Relapsed and/or refractory follicular lymphoma (R/R FL) remains a therapeutic challenge due to its chronic relapsing course and increasingly complex treatment landscape. Novel therapies, including immunomodulatory combinations, bispecific antibodies (BsAbs), Bruton tyrosine kinase inhibitors, and chimeric antigen receptor (CAR) T-cell therapies, have expanded treatment options and increased the complexity of treatment selection and sequencing. The Canadian Hematology Consensus Group (CHCG) convened a national panel of lymphoma experts to develop evidence-informed consensus recommendations for the management of adults with R/R FL in the Canadian context. Clinical questions informed a structured literature review of studies published through February 2026, including randomized trials, phase II studies, observational data, conference proceedings, and relevant guidelines. Recommendations were developed using a modified Delphi consensus process and graded using a framework adapted from the British Committee for Standards in Haematology. Key recommendations include repeat biopsy to exclude histologic transformation at relapse, individualized treatment selection based on timing of relapse and patient-specific factors, preferential use of lenalidomide-rituximab (LenR)-based triplet combinations in most second-line settings, and incorporation of BsAb and CAR T-cell therapy in third-line and later disease. These recommendations aim to provide practical guidance for Canadian clinicians managing patients with R/R FL.

Multiple myeloma (MM), the second most prevalent hematological malignancy, carries high morbidity with variability in clinical progression among patients. This necessitates accurate risk stratification for effective therapy and life planning. While extensively genomically and transcriptomically characterized, MM remains modestly studied from a proteomic perspective. As proteomics is a closer measure of phenotype than genomic and transcriptomic assessments, addressing this gap in the literature may yield new insights into disease biology and novel biomarkers. Herein, we applied a new sample preparation approach for mass-spectrometry based proteomics to bone marrow interstitial fluid (BMIF) from patients with MM or its precursors. We achieved deep coverage of the proteome, identifying > 11,000 protein groups (PGs) across our cohort, with an average of 8900 PGs per sample. Of these, 194 PGs were significantly associated with overall survival (OS). These survival-associated PGs were enriched for those involved in coagulation, and clustering newly diagnosed MM (NDMM) based on coagulation-related proteins revealed three distinct groups characterised by globally high, medium, and low intensity of coagulation-related proteins. The group with low intensity of coagulation-related PGs had significantly reduced OS (log-rank p = 0.00078). Clustering was independent of measured clinical covariates, including chemotherapeutic regimens used, Revised International Staging System (R-ISS stage), International Normalised Ratio (INR), and age, among others. Our findings support the value of fluid-based proteomic assessment of MM and suggest that coagulation-related PGs could serve as valuable novel biomarkers for risk stratification in multiple myeloma, warranting further investigation into this area.

