Kooperativer Bibliotheksverbund

In: BMJ Open, BMJ, Vol. 12, No. 6 ( 2022-06), p. e056147-

Kurzfassung: Multiple myeloma is a bone marrow cancer, which predominantly affects older people. The incidence is increasing in an ageing population. Over the last 10 years, patient outcomes have improved. However, this is less apparent in older, less fit patients, who are ineligible for stem cell transplant. Research is required in this patient group, taking into account frailty and aiming to improve: treatment tolerability, clinical outcomes and quality of life. Methods and analysis Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma is a national, phase III, multicentre, randomised controlled trial comparing standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with ixazomib, lenalidomide and dexamethasone (IRD), and to compare maintenance lenalidomide to lenalidomide+ixazomib, in patients with newly diagnosed multiple myeloma not suitable for stem cell transplant. Overall, 740 participants will be registered into the trial to allow 720 and 478 to be randomised at induction and maintenance, respectively. All participants will receive IRD induction with the dosing strategy randomised (1:1) at trial entry. Patients randomised to the standard, reactive arm will commence at the full dose followed by toxicity dependent reactive modifications. Patients randomised to the adaptive arm will commence at a dose level determined by their International Myeloma Working Group frailty score. Following 12 cycles of induction treatment, participants alive and progression free will undergo a second (double-blind) randomisation on a 1:1 basis to maintenance treatment with lenalidomide+placebo versus lenalidomide+ixazomib until disease progression or intolerance. Ethics and dissemination Ethical approval has been obtained from the North East—Tyne & Wear South Research Ethics Committee (19/NE/0125) and capacity and capability confirmed by local research and development departments for each participating centre prior to opening to recruitment. Participants are required to provide written informed consent prior to trial registration. Trial results will be disseminated by conference presentations and peer-reviewed publications. Trial registration number ISRCTN17973108 , NCT03720041 .

