Summary
Optimal red cell transfusion support in myelodysplastic syndromes (MDS) has not been tested and established. The aim of this study was to demonstrate feasibility of recruitment and follow‐up ...in an outpatient setting with an exploratory assessment of quality of life (QoL) outcomes (EORTC QLQ‐C30 and EQ‐5D‐5L). We randomised MDS patients to standardised transfusion algorithms comparing current restrictive transfusion thresholds (80 g/l, to maintain haemoglobin 85–100 g/l) with liberal thresholds (105 g/l, maintaining 110–125 g/l). The primary outcomes were measures of compliance to transfusion thresholds. Altogether 38 patients were randomised (n = 20 restrictive; n = 18 liberal) from 12 participating sites in UK, Australia and New Zealand. The compliance proportion for the intention‐to‐treat population was 86% (95% confidence interval 75–94%) and 99% (95–100%) for restrictive and liberal arms respectively. Mean pre‐transfusion haemoglobin concentrations for restrictive and liberal arms were 80 g/l (SD6) and 97 g/l (SD7). The total number of red cell units transfused on study was 82 in the restrictive and 192 in the liberal arm. In an exploratory analysis, the five main QoL domains were improved for participants in the liberal compared to restrictive arm. Our findings support the feasibility and need for a definitive trial to evaluate the effect of different red cell transfusion thresholds on patient‐centred outcomes.
Background
It is becoming increasingly important in the treatment of MM to improve our understanding of routine clinical practice and of the effectiveness of new agents and regimens outside the ...clinical trial setting. UVEA-IXA is a European, multicenter, observational, longitudinal cohort study of RRMM pts who received therapy with ixazomib, the first oral proteasome inhibitor (PI), at MM specialist centers via an Early Access Program (EAP) in 8 European countries (Czech Republic, Greece, Hungary, Italy, Slovakia, Slovenia, Spain, UK). Ixazomib was available in Europe via the EAP from Nov 2015, when it was initially approved in the US in combination with lenalidomide and dexamethasone for the treatment of MM pts who have received ≥1 prior therapy, until European approval in Nov 2016. Approvals were based on the results of the phase 3 TOURMALINE-MM1 study (Moreau NEJM 2016). We report data from the second interim analysis of pts enrolled in the UVEA-IXA study.
Methods
The UVEA-IXA observation period comprises two parts: a retrospective chart review, starting from ixazomib therapy initiation in the EAP, followed by a 1-yr prospective follow-up period from the date of chart abstraction, with data captured quarterly per local regulations. Pts eligible for the UVEA-IXA study were adult MM pts in biochemical and/or symptomatic relapse after 1-3 prior lines of therapy, who had not received any anti-MM therapy for >3 cycles (except steroids) at the time of ixazomib therapy initiation, and who had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Lenalidomide- or PI-refractory (disease progression on treatment or within 60 d after last dose) pts were excluded from UVEA-IXA. The primary endpoints of UVEA-IXA were response (per International Myeloma Working Group criteria) and progression-free survival (PFS; from ixazomib therapy initiation in the EAP to first documented disease progression/death during the observation period).