Background: The optimal treatment of treatment naïve (TN) Waldenström's macroglobulinaemia (WM) has not yet been defined. Recently we have shown high complete and very good partial responses (CR+VGPR) with a tolerable toxicity profile in participants with treatment-naïve WM treated in the BRAWM trial (NCT04624906). We have also reported that age was not a predictive variable for the primary endpoint of combined CR+VGPR rates or for negative peripheral blood (PB) Minimal Residual Disease (MRD) responses. Objectives: In this current analysis, we evaluate the efficacy, tolerability and dose intensity of this combination in participants with WM in the BRAWM trial who were less than age 70 and those greater than or equal to age 70. Methods: The BRAWM clinical trial is an investigator-initiated multicentre clinical trial that evaluated the combination of bendamustine, rituximab and acalabrutinib (100mg twice daily) in 63 participants with TN WM. CR+VGPR rates were 59% in this trial. In addition, the tolerability was acceptable. Here, we analyze the efficacy, dose intensity and toxicity profile of this treatment in participants entered in the trial who were <70 years old (y/o) and those who are ≥70 y/o. Results: Of the 63 participants entered in the BRAWM clinical trial, 31 were ≥70 y/o. Participants up to age 85 were treated in the trial. The baseline demographic factors, including B2 microglobulin, LDH, baseline haemoglobin or platelets, total IgM, IWWM-IPS, bone marrow involvement and MYD88MUT and CXCR4MUT status were similar in participants under between the two cohorts. At cycle 7, the combined CR+VGPR rate was very similar between the two groups at 59.4% in those <70 y/o and 58.1% in those ≥70 y/o. The PB MRD rate was 78.6% and 77.8% in those <70 y/o and in those ≥70 y/o, respectively. With respect to dose intensity, 24/31 participants ≥70 y/o received 81-100% of the planned acalabrutinib dose and 26/32 of participants <70 y/o received 81 to 100% of planned acalabrutinib dose. Two participants ≥70 y/o received less than 60% of acalabrutinib, whereas four participants <70 y/o received less than 60% of acalabrutinib. The response rates in participants <70 y/o and those ≥70 y/o in these different dose intensity groups for acalabrutinib were similar. Of the planned bendamustine administration, twenty-five participants ≥70 y/o received greater than 75%, and twenty-nine participants <70 y/o did. Of the five participants who received 50% or less of the expected bendamustine, three withdrew during combination therapy. Patients <70 y/o received a mean of 5.9 cycles of bendamustine (range 2-6 cycles), whereas patients >70 y/o received a mean of 5.5 cycles of bendamustine (range 1-6 cycles). Grade 3/4 neutropenia or febrile neutropenia occurred in 9 participants (29%) ≥70 y/o, and 12 participants (37.5%) <70 y/o during combination therapy. There were no major differences in frequency of grade 3/4 adverse events between the two age groups during monotherapy. Bendamustine was discontinued in 8 participants (26%) ≥70 y/o and 3 participants (9%) <70 y/o. There were no major differences between the two age groups in VGPR+CR rates or major responses in any of the different dose intensity groups. Conclusions: the BRAWM clinical trial for TN WM produces amongst the highest CR and VGPR rates for this patient population. This combination treatment was equally effective in participants ≥70 y/o or <70 y/o. In addition, both age cohorts were able to tolerate similar dose intensities of bendamustine and acalabrutinib. Older patients received a slightly lower mean number of cycles of bendamustine. Although more patients ≥70 y/o discontinued bendamustine due to toxicities, this did not appear to compromise efficacy. The toxicity profile also was very similar. We conclude that this regimen can be administered effectively to patients with TN WN, as age does not appear to be a limitation for administration with no impact on efficacy, tolerability or dose intensity of this regimen.

PURPOSE In patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), brentuximab vedotin (BV) as monotherapy or combined with either lenalidomide (Len) or rituximab (R) has demonstrated efficacy with acceptable safety. We evaluated the efficacy and safety of BV + Len + R versus placebo + Len + R in patients with R/R DLBCL. METHODS ECHELON-3 is a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial comparing BV + Len + R with placebo + Len + R in patients with R/R DLBCL. Patients received BV or placebo once every 3 weeks, Len once daily, and R once every 3 weeks. The primary end point was overall survival (OS), and secondary end points included investigator-assessed progression-free survival (PFS) and objective response rate (ORR). A prespecified interim analysis was performed after 134 OS events, with two-sided P = .0232 as the efficacy boundary. RESULTS Patients (N = 230) were randomly assigned to receive BV + Len + R (n = 112) or placebo + Len + R (n = 118). Two patients in the placebo arm did not receive treatment. With a median follow-up of 16.4 months, the median OS was 13.8 months with BV + Len + R versus 8.5 months with placebo + Len + R (hazard ratio, 0.63 [95% CI, 0.45 to 0.89]; two-sided P = .009). The median PFS was 4.2 months with BV + Len + R versus 2.6 months with placebo + Len + R (hazard ratio, 0.53 [95% CI, 0.38 to 0.73]; two-sided P < .001). The ORR was 64% ([95% CI, 55 to 73]; two-sided P < .001) with BV + Len + R and 42% (95% CI, 33 to 51) with placebo + Len + R; complete response rates were 40% and 19%, respectively. Treatment-emergent adverse events (AEs) occurred in 97% of patients in both arms. In both arms, the most common treatment-emergent AEs were neutropenia, thrombocytopenia, diarrhea, and anemia. CONCLUSION BV + Len + R demonstrated a statistically significant survival benefit with a manageable safety profile in heavily pretreated patients with R/R DLBCL.