Materialart: Online-Ressource

ISSN: 2044-6055 , 2044-6055

URL: Article

DOI: 10.1136/bmjopen-2021-056147

Sprache: Englisch

Verlag: BMJ

Publikationsdatum: 2022

ZDB Id: 2599832-8

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 81-81

Kurzfassung: Background Although the median age of patients with newly diagnosed multiple myeloma (MM) is 70-74 years, recruitment of frail older patients to clinical trials is poor. The International Myeloma Working Group (IMWG) frailty score predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living, the Lawton Instrumental Activity of Daily Living, and the Charlson Comorbidity Index, rather than age alone. Despite IMWG score prognostic biomarker capability, to date no evidence exists of its predictive biomarker potential. The UK-MRA Myeloma Risk Profile (MRP) has also been shown in both clinical trial and real-world populations to be a prognostic biomarker in transplant ineligible patients but prospective comparisons of the two scores have not been previously conducted. Study Design/Methods The FiTNEss trial (Myeloma XIV, NCT03720041, Figure 1A) is a UK-MRA phase III, multi-centre, randomised controlled trial for newly diagnosed MM patients not suitable for stem cell transplant. The primary objectives are 1) to compare early treatment cessation ( & lt;60 days from randomisation) between patients randomised to standard (reactive) and frailty-adjusted (adaptive, based on IMWG score) induction therapy delivery with the triplet ixazomib, lenalidomide and dexamethasone (IRd) 2) to compare progression free survival for maintenance lenalidomide plus placebo (R) and lenalidomide plus ixazomib (IR). The FiTNEss trial is designed as an all-comers study with few exclusion criteria other than necessary for safety including some haematological and biochemical parameters, but there is no exclusion based on renal function. Patients with grade 2 or greater baseline peripheral neuropathy, current systemic infection or recent surgery or other cancer are excluded. Here we report the demographics for the first patients recruited, including IMWG frailty assessments and MRP to demonstrate the feasibility of recruiting frail patients to randomised phase III clinical trials. Results The FiTNEss trial opened on 04/08/2020 during the second wave of the COVID-19 pandemic in the UK. At the time of data cut off (14/07/2021) recruitment is active at 84 sites, with 180 patients randomised. Baseline characteristics for the randomised patients are shown in Figure 1B. The median age of patients is 77 years (range 64, 93) with 36.1% aged 76-80 and 26.1% over 80. In keeping with the older patient population 26.6% have an ECOG performance status of 2 or 3 and 31.7% ISS stage III. The IMWG frailty classification at baseline is FIT 43/180 (23.9%), UNFIT 53/180 (29.4%) and FRAIL 84/180 (46.7%). The effect of using age groups on the definition of patient frailty was explored. The IMWG frailty score defines all patients over 80 as FRAIL whilst an age of 76-80 contributes one point to the score. An analysis of patients' frailty was repeated with the contribution of age removed. For those aged over 80 years (n=47, 100% FRAIL) we found that 20 (42.6%) would have been re-classified as FIT and 18 (38.3%) as UNFIT, with only 9 (19.2%) retaining the FRAIL category. For those aged 76-80 (n=65, 53.8% UNFIT, 46.2% FRAIL) all 35 patients previously classified as UNFIT became FIT (53.8%) whilst 19 (29.2%) classed as FRAIL became UNFIT with 11 (16.9%) remaining FRAIL. The MRP classification, using age as a continuous variable, was Low-risk 45/180 (25.0%), Medium-risk 46/180 (25.6%), High-risk 75/180 (41.7%) and not available for 14/180 (7.8%) patients. Concordance between the IMWG frailty score and the MRP occurred in 48.9% of patients (88/180). 37.2% of FIT patients were classified as MRP Low-risk, 32.1% of UNFIT patients as MRP Medium-risk and 65.5% of FRAIL patients as MRP High-risk. Discussion The FiTNEss trial demonstrates the feasibility of recruiting older, less fit patients to clinical trials. Recruitment of patients classified as FRAIL was very high despite the COVID pandemic, likely due to the all-oral nature of the regimen under investigation enabling patients to avoid attendance at hospital day units for treatment and associated exposure risk. In the population recruited to date we found age to be a key contributor to the FRAIL category of the IMWG frailty score. Concordance between IMWG frailty score and MRP was highest in FRAIL/High-risk patients. The first interim analysis of the primary objectives is planned when 50% of required participants for R1 have reached 60 days post R1, which is anticipated in Q2 of 2022. Figure 1 Figure 1. Disclosures Cook: Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Pawlyn: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: 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; Amgen: Honoraria. Royle: BMS: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Coulson: BMS / Celgene: Honoraria; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Kishore: Sanofi: Other: Attending fees; Celgene: Other: Attending fees; Takeda: Other: Attending fees; Jannsen: Other: Attending fees. 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. Best: BMS/Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Gillson: BMS / Celgene: Research Funding; Meck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Henderson: Takeda: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; BMS / Celgene: Research Funding. Olivier: Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Celgene / BMS: Research Funding. Kaiser: AbbVie: Consultancy; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty-score adapted dosing strategies

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146650

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2021

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 25 ( 2022-09-01), p. 2889-2900

Kurzfassung: Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk. METHODS Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9). RESULTS At ASCT + 3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. MRD-negative status was associated with improved PFS (hazard ratio [HR] = 0.47; 95% CI, 0.37 to 0.58 P 〈 .001) and OS (HR = 0.59; 95% CI, 0.40 to 0.85; P = .0046). At ASCT + 9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was associated with improved PFS (HR = 0.20; 95% CI, 0.13 to 0.31; P 〈 .0001) and OS (HR = 0.33; 95% CI, 0.15 to 0.75; P = .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9. CONCLUSION In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS.