Results
A total of 359 pts were enrolled into UVEA-IXA. At data cutoff (May 22, 2020), 302 pts were evaluable for analysis; 55% were male; median age at enrollment was 68 yrs (range 36-92), with 39% aged ≥70 yrs. At the time of initiating ixazomib therapy, 36/117 (31%) pts had International Staging System (ISS) stage III disease, and 61/301 (20%) had an ECOG PS of 2; 60% of all evaluable pts had ≥1 comorbidity, including hypertension (26%), renal disease (23%), and diabetes (10%). Median time from MM diagnosis was 37.0 mos (range 4.9-231.7), and 39%, 43%, and 18% of pts had received 1, 2, and 3 prior lines of therapy. These included (in any line) bortezomib (89%), thalidomide (52%), transplant (47%), melphalan (22%), lenalidomide (17%), carfilzomib (5%), and pomalidomide (2%). The median follow-up period among 295 pts with available data was 24.9 mos (range 0.2-49.3); of all evaluable pts, 160 (53%) discontinued the study (of these, 88% discontinued due to death). Pts received ixazomib for a median of 10.8 mos (range 0.2-49.3), and most pts also received lenalidomide (97%) and dexamethasone (96%). Among 275 pts with data on best response, the overall response rate (ORR) was 60% (Table 1). Median PFS was 15.6 mos (95% CI 11.8-20.0; Figure). Ixazomib and lenalidomide dose reductions and discontinuations are summarized in Table 2. In 187 pts who received ≥4 cycles of ixazomib, rates of any-grade, grade ≥3, and serious adverse events (AEs) were 60%, 33%, and 23%; the most common AEs of any grade were diarrhea and thrombocytopenia (14% each), rash (7%), peripheral neuropathy (6%), and nausea/vomiting (5%); the most common grade ≥3 AE was thrombocytopenia (6%).
Conclusions
Data from the second interim analysis of UVEA-IXA demonstrate that ixazomib-based therapy is effective outside the clinical trial setting, with an ORR of 60% and a median PFS of 15.6 mos. Compared with TOURMALINE-MM1 pts (ixazomib arm; ORR 78%, median PFS 20.6 mos), UVEA-IXA pts have higher rates of ECOG PS 2 (20% vs 5%) and ISS stage III MM (31% vs 12%), and had received more prior therapies (61% vs 38% had ≥2 prior therapies). The most common AEs were gastrointestinal and hematologic AEs, in line with the well-characterized and manageable safety profile of ixazomib, although data are not directly comparable with clinical trial safety data due to the retrospective/infrequent prospective collection schedule. Ixazomib-based therapy is an effective and tolerable treatment option outside the clinical trial setting.
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Ludwig:Celgene: Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Takeda: Research Funding; Seattle Genetics: Other: Advisory Boards; Janssen: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau. Terpos:Genesis: Research Funding; Sanofi: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Janssen: Research Funding; Takeda: Research Funding; BMS: Honoraria; Amgen: Research Funding; Celgene: Honoraria. Mateos:Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: 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; AbbVie: 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; Sanofi: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kishore:Celgene: Other. Ramasamy:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Fernandez:MediNeos Observational Research: Current Employment. Ferri:MediNeos Observational Research: Current Employment. Bent-Ennakhil:Takeda Pharmaceuticals International AG: Current Employment. Zomas:Takeda Pharmaceuticals International AG: Current Employment. Gavini:Takeda Pharmaceuticals International AG: Current Employment. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.
Background Multiple myeloma (MM) is a blood cancer that predominates in the older adult with significant morbidity and mortality. Frailty is increasingly recognized as a predictor for long- and ...short-term outcomes, with those who are frailer at risk of greater toxicity, treatment discontinuation and poorer survival. Identifying and tailoring treatment for frail older patients with MM remains an unmet need. The International Myeloma Working Group frailty score (IMWG FS) is a prognostic biomarker for survival, but no evidence exists for its predictive biomarker potential. In addition, defining frailty at a single timepoint (baseline) by the IMWG FS may mask disease overlay and the improvements seen with therapy delivery. Understanding both improvements and deteriorations in frailty during treatment may have important implications for dynamic treatment delivery. Study Design