SPiReL is a phase II clinical trial evaluating combination immunotherapy, pembrolizumab and cyclophosphamide, with maveropepimut-S, in survivin-expressing relapsed/refractory (R/R) Diffuse Large B Cell Lymphoma (DLBCL). We describe baseline tumor survivin expression and associations with clinico-pathological variables in 25 participants. The median number of survivin-expressing cells was 99%, and the intensity of survivin expression within tumors was heterogeneous by semi-quantitative immunohistochemistry assessment. Tumors with higher numbers of cells expressing 2+/3+ survivin were associated with characteristics of poor outcome, (Lactate dehydrogenase and cell-of-origin). Greater total baseline tumor area was associated with lower proportions of 1+ cells and greater proportions of 2+/3+ cells. High intensity survivin expression is associated with aggressive clinical features supporting a pathobiological role in R/R DLBCL. Future prognostic models incorporating survivin as a clinical biomarker require assessment of intensity, overall expression and should include potential threshold effects of survivin in DLBCL pathobiology.

LBA7005 Background: Despite recent advances, there remains a need for novel therapies for pts with R/R DLBCL. BV, an anti-CD30 antibody-drug conjugate, has shown efficacy and safety when combined with lenalidomide (len) and with rituximab (R) in heavily pretreated populations (Bartlett 2022; Ward 2022). The double-blind, global phase 3 ECHELON-3 study (NCT04404283) compared BV with R+len (R2) vs R2 in pts with R/R DLBCL who are ineligible for HSCT or CAR T-cell therapy. Here, we present results from the interim analysis (IA) for overall survival (OS). Methods: Pts with R/R DLBCL received BV+R2 or placebo+R2 (randomized 1:1). Pts received BV (1.2 mg/kg) or placebo q3w, R (375 mg/m2) q3w, and len (20 mg) qd. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (ORR), and complete response (CR) rate. The preplanned IA was performed at 134 OS events with a prespecified efficacy boundary of 2-sided P=0.0232. Results: 230 pts were randomized: 112 to BV+R2 and 118 to R2; all but 2 pts (both in R2 arm) received ≥1 dose of study drug. Median age was 71 yrs (range, 21-89), 56.5% were male, and 10.9% had an ECOG of 2. Median prior lines of therapy was 3 (range, 2-8); 29% had prior CAR T-cell therapy and 68% were CD30- (<1% CD30 tumor expression). At median follow-up of 16.4 months (mos) (range, 0.1-31.5) (cut-off: January 22, 2024), median OS was 13.8 mos (95% CI: 10.3-18.8) with BV+R2 vs 8.5 mos (95% CI: 5.4-11.7) with R2 (HR 0.629; 95% CI: 0.445-0.891; P=0.0085); OS benefit was consistent across key subgroups. Median PFS was 4.2 mos (95% CI: 2.9-7.1) with BV+R2 vs 2.6 mos (95% CI: 1.4-3.1) with R2 (HR 0.527; 95% CI: 0.380-0.729; P<0.0001). ORR was 64.3% (95% CI: 54.7-73.1) with BV+R2 vs 41.5% with R2 (95% CI: 32.5-51.0; P=0.0006); CR rate was 40.2% vs 18.6%, respectively. In CD30+ vs CD30- subgroups, ORR/CR was 72.2%/38.9% vs 60.5%/40.8% with BV+R2, respectively, and 50.0%/26.3% vs 37.5%/15.0% with R2, respectively. Efficacy analysis including cell of origin will be presented. The safety profile of BV+R2 was tolerable vs R2: Grade (Gr) ≥3 treatment-emergent adverse events (TEAEs) were 88% vs 77%, serious TEAEs were 60% vs 50%, and Gr 5 TEAEs were 12% vs 8%, respectively. Most common TEAEs were neutropenia (46% vs 32%), anemia (29% vs 27%), and diarrhea (31% vs 23%). Rates of peripheral neuropathy for BV+R2 vs R2 were 31% vs 24% (all Gr) and 6% vs 2% (Gr 3). Median treatment duration was 3.6 mos with BV+R2 vs 2.0 mos with R2. Conclusions: Treatment with BV+R2 triplet, compared to R2, demonstrated statistically significant and clinically meaningful improvements in all key efficacy outcomes including OS in high-risk subgroups, with manageable safety. This triplet regimen represents a novel treatment option for pts with heavily pretreated R/R DLBCL. Clinical trial information: NCT04404283 .