Materialart: Online-Ressource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.21.02228

Sprache: Englisch

Verlag: American Society of Clinical Oncology (ASCO)

Publikationsdatum: 2022

ZDB Id: 2005181-5

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 40-43

Kurzfassung: Background The most common cause of severe renal impairment in myeloma (MM) is the direct effect of a high concentration of nephrotoxic monoclonal free light chains (LC) leading to MM cast nephropathy. Decreasing LC and therefore improving renal function is important for long term outcome. In the UK NCRI Myeloma XI trial the addition of the second generation PI carfilzomib (K) to the immunomodulatory agent (IMiD) lenalidomide, cyclophosphamide and dexamethasone (Rdc) improved progression-free survival (PFS) in newly diagnosed MM patients (NDMM) eligible for autologous stem cell transplant (ASCT) (median PFS KRdc not reached (NR) v Rdc 36 months HR 0.66 (95% CI 0.52, 0.83, P=0.0004). This exploratory subgroup analysis compares PFS and renal recovery between patients receiving KRdc and Rdc within renal function subgroups. Methods Myeloma XI is a phase III, randomized controlled trial with an adaptive design for symptomatic NDMM patients of all ages. This renal analysis is of the transplant eligible (TE) pathway and compares induction treatment with the quadruplet KRdc to triplet Rdc. Patients were randomized contemporaneously 2:1. All patients were randomized to post-ASCT R maintenance or observation. For further exploratory analysis patients randomized earlier in the study to Rdc were also included. Relevant exclusion criteria were acute renal failure non-responsive to 72 hours rehydration (creatinine & gt;500umol/L, urine output & lt;400ml/day or dialysis). The Modification of Diet in Renal Disease formula was used to calculate the baseline estimated glomerular filtration rate (eGFR). Renal function was normal, eGFR & gt;=60 ml/min/1.73m2, moderately impaired 30-59 or severely impaired & lt;30. Potentially nephrotoxic LC were considered those with a difference of & gt;=500mg/L between the involved and uninvolved (dFLC). Renal recovery was defined as an improvement in eGFR of ≥25% at the end of induction therapy. Results 1547 patients were randomized to KRdc n=526 or Rdc n=1021 (265 contemporaneous, 756 not). In the contemporaneous group baseline renal function was normal in 609/791 (77.0%), moderately impaired in 141/791 (17.8%) and severely impaired in 40/791 (5.1%) (data n/a in 1 patient). Patients with moderately or severely impaired renal function had shorter PFS compared to those with normal renal function. Subgroup analysis showed consistent outcomes for KRdc compared to Rdc across all renal subgroups with no evidence of significant heterogeneity (Figure 1, Phet=0.9354). Further exploratory analysis combined patients with moderate or severe renal impairment into one group. Difference in PFS and renal recovery between patients with normal or impaired renal function and high ( & gt;=500) or low ( & lt;500) dFLC were examined. Consistent with the findings in the contemporaneous group, KRdc was associated with a significant improvement in PFS compared to Rdc in both the normal and renal function impaired groups. Within the group of patients with normal renal function at baseline those with high dFLC had shorter PFS than those with low dFLC. KRdc was associated with improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 39, NR) v Rdc 34 months (30, 39) and low dFLC KRdc NR (44, NR) v Rdc 41 (37, 47). In the group of patients with renal impairment at baseline KRdc was also associated with an improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 29, NR) v Rdc 32 months (28, 42) and low dFLC KRdc 37 (25, NR) v Rdc 27 (24, 33). In contrast to those with normal renal function, however, patients with renal impairment and high dFLC had a longer PFS than those with low dFLC. This observation was apparent whether patients received KRdc or Rdc and suggests that patients with high dFLC may have had reversible renal impairment, improving their ultimate outcomes. Supporting this hypothesis, measurable renal recovery in the renal impaired group at the end of induction was more common in patients with high dFLC (dFLC & gt;=500 68.6% v dFLC & lt;500 53.2%). Interestingly the rate of renal recovery was similar between KRdc and Rdc in the high dFLC group (KRdc 71.1% v Rdc 67.5%) suggesting the improved PFS seen with KRdc in the group with renal impairment is not due to an increased rate of renal recovery. Conclusions KRdc was associated with improved PFS compared to Rdc in NDMM patients across all renal subgroups. Irrespective of treatment, renal function is more likely to improve if attributable to nephrotoxic LC. Disclosures Pawlyn: Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses; Takeda: Consultancy, Other: Travel expenses. Menzies:Celgene, Amgen, Merck: Research Funding. Davies:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, 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, Research Funding. Cook:Celgene, Janssen, Takeda: Research Funding; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Sanofi: Honoraria; Karyopharm: Honoraria. Gregory:Celgene, Amgen, Merck: Research Funding; Janssen: Honoraria; Celgene: Consultancy. Jenner:Amgen, Janssen, Celgene, Takeda, Novartis, Sanofi, GSK: Consultancy; Janssen, Takeda, Amgen, Celgene, Novartis: Honoraria; Janssen, Celgene: Research Funding; Janssen, Takeda, Amgen: Other: Travel expenses. Jones:Celgene: Honoraria, Research Funding. Kaiser:Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Owen:Takeda: Honoraria, Other: Travel expenses; Janssen: Consultancy, Other: Travel expenses; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; GSK: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson:Takeda: Honoraria, Research Funding, Speakers Bureau; Gsk: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Cairns:Celgene, Amgen, Merck: Research Funding; Celgene: Other: Travel Support. OffLabel Disclosure: Carfilzomib, lenalidomide, dexamethasone and cyclophosphamide combination induction therapy for newly diagnosed myeloma

