Multiple myeloma is an incurable malignancy which despite progressive improvements in overall survival over the last decade remains characterised by recurrent relapse with progressively shorter ...duration of response and treatment-free intervals with each subsequent treatment. Efforts to unravel the complex and heterogeneous genomic alterations, the marked dysregulation of the immune system and the multifarious interplay between malignant plasma cells and those of the tumour microenvironment have not only led to improved understanding of myelomagenesis and disease progression but have facilitated the rapid development of novel therapeutics including immunotherapies and small molecules bringing us a step closer to therapies that no doubt will extend survival. Novel therapeutic combinations both in the upfront and relapsed setting as well as novel methods to assess response and guide management are rapidly transforming the management of myeloma.
A dysfunctional immune tumor microenvironment facilitates disease progression in multiple myeloma (MM). Using multiplex immunohistochemistry (mIHC), we describe the quantitative and qualitative ...changes in CD3+CD8+ cytotoxic T cells and assess their proximity to malignant plasma cells (PC) in patients with monoclonal gammopathy of undetermined significance (MGUS), and newly diagnosed (ND) and relapsed and/or refractory (RR) MM. Formalin-fixed, paraffin-embedded trephine sections from patients with MGUS (N=32), NDMM (N=65), and RRMM (N=59) were sequentially stained for CD138, CD3, CD8, and checkpoint receptors (CPR) Tim-3, Lag-3, and PD-1. The Halo® image analysis platform was used for cell segmentation and phenotyping, facilitating enumeration of cytotoxic T cells and analysis of proximity to PC. The percentage of CD8+ cytotoxic T cells in proximity to PC is greater in patients with NDMM than patients with RRMM (at 50 μm distance, 90.8% vs. 81.5%; P=0.038). There is a trend for more CD3+ T cells in MGUS (P=0.08) but no difference was observed in the prevalence of CD8+ cytotoxic T cells (P=0.48). Lag-3 is the most common CPR expressed on cytotoxic T cells in myeloma (P<0.0001), while PD-1 is the most common CPR on CD8- T cells of patients with MGUS and RRMM. Our study is the first to report on the spatial relationship between T cells and PC using mIHC on FFPE bone marrow trephine sections from patients with PC dyscrasia. The proximity of T cells to PC during early stages of MM, and overexpression of Lag-3, validate the move of immune therapeutic strategies, including T-cell engagers and checkpoint inhibitors, to upfront treatment or in early-line treatment of MM.
This multicentre, phase II study of the Australian Lymphoma and Leukaemia Group (ALLG) and the Asian Myeloma Network (AMN) investigated fixed-duration (18-month) treatment with carfilzomib (K), ...thalidomide (T), and dexamethasone (d; KTd) in patients with relapsed and/or refractory multiple myeloma and 1-3 prior lines of therapy. Patients received induction with up to twelve 28-day cycles of K 20mg/m2 IV cycle 1 day 1 and 2, 56mg/m2 (36mg/m2 for patients ≥75 years) from day 8 onwards), T 100mg PO nocte and weekly dexamethasone 40mg (20mg for patients ≥75 years). During maintenance T was omitted, while K continued on days 1,2,15,16 with fortnightly dexamethasone. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate, overall survival (OS), duration of response, safety, and tolerability. Ninety-three patients (median age 66.3 years (41.9 - 84.5)) were enrolled with a median follow-up of 26.4 (1.6 - 54.6) months. The median PFS was 22.3 months (95% CI 15.7 - 25.6) with a 46.3% (95% CI 35.1 - 52.8) 2-year PFS. Median OS was not reached and was 73.8% (95% CI 62.9 - 81.9) at 2 years. The overall response rate was 88% (≥ VGPR 73%). There was no difference in the depth of response, PFS or OS comparing Asian and Non-Asian cohorts (p=0.61). The safety profile for KTd was consistent with each individual drug. KTd is well tolerated and effective in patients with RRMM irrespective of Asian or non-Asian ethnicity and provides an alternative option particularly where use of KRd is limited by access, cost, or renal impairment.