Introduction:Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have an unmet medical need. The objective of this trial was to assess the efficacy and toxicities of a novel triple immunotherapy regimen-pembrolizumab, low-dose cyclophosphamide, and maveropepimut-S (MVP-S). This regimen was designed to activate tumor-specific T cells by targeting the tumor-associated antigen survivin with MVP-S and reducing two important T cell inhibitory pathways: T cell exhaustion and regulatory T cells with pembrolizumab and metronomic cyclophosphamide, respectively. Methods:This was a single-arm Phase II clinical trial in 25 participants with R/R DLBCL-SPiReL trial (NCT03349450). Results:The median overall survival was 10.1 months and a third of participants survived over 2 years. Enhanced long-term survival was associated with favorable clinical characteristics and enhanced immune reactivity, as assessed by ELISpot and ISR-immune reactive responses. The regimen was well-tolerated with minimal Grade 3-4 toxicities. Conclusion:Combination immunotherapy regimens such as this could offer a promising alternative to other treatments with significant toxicities for select patients.

Background ECHELON-3 (NCT04404283) is a randomized, double-blinded, placebo-controlled phase 3 study comparing BV plus R+len (R2) vs placebo+R2 in patients with R/R DLBCL who are ineligible for HSCT/CAR T-cell therapy. We present results from the interim analysis (IA). Methods Patients with R/R DLBCL were randomized 1:1 to receive BV+R2 or placebo+R2 (ie, BV 1.2 mg/kg or placebo q3w, R 375 mg/m2 q3w, and len 20 mg qd). Primary endpoint was OS in the intent-to-treat population. Secondary endpoints were investigator-assessed PFS and ORR. Preplanned IA was performed at 134 OS events with prespecified efficacy boundary of 2-sided P=.0232. Results As of January 22, 2024, 230 patients were randomized (BV+R2, n=112; R2, n=118). Median age was 71 years, median prior therapy lines was 3, 29% had prior CAR T-cell therapy, and 68% had <1% CD30 tumor expression. Consistent results across efficacy endpoints were observed with BV+R2 vs R2: mOS 13.8 (95% CI, 10.3-18.8) vs 8.5 months (95% CI, 5.4-11.7) (HR, 0.629; 95% CI, 0.445-0.891; P=.0085; median follow-up, 16.4 months); mPFS 4.2 (95% CI, 2.9-7.1) vs 2.6 months (95% CI, 1.4-3.1) (HR, 0.527; 95% CI, 0.380-0.729; P<.0001); ORR 64.3% (95% CI, 54.7-73.1) vs 41.5% (95% CI, 32.5-51.0) (P=.0006); CR rate 40.2% vs 18.6%. OS benefit was observed in key subgroups. Efficacy analysis including cell of origin and CD30 status will be presented. Safety profile of BV+R2 was tolerable vs R2 (grade ≥3 treatment-emergent adverse event [TEAE] rate, 88% vs 77%; serious TEAE rate, 60% vs 50%; grade 5 TEAE rate, 12% vs 8%). Most common TEAEs were neutropenia (46% vs 32%), anemia (29% vs 27%), and diarrhea (31% vs 23%). Peripheral neuropathy rates with BV+R2 vs R2 were 31% vs 24% (all grade) and 6% vs 2% (grade 3). Median treatment duration was 3.6 vs 2.0 months. Conclusions Compared with R2, BV+R2 demonstrated statistically significant and clinically meaningful OS improvements with a manageable safety profile. BV+R2 is a promising treatment option for patients with R/R DLBCL.

Patients with relapsed/refractory diffuse large B‐cell lymphoma (R/R DLBCL) have limited treatment options.