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-139238

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2020

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1371-1372

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-165376

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2022

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 4299-4300

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-169774

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2022

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. 9 ( 2020-08-27), p. 1091-1104

Kurzfassung: Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554] ; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI] , 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419] ; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008] ; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008] ; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2020005125

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2020

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 6-6

Kurzfassung: Introduction: Immunoparesis, or suppression of polyclonal immunoglobulins, is a common issue in multiple myeloma (MM). Prior studies have shown that the degree of IgM immunoparesis is prognostic for survival, as patients with the most severe IgM immunoparesis at diagnosis have the poorest survival outcomes. Little is known regarding the cause of this immunoparesis, with many assuming it is due to tumor bulk alone. More recent data has suggested that MM can be divided into subgroups with distinct biologies and outcomes based on etiological cytogenetic abnormalities. These include hyperdiploidy and translocation t(11;14), t(4;14), t(14;16), or t(14;20), with the latter three groups being associated with high-risk disease. We hypothesized that the different etiological cytogenetic abnormalities drive bone marrow microenvironmental changes, resulting in different degrees of immunoparesis and subgroup-dependent effects on clinical outcomes. Methods: We performed a retrospective review of newly diagnosed MM patients enrolled in the MRC Myeloma IX and Cancer Research UK Myeloma XI trials. Patients with hyperdiploidy, t(11;14), t(4;14), t(14;16), or t(14;20) were included in the analysis. Polyclonal IgG, IgA, and IgM levels were measured at diagnosis, and the normal range was established by the 5th - 95th percentiles of adults over age 45 years in the UK: IgG 6 - 16 g/L, IgA 0.8 - 4 g/L, and IgM 0.5 - 2 g/L. Cytogenetic abnormalities were determined by FISH, multiplex ligation-dependent probe amplification (MLPA), or next generation sequencing (NGS). Overall survival (OS) was defined as time from date of trial entry to date of death, or censored at date last known to be alive. Progression-free survival (PFS) was defined as time from date of trial entry to progression or death, or censored at date last known to be alive and progression-free. Results: The study included 985 patients, of whom 47% were at least age 65 years and 61.1% were male. The most common MM subtype was IgG (63.4%), followed by IgA (24.5%), light chain only (8.4%), IgD (1.9%), oligosecretory (1.0%), IgM (0.5%), and non-secretory (0.3%). Hyperdiploidy represented 58.9% of cases, with t(11;14) seen in 18.2%, and t(4;14), t(14;16), or t(14;20) seen in 22.9%. The MM subtype was not distributed evenly amongst the different etiological cytogenetic abnormalities with IgG overrepresented in the hyperdiploid subgroup (69.4%), compared to 11% in t(11;14) and 19.5% in high-risk