and Methods The UKMRA Myeloma XIV FiTNEss trial (NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed patients with MM ineligible for a stem cell transplant. The primary objectives of the study are 1) to compare early treatment cessation (within 60 days of randomisation) between patients randomised to standard (reactive) and frailty-adjusted (adaptive, based on IMWG FS) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd) and 2) to compare progression-free survival for maintenance lenalidomide (R) and lenalidomide plus ixazomib (IR). Baseline revised IMWG FS (considering only those scoring >=3 frail) and UKMRA Myeloma Risk Profile (MRP) were determined. Here we report the changes in IMWG FS for the patients recruited to the standard (toxicity-reactive) arm, including demographic data and the identification of an ultra-frail group. Results The FiTNEss trial opened on 04/08/2020 and at the time of data cut off (01/06/2023) recruitment is active at 84 sites, with 638 patients randomised. Baseline characteristics for the randomised patients are shown in Table 1. The median age of patients is 76 years (range 62, 93) with 34.8% aged 76-80 and 22.3% over 80. The IMWG FS at baseline for the full trial cohort was FIT 182/638 (28.5%), UNFIT 207/638 (32.4%) and FRAIL 249/638 (39.0%). Revised IMWG FS at baseline was Fit 28.5%, Unfit 56.0% and Frail 15.5% with MRP non-high risk (Fit or Unfit, nHR) in 64.3% and MRP HR (Frail) in 35.7% in patients with data available. For descriptive analysis of FS dynamism, we assessed the impact on FS of delivery of IRD in the control arm (n=319), calculating the FS at 2, 4, 6 and 12 months. The majority of changes were seen at 2 months across the frailty categories. For Fit patients, 20.9% demonstrated a deterioration in FS score at any timepoint. For Unfit patients, 26.7% demonstrated a deterioration in FS score whilst 16.2% demonstrated an improvement in FS at any timepoint. For Frail patients, 15.4% demonstrated an improvement in FS at any timepoint (Figure 1). Of those who demonstrated a deterioration in FS, 59.1% experienced a treatment related safety event. In those who demonstrated an improvement in FS, 26.3% experienced a treatment related safety event. Of the 250 whose FS remained constant 34% experienced a treatment related safety event. For frail patients, 119 could be stratified further and 57% were classified as Ultra-Frail (IMWG FS Frail and MRP HR). Conclusion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. The IMWG FS does demonstrate a dynamic biomarker potential both representing improved functionality in relation to disease response to therapy, as well as deterioration consequential to treatment-emergent toxicity. In addition, the concept of ultra-frail represents an exciting possibility to further stratify patients who may need additional support in order to improve their outcomes. Further work in these two areas is on-going as the trial dataset matures.
Introduction In the UK in 2016-2018, more than 4 in 10 new diagnoses of multiple myeloma (MM) were in people aged at least 75 years old. Transplant-ineligible (TNE) patients are a heterogeneous group ...that is not well-defined by age, but by the interplay of age, physical function, cognition and comorbidity better defined as ‘frailty’. There is little evidence on the effect of frailty on HRQoL in patients with MM. We examined patient-reported outcomes from participants enrolled in the FiTNEss study to understand HRQoL according to frailty group and the contribution of different elements of the International Myeloma Working Group (IMWG) frailty score (FS) to HRQoL. Methods FiTNEss (UK-MRA Myeloma XIV, NCT03720041) is a phase III, multi-centre, randomised controlled trial for newly diagnosed TNE MM patients. Patients receive lenalidomide, ixazomib, and dexamethasone induction and maintenance, comparing frailty score-adjusted up-front dose reductions and standard up-front dosing followed by toxicity dependent reactive dose adjustments. Frailty was defined using the IMWG FS. It includes age (<75y, 75-80y, >80y), Katz Activity of Daily Living (ADL<=4), Lawton Instrumental Activity of Daily Living (IADL<=5), and the Charlson Comorbidity Index (CCI<=1). The UK-MRA Myeloma Risk Profile (MRP) 1 was scored using age, performance status (PS), ISS and CRP. HRQoL was measured by EORTC QLQ C30 and MY20 completed at trial entry. We used a one-way ANOVA and two-sample unequal variance t-tests to compare subscales in different frailty groups. We sought minimally important differences that were at least medium size 2, and adjusted p-values using the Bonferonni correction for the 19 subscales (adjusted P = 0.05/19 = 0.0026). Results Baseline HRQoL was available for 559 trial participants. Median age was 77y (<75y: 183 32.7%, 75-80y: 248 44.4%, >80y 128 22.9%), 307 (54.9%) were male and 427 (76.2%) ECOG PS0-1. 