The prognostic impact of t(11;14) in multiple myeloma (MM) needs to be better understood to inform future treatment decisions. The Australian Lymphoma Leukaemia Group embarked on a retrospective, ...observational cohort study using real‐world data to interrogate treatment patterns and outcomes in 74 MM patients with t(11;14) t(11;14)‐MM diagnosed over 10 years. This was compared to 159 and 111 MM patients with high‐risk IgH translocations (IgH HR‐MM) and hyperdiploidy (Hyperdiploid‐MM), respectively, from the Australian Myeloma and Related Diseases Registry. No appreciable differences in age, gender, ISS, LDH levels, 1q21 or del(17p) status, or treatment patterns were observed between groups. Median PFS‐1 was not different between groups but both t(11;14)‐MM and IgH HR‐MM had an inferior PFS‐2 vs. Hyperdiploid‐MM: median PFS–2 8.2 months, 10.0 months, and 19.8 months (p = 0.002), respectively. The 3‐year OS were 69%, 71%, and 82% (p = 0.026), respectively. In the t(11;14)‐MM group, gain or amplification of 1q21 at diagnosis predicted for poorer OS (HR 3.46, p = 0.002). Eleven patients had received venetoclax with 45% achieving better than a very good partial response. Results suggest that t(11;14) MM may confer an unfavorable risk profile and that the use of targeted therapies such as venetoclax earlier in the treatment algorithm should be explored.
Non-Hodgkin lymphoma Ninkovic, Slavisa; Lambert, Jonathan
Medicine (Abingdon. 1995, UK ed.),
05/2017, Volume:
45, Issue:
5
Journal Article
Peer reviewed
Abstract Non-Hodgkin lymphoma (NHL) is the sixth most common cancer in the UK and represents a heterogenous group of malignancies. This article gives a brief overview of current classification of B ...and T cell NHL, the increased understanding of molecular and cytogenetic abnormalities associated with their pathogenesis, as well as current management principles. Although advances in immuno-chemotherapy and supportive care have resulted in better patient outcomes, many challenges remain, especially with relapsed and refractory disease. The recent introduction of novel agents in the treatment of lymphoma has resulted in some promising outcomes.
A dysfunctional immune tumour microenvironment (iTME) facilitates disease progression in MM. Using multiplex immunohistochemistry (mIHC) we aim to describe quantitative and qualitative changes in ...CD3+CD8+ T-cells (Tcytotoxic) in patients with MGUS, ND and relapsed/refractory MM (RRMM) and assess spatial proximity to PCs.
Formalin-fixed, paraffin-embedded trephine sections from pts with MGUS (n=32), NDMM (n=65) and RRMM (n=59) were sequentially stained for CD138, CD3, CD8 and checkpoint receptors (CPs) Tim3, Lag-3 and PD-1 (Figure 1). Halo® image analysis platform was used for cell segmentation and phenotyping, facilitating enumeration of Tcytotoxic populations and analysis of proximity to PCs. Descriptive statistics and ordinary one-way ANOVA were applied as appropriate.
Patient demographics, disease characteristics, treatment (including prior therapies, where applicable), best response, duration of response, median progression free (PFS) and overall survival (OS) will be presented for all cohorts. There was no difference in BM cellularity or total number of nucleated cells assessed across the cohorts (p=0.16 and p=0.25). PC % was higher in the ND and RRMM compared to MUGS cohort (p<0.001). The average distance between Tcytotoxic and PCs was similar between the cohorts (p=0.38), but a higher proportion of Tcytotoxic were within 50μm of a PC in the ND cohort (p=0.0036, 90.8±15.8% (ND) vs. 77.6±19.5% (MGUS) and 80.1±25.9% (RR)). The % of unique PCs with a single Tcytotoxic within 100µm is higher in patients with MGUS and RRMM than NDMM (p=0.0007). There was no difference in the %CD3+, %CD3+CD8+ or %CD3+ cells expressing CD8 (p=0.22, p=0.62, p=0.48). CP expression on Tcytotoxic was similar (Tim3 p=0.46, Lag-3 p=0.35; PD-1 p=0.54) with no difference in dual or triple CP expression. Sub-analyses assessing CP expression patterns and Tcytotoxic/PC proximity within individual cohorts based on response to treatment/disease progression are to follow.
Multiplex IHC is a novel technique to assess the iTME. While there is no discernible quantitative difference in cytotoxic T-cells or checkpoint receptor expression, we demonstrate increased proximity of cytotoxic T-cells to plasma cells in newly diagnosed patients suggestive of a more robust immune system compared to multiply treated patients.
