1:1 randomisation to ASCT or 4 x KCd cons followed by 18 cycles K maintenance (56mg/m2 D1,8,15). Flow cytometric MRD (10-5) was assessed post induction, pre-maintenance and at 6 months maintenance. Primary endpoints were ≥VGPR post induction and 2-year PFS from randomisation. Secondary endpoints included improvements in disease response and MRD conversion following ASCT/ cons and maintenance. Results: 281 patients were registered, with 218 randomised to either ASCT or cons. The median PFS for ASCT was not yet reached vs 3.4 years for cons, with cons failing to show non-inferiority (difference in 2-year PFS 6.5%, 70% CI 1.0% to 11.1%). 196 patients received K maintenance (99 ASCT, 97 cons), 17 remain on treatment. A median of 16 cycles (1-18) were given over a median of 15.9 months (0-21.5). COVID-19 led to maintenance treatment interruptions in 41 (8 ASCT, 6 Cons) and treatment discontinuation in 15 (9 ASCT, 6 Cons). The median K dose given was 50.6mg/m2 and was similar across both arms (51.2 vs 49.4mg/m2, p=0.03). K maintenance was discontinued for PD in 14.1% (ASCT) vs 22.7% (cons), and for adverse events (AEs) in 7.1% (ASCT) vs 4.1% (cons). Most common AEs were hypertension and infections and more ≥G3 AEs were noted in ASCT vs cons (p=0.01). Patient/ clinician withdrawals from maintenance were low but occurred more in the ASCT arm (9.1% vs 1%). MRD neg patients post ASCT/ Cons had a longer PFS than MRD pos (p=0.002);with a higher MRD neg rate in the ASCT arm (53.6% vs 35.1% in Cons, p=0.01). MRD neg patients at 6 months post maintenance also had longer PFS (p=0.004 cf MRD pos patients);again with higher MRD neg rates in the ASCT arm (58.1% ASCT vs 40.5% Cons, p=0.02). There was no difference in PFS for MRD neg patients according to treatment arm from PBSCH, post-ASCT/ Cons or 6 months maintenance timepoints. Overall, 27.8% of MRD pos patients converted to MRD neg post ASCT/ Cons with more converting with ASCT (39.1% ASCT vs 16.1%, p=0.004). 23.5% of MRD pos patients converted to neg during maintenance (30.6% ASCT, 17.8%: p=0.2). Maintenance of MRD negativity over the first 6 months was similar between ASCT and Cons arms (p=0.3). There was no evidence that the timing of achievement of MRD negativity impacted PFS. Conclusions: K maintenance at 56mg/m2 weekly was deliverable and tolerable, with continued higher MRD neg rates at 6 months post-ASCT compared to post-Cons. However more ≥G3 AEs and discontinuations for AEs/ patient choice were noted for K maintenance after ASCT.
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.