Background: Waldenström’s macroglobulinaemia (WM) is an uncommon lymphoproliferative disorder. Many options are available, however, an optimal first-line therapy for WM has not be defined. We postulated that combining bendamustine and rituximab (BR) with a next generation BTK inhibitor would result in deeper responses as measured by complete response (CR) and very good partial response (VGPR) rates, and provide a longer duration of response. Objectives: The primary objective of this trial is to document the CR and VGPR rates Methods: The BRAWM clinical trial combines BR with acalabrutinib in a fixed duration treatment course including six cycles of BR and 12 months of acalabrutinib. This trial is taking place at 8 clinical sites across Canada and 33 patients have been enrolled, with a recruitment goal of 59. Results: A pre-defined interim analysis of the first 30 enrolled patients showed; median age of patients was 66; 25 were male; two patients were low risk, 14, intermediate and 15 high risk. Seventeen patients completed combination therapy, 9 completed monotherapy and 2 were followed-up at 18 months (6 months post therapy). Clinical results to date: Two patients discontinued treatment early; 1 at cycle 7 (with a VGPR) but experienced an adverse event requiring treatment; 1 at cycle 3 with possible disease progression. There were 186 treatment related adverse events (TRAEs) among 25 of 30 participants; 5 participants did not experience a TRAE; 163 of these occurred during combination therapy; 23 during monotherapy in 7 of 17 participants, where 10 participants did not experience a TRAE. During combination therapy, 16 of the 163 TRAE’s were grade 3; neutropenia (n = 8), including 2 that were febrile neutropenia, n = 1 for each: atrial fibrillation, transaminitis, cellulitis, fatigue and pulmonary emphysema. An additional five were also considered serious and included febrile neutropenia (n = 2), and n = 1 for each fever, allergic reaction and bowel obstruction. During monotherapy, there were no serious TRAEs. There were 2 grade 3 events during monotherapy in two different patients; decreased neutrophil count, and syncope. There were 21 dose interruptions in 11 participants, all but one of whom returned to regular dosage. Of assessed patients, 20/20 have MyD88 mutations, 4/20 have a CXCR4 mutation, and none had a TP53 mutation. Minimal residual disease (MRD) analysis using next generation sequencing of the IgV regions will be reported. Conclusions: Bendamustine, rituximab and acalabrutinib front-line therapy for WM is safe and well tolerated and initial clinical results show that this treatment induces a high percentage of VGPRs. The research was funded by: AstraZeneca Keywords: Combination Therapies, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. N. L. Berinstein Consultant or advisory role: AstraZeneca Research funding: AstraZeneca, Merck, IMV N. Forward Honoraria: AstraZeneca, AbbVie, BeiGene, Celgene/BMS, IMV, Kite, Janssen, Pfizer, Roche, Servier Research funding: Astellas, AstraZeneca, IMV, Merk, MorphoSys, Seattle Genetics, Roche Other remuneration: Speaker Fees: Pfizer, BeiGene, AstraZeneca M. Shafey Consultant or advisory role: Jansen, Roche Canada, Kite/Gilead, Novartis, BeiGene, Incyte, Abbvie, BMS, AstraZeneca A. Nikonova Consultant or advisory role: Forus, Janssen, Astra Zeneca, Apotex, Incyte Educational grants: Janssen D. MacDonald Honoraria: Abbvie, Astra Zeneca, Beigene, BMS, Incyte, Kite Gilead, Roche, and Seattle Genetics D. Villa Consultant or advisory role: AZ, BeiGene, Janssen, Roche, Kite/Gilead, Merck, BMS/Celgene, ONO Pharmaceuticals. Honoraria: AZ, BeiGene, Janssen, Roche, Kite/Gilead, Merck, BMS/Celgene, ONO Pharmaceuticals. Research funding: Roche, AstraZeneca I. Sandhu Honoraria: Celgene/BMS, Kite/Gilead, Janssen, Sanofi, FORUS, Pfizer M. Aljama Consultant or advisory role: Jansen, Sanofi, Pfizer, Beigene J. Larouche Consultant or advisory role: Incyte, Gilead Research funding: Incyte, Astra-Zeneca, Genmab