Background: GRP78, an endoplasmic reticulum stress-inducible molecular chaperone, is up-regulated at times of cellular stress to limit proteotoxicity and promote cell survival. Translocation of GRP78 ...to the cell surface (csGRP78) is emerging as a critical step providing tumour cells with a survival advantage. Here we quantified, monitored and correlated plasma cell (PC) csGRP78 expression in patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with carfilzomib, thalidomide and dexamethasone (KTd).
Method: Patients enrolled in the single arm, multicentre, phase II Australasian Leukaemia & Lymphoma Group MM018/Asian Myeloma Network 002 study were treated with KTd as described previously (Quach et al. Blood 2018 132:1955). Formalin-fixed, paraffin-embedded BM trephine sections collected at baseline (n=29), after 6-months (mo) of KTd (n=19) and at time of disease progression (PD; n=5) were stained for CD138 and GRP78 by multiplex immunofluorescence histochemistry using the OpalTM workflow. Membrane expression of CD138 and GRP78 was extracted using inForm® software, compared across timepoints and correlated to disease characteristics and treatment outcomes. Descriptive statistics, paired/unpaired two-tailed t-test, Pearson's or Spearman's correlation were applied as appropriate.
Results: Correlative BM biopsies were collected for 29 pts male = 18, mean age = 65.0 years (range 41.9-83.2), 2 median prior lines of therapy (range 1-3) at baseline, 21 pts after 6 months of KTd (7 had PD/died prior to cycle 6, 1 came off study due to grade 4 AE after 5 cycles) and 5 pts at time of PD. There was no difference in the number of fields, BM cellularity (%) or number of nucleated cells (NCs) assessed at baseline and 6mo (p=0.927, 0.331 and 0.491 respectively). PC burden (%; mean±SD) reduced significantly following 6mo KTd (28.3±28.1 vs. 2.12±2.37; p=0.0007). The number of plasma cells expressing csGRP78 (% of all NCs) was reduced following 6mo KTd treatment (27.04±26.83 vs. 2.05±2.32; p=0.0007) while the % of CD138-ve BM cells expressing csGRP78 (% of all NCs; mean±SD) increased (62.61±27.55 vs. 87.46±10.11; p=0.0005). Globally, there was a trend for reduced intensity of csGRP78 expression after 6mo KTd (H-score 70.79±62.16 vs. 53.53±51.45; p=0.2073). There was no correlation between baseline BM NC GRP78 H-score and baseline paraprotein level, involved/uninvolved serum free light chain ratio or depth of response to KTd. Pts with early (<6mo) disease progression/mortality (n=7) had a significantly higher baseline H-score (136±78.8 vs. 75.1±65.2; p=0.049). There was a separation of survival curves, but no significant difference regarding risk of early PD/mortality based a baseline H-score >75th percentile of the cohort (>152); p=0.1472 (Figure 1).
Conclusion: Here we demonstrate that cell surface expression of GRP78 is prominent in both the plasma cells and cells of the tumour microenvironment in patients with RRMM and persists in the TME cells in patients on treatment. Early (<6mo) disease progression or mortality is associated with higher baseline intensity of global cell surface GRP78 expression. Additional studies are being performed to evaluate the promise of cell surface GRP78 expression on plasma cells as a potential biomarker of response to therapy.
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Harrison:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding. Quach:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees.
Summary
The MATRix chemoimmunotherapy regimen is highly effective in patients with newly diagnosed primary diffuse large B‐cell lymphoma of the central nervous system (PCNSL). However, nothing is ...known about its feasibility and efficacy in everyday practice, where patients are more often older/frailer than those enrolled in clinical trials. We conducted a retrospective study addressing tolerability/efficacy of MATRix in 156 consecutive patients with newly diagnosed PCNSL treated outside a clinical trial. Median age and ECOG Performance Status of considered patients were 62 years (range 28–78) and 2 (range 0–4). The overall response rate after MATRix was 79%. Nine (6%) treatment‐related deaths were recorded. After a median follow‐up of 27.4 months (95% confidence interval CI 24.4–31.9%), the two‐year progression‐free and overall survival were 56% (95% CI 48.4–64.9%) and 64.1% (95% CI 56.7–72.5%) respectively. Patients not eligible for the IELSG32 trial were treated with lower dose intensity and had substantially worse outcomes than those fulfilling inclusion criteria. This is the largest series of PCNSL patients treated with MATRix outside a trial and recapitulates the IELSG32 trial outcomes in the non‐trial setting for patients who fit the trial criteria. These data underscore the feasibility and efficacy of MATRix as induction treatment for fit patients in routine practice.
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