160 (28.6%) patients were classified as Fit, 182 (32.6%) were Unfit and 217 (38.8%) were Frail according to IMWG FS. 105 (18.8%) patients had CCI <=1, 60 (10.7%) had ADL<=4 and 115 (20.6%) had IADL <=5. 167 (31.0%) patients were classified as low risk, 180 (33.5%) were intermediate risk and 191 (35.5%) were high-risk according to MRP. Contrasting IMWG fit, unfit and frail patients, significant differences were evident in 7 of 15 C30 subscales (Global Health Status QL, Physical PF, Role RF, Cognitive CF and Emotional Functioning EP, Appetite loss AP, Dyspnoea DY) and 1 of 4 MY20 subscales (Side Effects MYSE) (Figure A). The largest differences in subscales were between the Fit/Unfit and Frail groups with only a single nominally different subscale (PF) between Fit and Unfit. When comparing the frailty score elements, age group and CCI were not significantly different using C30 or MY20 subscales. However, when considering ADL: 11 of 15 C30 (QL, PF, RF. CF, Social Functioning SF, Fatigue FA, Pain PA, AP, Constipation CO, DY, Financial Problems FP) subscales and 2 of 4 MY20 subscales (Disease Symptoms MYDS, MYSE) were significantly different. Similarly, when considering IADL: 10 of 15 C30 subscales (QL, PF, RF, CF, SF, FA, PA, AP, CO and DY) and 4 of 4 MY20 subscales (MYDS, MYSE, Body Image, Future Perspective Worries) were significantly different (Figure B). When comparing between MRP risk groups, 10 of 15 C30 subscales (QL, PF, RF, CF, SF, FA, PA, AP, CO and DY) and 2 of 4 MY20 subscales (MYDS, MYSE) were significantly different. Unlike IMWG FS, 5 subscales were nominally significantly different between low and medium risk groups (QL, PF, RF, SF, DY). Conclusion The IMWG FS is associated with several domains from EORTC QLQ-C30 and MY20 at baseline with worse function and symptomatology among frail patients. Examining FS elements show that age and comorbidities do not contribute to heterogeneity in HRQoL. However, ADL and IADL are significantly associated with HRQoL. ADL elements may identify components of frailty that are potentially modifiable through supportive care and rehabilitation and could enhance HRQOL and treatment tolerability in older patients. The MRP risk profile is associated with baseline HRQoL as shown previously and with a number of other subscales as shown here. There is evidence that the MRP can delineate subscales, including QL better than the IMWG FS. 1. Cook G, et al, The Lancet Haematology, 6(3): E154-E166. 2. Cocks K, et al, Journal of Clinical Oncology, 29(1): 89-96.
Introduction
High dose chemotherapy followed by autologous peripheral blood stem cell transplant (APBSCT) is the current standard of care for myeloma patients younger than 70 years of age with good ...performance status. Busy haematology centres have severe pressure on bed availability which can limit their ability to deliver multiple cycles of intensive chemotherapy on time. G-CSF use in APBSCT has been shown to hasten neutrophil engraftment and to shorten the number of days of febrile neutropenia. In our centre we have had experience of using pegfilgastrim (day +1 post high dose therapy), lenograstim(day+7 post high dose therapy) or no G-CSF. We reviewed these cohorts and compared engraftment kinetics, inpatient stay, progression free survival(PFS) and overall survival(OS).
Patients and methods
This retrospective study included 142 (M: 94; F: 48) patients who had APBSCT for myeloma between January 2006 and March 2014. Patients had induction treatment followed by autologous peripheral blood stem cell (PBSC) mobilisation with G-CSF alone or by cyclophosphamide (3g/m2) + G-CSF schedule. One hundred thirteen patients received first APBSCT and twenty nine received second APBSCT with high dose melphalan (200 mg/ m2) conditioning and the day of stem cell re-infusion was termed day 0. Statistical analysis was carried out using SPSS 23 for Windows. Median age at APBSCT was 62 years (range: 38-74). Prior to transplant 8.5%, 67.4% & 24.1% were in complete, very good partial and partial remission respectively. Twenty two patients received pegfilgrastim, 84 received lenograstim from day+7 whereas some of the remaining 34 patients received varying duration of conventional G-CSF if they had no neutrophil engraftment by day +12.