Background: Waldenström's macroglobulinaemia (WM) is an uncommon lymphoproliferative disorder. Although many options are available, an optimal first-line therapy for WM has not been defined. We postulated that combining bendamustine and rituximab (BR) with a next generation BTK inhibitor would result in deeper responses as measured by complete response (CR) and very good partial response (VGPR) rates, and provide a longer duration of response. Objectives: The primary objective of this trial is to document the CR and VGPR rates Methods: The BRAWM clinical trial combines BR with acalabrutinib in a one-year, fixed duration treatment course including six cycles of BR and 12 months of acalabrutinib (6 months of monotherapy). This ongoing trial is taking place at 9 clinical sites across Canada and 44 patients have been enrolled as of July 1, 2023, with a recruitment goal of 59. Results: Median age of participants was 68; 34 were male; 3 participants were low risk, 21 intermediate and 20 high risk. 27 participants completed combination therapy, 17 completed monotherapy and 7 were followed-up at 18 months, and 3 at 24 months after first dose. Table 1 shows the observed Clinical Responses using 6 th IWWM; 2 participants improved from a VGPR to a CR between cycles 7 and 12, both of whom have not reached month 18 for assessment. The interim primary endpoint of combined CR and VGPR rate is 13/17 (77%), with no participants having progressed at this interim analysis. 3 participants discontinued treatment early: 1 at cycle 7 (with a VGPR) who experienced an adverse event requiring treatment; 1 at cycle 3 with inter-current illness, and 1 at cycle 2 for personal reasons not related to treatment. The total observed Treatment Related Adverse Events (TRAEs) in combination therapy was 188 amongst 35 participants, and n= 24 in 10 participants during monotherapy. There were 24 Grade 3/4 TRAEs (combination n= 20, monotherapy n= 4). Total observed Serious Adverse Events was 18, and 7 TRSAEs 7; 6 during combination therapy (3 febrile neutropenia and 1 for each fever, allergic reaction and bowel obstruction) and 1 pneumonia during monotherapy. Grade 3/4 TRAEs resulted in 29 dose interruptions in 13 participants, and 2 dose reductions. Mutational analysis of participants with adequate sample for assessment (n=35), showed 33 with MYD88 mutation, 10 with a CXCR4 mutation, and 1 with a TP53 mutation. Minimal residual disease (MRD) analysis of Peripheral Blood (PB) and Bone Marrow, using next generation sequencing, is underway. Initial review shows that most evaluable patients (those with samples at two or more time-points) have become MRD undetectable in PB. Uni- and multi-variate analyses of variables that may be associated with outcomes is underway. Conclusions: Bendamustine, rituximab and acalabrutinib front-line therapy for WM is safe and well tolerated and initial clinical results show that this treatment induces a high percentage of CR + VGPRs. Table 1: Clinical Responses using 6 th IWWM. *The 2 participants observed to have a CR at month 12 have not reached month 18 for progression or survival follow-up.

Waldenström macroglobulinemia (WM) is a slowly progressing B-cell non-Hodgkin lymphoma characterized by monoclonal IgM gammopathy in the blood and infiltration of the bone marrow by clonal lymphoplasmacytic cells. As an incurable disease, the goals for therapy for WM are to relieve symptoms, slow disease progression, prevent organ damage, and maintain quality of life. However, given the rarity of WM, clinical trials comparing treatments for WM are limited and there is no definitive standard of care. The selection of first-line WM therapy is thus based on patient factors, disease characteristics, and drug access, with bendamustine-rituximab and Bruton's tyrosine kinase (BTK) inhibitor therapy considered preferred treatments. Other treatments such as proteasome inhibitor- or purine analogue-based therapy, alternative chemoimmunotherapy, and autologous stem cell transplantation are generally reserved for the relapsed setting but may be used in rare circumstances in earlier lines of therapy. This paper summarizes the efficacy and safety of these WM therapies and discusses considerations for treatment from a Canadian perspective.

Multiple myeloma presents with numerous primary genomic lesions that broadly dichotomize cases into hyperdiploidy or IgH translocated. Clinically, these large alterations are assessed by fluorescence in situ hybridization (FISH) for risk stratification at diagnosis. Secondary focal events, including indels and single-nucleotide variants, are also reported; however, their clinical correlates are poorly described, and FISH has insufficient resolution to assess many of them. This study examined the exonic sequences of 26 genes reported to be mutated in >1% of patients with myeloma using a custom panel. These exons were sequenced to approximately 1000 times in a cohort of 76 patients from Atlantic Canada with detailed clinical correlates and in four multiple myeloma cell lines. Across the 76 patients, 255 mutations and 33 focal copy number variations were identified. High-severity mutations and mutations predicted by FATHMM-XF to be pathogenic identified patients with significantly reduced progression-free survival. These mutations were mutually exclusive from the Revised International Staging System high-risk FISH markers and were independent of all biochemical parameters of the Revised International Staging System. Applying our panel to patients classified by FISH to be standard risk successfully reclassified patients into high- and standard-risk groups. Furthermore, three patients in our cohort each had two high-risk markers; two of these patients developed plasma cell leukemia, a rare and severe clinical sequela of multiple myeloma.