cases. IgA was overrepresented in high-risk cases (45.2%), compared to 41.1% in hyperdiploidy and 13.7% in t(11;14). The high-risk subgroup had more immunoparesis compared to the hyperdiploid and t(11;14) subgroups (median polyclonal IgG 3.0 vs. 3.8 vs. 3.9 g/L, IgA 0.2 vs. 0.4 vs. 0.2 g/L, IgM 0.1 vs. 0.2 vs. 0.2 g/L, respectively). There were also significantly more patients in the high-risk subgroup with polyclonal immunoglobulin levels below the normal range compared to the hyperdiploid and t(11;14) subgroups (IgG 96.9% vs. 86.0% vs. 88.2%, p = 0.0045; IgA 89.9% vs. 77.1% vs. 92.4%, p & lt; 0.0001; IgM 94.0% vs. 88.9% vs. 92.7%, p & lt; 0.0001). With median follow up of 77 months, the overall median PFS and OS were 19 months and 53 months, respectively. As expected, patients in the high-risk subgroup had significantly lower PFS and OS (14 and 35 months, respectively, p & lt; 0.001), compared to the hyperdiploid (21 and 60 months) and t(11;14) subgroups (22 and 53 months). The effect of the degree of immunoparesis on PFS depended on the cytogenetic subgroup. Using polyclonal IgM as a continuous variable, Cox regression analysis demonstrated a significant effect on PFS in patients with hyperdiploidy (HR 0.482, 95% CI 0.325 - 0.717, p = 0.0003). No difference was seen in the t(11;14) (HR 0.610, 95% CI 0.262 - 1.418, p = 0.2507) or high-risk subgroups (HR 1.087, 95% CI 0.505 - 2.341, p = 0.8304). Conclusions: Our study demonstrates that the etiological cytogenetic subgroup influences the degree and clinical impact of immunoparesis in newly diagnosed MM patients. A significant proportion of patients with t(4;14), t(14;16), or t(14;20) have IgG, IgA, and IgM levels below the normal range compared to patients with hyperdiploidy and t(11;14). This suggests that the underlying genetic abnormality (i.e., NSD2, C-MAF, and MAF-B, respectively) drives changes in the bone marrow microenvironment remodeling the plasma cell niche, resulting in suppression of normal plasma cell function and immunoglobulin levels. Disclosures Cairns: Celgene: Other: Travel Support; Celgene, Amgen, Merck: Research Funding. Menzies:Celgene, Amgen, Merck: Research Funding. Pawlyn:Takeda: Consultancy, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses. Morgan:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Cook:Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; IQVIA: Research Funding; Sanofi: Consultancy; Amgen: Consultancy; Roche: Consultancy. Kaiser:Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Owen:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Janssen: Consultancy, Other: Travel expenses. Jackson:Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Gsk: Honoraria, Speakers Bureau. Davies:Sanofi: Honoraria, 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, Research Funding; Adaptive Biotech: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-133516

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2020

ZDB Id: 1468538-3

ZDB Id: 80069-7

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 21, No. 10 ( 2021-10), p. 667-675

Materialart: Online-Ressource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2021.04.013

Sprache: Englisch

Verlag: Elsevier BV

Publikationsdatum: 2021

ZDB Id: 2540998-0

ZDB Id: 2193618-3

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 4232-4233

Materialart: Online-Ressource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-169628

Sprache: Englisch

Verlag: American Society of Hematology

Publikationsdatum: 2022

ZDB Id: 1468538-3

ZDB Id: 80069-7