Results:
Median duration for neutrophil engraftment in the pegfilgrastim, lenograstim and no G-CSF cohort was 12, 12.7 and 14 days respectively (Mann Whitney test; p value: 0.0005). Median duration for platelet engraftment in the pegfilgrastim and the no G-CSF cohort was 21.5 and 16.5 days respectively (Mann Whitney test; p value: 0.253). Median inpatient stay in the pegfilgrastim, lenograstim and the no G-CST cohort was 16, 16.5 and 18 days respectively (Mann Whitney test; p value: 0.024).
Our data suggests that the use of colony stimulating factors (pegfilgrastim & lenograstim) is associated with shorter duration to neutrophil engraftment and reduced inpatient stay which unfortunately does not translate into PFS or OS advantage. This is very useful considering the severe pressure on the bed availability in the tertiary referral centres. We also need to study whether bio similar colony stimulating factors provide the similar benefit.
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Kishore:Jazz pharma: Honoraria; Celgene: Honoraria. Nikolousis:Alexion: Honoraria. Paneesha:Janssen: Consultancy.
Summary
Daratumumab, bortezomib and dexamethasone (DVd) is approved for patients with relapsed multiple myeloma following the CASTOR phase 3 clinical trial. This retrospective multicentre analysis ...assesses the overall response rate (ORR) and progression‐free survival (PFS) in routine clinical practice for patients at first relapse treated with DVd incorporating weekly bortezomib. Data were collected from 296 sequential patients treated across 15 UK centres. After a median follow‐up of 21 months, the ORR was 82% (26% partial response, 56% very good partial response or better) and the median PFS was 16 months 95% confidence interval (CI) 12–20 months. Results were similar regardless of prior lenalidomide exposure. The median time to next treatment was 20 months (95% CI 15–25 months) and the estimated overall survival at two years was 74%. Patients with high‐risk features (by cytogenetics, International Staging System or extramedullary disease) and those treated within 18 months of initiation of progression‐free treatment, or within 12 months of autologous stem cell transplant, had significantly inferior outcomes. The grade 2 and 3 peripheral neuropathy rate was 7%. DVd with weekly bortezomib was effective in a heterogenous real‐world population at first relapse with a low rate of peripheral neuropathy. However, high‐risk patients had inferior outcomes and should be considered for alternative treatments.
Proteasome inhibitors are the backbone of AL amyloidosis treatment - bortezomib being most widely used. Carfilzomib is a proteasome inhibitor licenced to treat multiple myeloma; autonomic and ...peripheral neuropathy are uncommon toxicities with carfilzomib. There is limited data on the use of carfilzomib in AL amyloidosis. Here, we report the results of a phase Ib dose-escalation study of Carfilzomib-Thalidomide-Dexamethasone (KTD) in relapsed/refractory AL amyloidosis.
The trial registered 11 patients from 6 UK centres from September 2017 to January 2019; 10 patients received at least one dose of trial treatment. 80 adverse events were reported from 10 patients in the 1
st
three cycles. One patient experienced dose-limiting toxicity (acute kidney injury) at a dose of 45 mg/m
2,
and another patient had a SAR (fever). Five patients experienced an AE ≥ grade 3. There were no haematologic, infectious, or cardiac AE ≥ grade 3. The overall haematological response rate (ORR) at the end of three cycles of treatment was 60%.
Carfilzomib 45 mg/m
2
weekly can be safely given with thalidomide and dexamethasone. The efficacy and tolerability profile appears comparable to other agents in relapsed AL amyloidosis. These data provide a framework for further studies of carfilzomib combinations in AL amyloidosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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