Background Treatment of recurrent/refractory (r/r) DLBCL remains an unmet clinical need, and new effective and well-tolerated treatments are required. DPX-Survivac is a unique T cell activation therapy that targets survivin-expressing tumor cells and has shown anti-tumor activity in clinical trials. This trial is evaluating a novel immunotherapy combination with DPX-Survivac, intermittent low dose CPA and pembrolizumab. Methods ‘SPiReL’ is a Phase 2 non-randomized, open label, efficacy and safety study of a novel immunotherapy combination with DPX-Survivac (a unique T cell activation therapy that targets survivin-expressing tumor cells), intermittent low dose CPA and pembrolizumab, treatment regimen as described in figure 1. Subjects with r/r incurable DLBCL and survivin expression are eligible for participation. This study was approved by the Ontario Cancer Research Ethics Board, approval number 0981.ORR is assessed by modified Cheson criteria. For translational analyses, baseline and on-treatment PBMCs, along with tumor biopsy samples are collected from each subject. Survivin-specific systemic T cell responses are assessed using IFNγ-ELISPOT assay and tumour immune-infiltrate profile by multiplex-IHC. Results Twenty-two subjects have been enrolled to date, 19 are included in the intent to treat (ITT) population and 11 subjects are evaluable in the per protocol (PP) population. In the PP, the ORR is 63.6% including 3 CRs (27.3%), 4 PRs (36.4%) and the DCR is 81.8% (9/11). In the ITT, the ORR is 35% (7/19), and DCR is 52.0% (10/19). Preliminary results show that non-GCB subjects had a higher proportion of clinical response (4/8, 50%), compared to 3/10 (30%) in GCB subjects.DPX-Survivac-induced T cell responses were observed in 8/19 subjects (42.1%) including 6 subjects with clinical response (PR, CR), one SD and one PD. Multiplex-IHC analyses demonstrated baseline tumor PD-L1 expression in 6/7 subjects with a clinical response (85.7%, p Conclusions DPX-Survivac, intermittent low-dose CPA and pembrolizumab is generally well tolerated and can induce clinical responses in subjects with r/r DLBCL (7/11, 63.6% of evaluable subjects), including subjects with both non-GCB and GCB subtypes. Pre-treatment biopsies of clinical responders were characterized by higher baseline tumor PD-L1 expression and CD4 and CD8 infiltration. Extending this exploratory data in a larger cohort may define a r/r DLBCL patient population with a higher likelihood to respond to this novel combination immunotherapy. Trial Registration NCT03349450 Ethics Approval This study was approved by the Ontario Cancer Research Ethics Board, approval number 0981.

Multiple myeloma (MM) is an incurable hematological malignancy that relies on cytogenetic determination of copy number abnormalities (CNAs) for prognosis and management. Low-depth whole genome sequencing (LD-WGS) is a cost-effective alternative to targeted genomics for CNA detection, but its value has yet to be explored in MM. DNA from CD138+ cells from MM patients were sequenced using an Illumina NextSeq at <1x depth (ultralow-depth). Subsampling analysis and window size adjustment were performed for determining sensitivity limits and results compared to fluorescent in-Situ hybridization (FISH). CNA calls made down to 5 million (M) reads were comparable to those at 20 M reads at a window size of 100 kb had a sensitivity and specificity of 93%, 92% and an area under the curve of 0.94. All CNAs detected by FISH on the MM samples were also detected by LD-WGS; the latter detected a further 36 focal CNAs not detected by FISH. Cost per sample of LD-WGS was significantly lower for our organization than FISH testing. LD-WGS for MM is significantly more sensitive than targeted technologies such as FISH in CNA detection and resolution, provides a more cost-effective option for clinical purposes and potential for exploring prognostically relevant and drug discovery targets.

The presence of eosinophils in the lung is often regarded as a defining feature of asthma. On allergen stimulation, numbers of eosinophils and their progenitors are increased in both the bone marrow and lungs. Eosinophil progenitors provide an ongoing supply of mature eosinophils. Here, we report that deficiency in the regulator of calcineurin 1 gene (Rcan1) leads to a near-complete absence of eosinophilia in ovalbumin-induced allergic asthma in mice. In the absence of Rcan1, bone marrow cells produce significantly fewer eosinophils in vivo and in vitro on interleukin-5 stimulation. Importantly, eosinophil progenitor populations are significantly reduced in both naïve and ovalbumin-challenged Rcan1(-/-) mice. Bone marrow cells from Rcan1(-/-) mice are capable of developing into fully mature eosinophils, suggesting that Rcan1 is required for eosinophil progenitor production but may not be necessary for eosinophil maturation. Thus, Rcan1 represents a novel contributor in the development of eosinophilia in allergic asthma through regulation of eosinophil progenitor production.