ALBERT

Description: Background: State of the art treatment for patients with NDMM involves induction with triplet-based regimens utilizing combinations of immunomodulatory drugs and proteasome inhibitors (PI) which improve time to progression (TTP), progression-free survival, and overall survival (OS) over doublet regimens. Carfilzomib is a selective PI with FDA approval in the KRd combination regimen for the treatment of patients with relapsed or refractory MM. Carfilzomib-based combinations are associated with increased clinical benefit over bortezomib-based combinations and carfilzomib does not cause neuropathy. This phase 2 study of 45 patients demonstrated that deep responses with KRd-r is achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing response to present the long-term durability of minimal residual disease negativity (MRDneg) complete response (CR) and time to progression. We also characterize TTP by depth of response, age, and cytogenetic risk profile. Methods:Treatment-naïve patients with MM were treated for 8 cycles (28-day cycles) with carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles and then continued KRd treatment (i.e. without default autologous stem cell transplant (ASCT)). After 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg PO maintenance on days 1-21. The primary objective of the study was to estimate the rate of ≥ Grade 3 peripheral neuropathy with secondary objectives of International Myeloma Working Group criteria for overall response rate (ORR), MRDneg CR, TTP, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg CR by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, 1 and 2 years of lenalidomide maintenance, and then annually. Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; 42% ≥ age 65, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda; 33% high risk cytogenetics, del(17p), t(4;14), t(14;16)or t(14;20)). The median potential follow up was 5.7 years (68.3 months). The ORR was 97.8% (95% Confidence Interval (CI): 88.2-99.9%) with a median DoR of 65.7 months (95% CI: 55.6-not reached (NR) months). Strikingly, 28 of the 45 patients, 62.2%, (95% CI: 46.5-76.2%) attained deep responses of MRDneg CR; durability of MRDneg CR was observed up to at least 70 months with a median duration of over 4 years (52.4 months; 95% CI: 35.3-61.6 months). Moreover, the median TTP was over five and a half years (67.3 months; 95% CI: 51.0-NR months) and the median OS was NR, however, at 80 months, 84.3% of patients were still alive. As expected, patients who attained MRDneg CR, by cycle 8, had a 78% reduction in the risk of progression (Hazard Ratio (HR): 0.22 (95% CI: 0.07-0.69); p=0.005) (Figure 1). Importantly, these deep responses of MRDneg CR and long progression free durations were observed regardless of age group or cytogenetic-based risk profile (Table 1). Toxicities have been previously reported and were generally manageable with no Grade ≥ 3 neuropathy or death due to toxicity. Conclusions: Upfront treatment of NDMM with the modern and highly efficacious KRd-r regimen incorporating a "by-default-delayed" ASCT strategy led to high rates of MRDneg CR (10-5 sensitivity) which even more importantly were sustained with a median duration of over 4 years. Moreover, attaining MRDneg CR, was strongly associated with a delay in progression. Clinically important, we observed that these deep responses and long progression-free durations are observed regardless of age or cytogenetic risk and stress the importance of utilizing highly efficacious triplet-based regimens for these sub-categories of NDMM. Lastly, our results with KRd-r in NDMM compare favorably to ASCT-based regimens and question the use of upfront ASCT for all patients. Our observed median TTP of 67 months is approximately 17 months longer than published data using the regimen of bortezomib, lenalidomide, and dexamethasone with ASCT (Attal et al. NEJM 2017). Updated results will be presented at the Annual Meeting. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: BACKGROUND Pediatric aggressive large B-cell lymphomas (LBCL) share morphological and phenotypic features with adult types but seem to have better prognosis. Additionally, a specific subtype carrying IRF4 translocations (LBCL-IRF4) has been recently identified in this age group. In adults, the cell-of-origin (COO) distinction of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures (germinal center B-cell like, GCB and activated B-cell like, ABC) and more recently clusters of genetic alterations have identified molecularly distinct DLBCL subsets that may benefit from novel therapeutic targets. The integration of pediatric population in these clinically relevant molecular subgroups and its clinical importance is not well known. The aim of this study was to characterize the molecular heterogeneity of LBCL in pediatric and young adult patients and evaluate their potential clinical impact. DESIGN Sixty-one LBCL diagnosed in patients ≤25 years-old (median age 14 years old, male/female 38/23) were included in the study. Molecular analyses included fluorescence in situ hybridization for MYC, BCL2, IRF4 and BCL6, copy number (CN) analysis (Oncoscan, Affymetrix), COO Lymph2Cx assay (NanoString) and targeted next generation sequencing of 96 B-cell lymphoma driver genes (SureSelect XT, Agilent Technologies). CNA and mutational profiles were compared to those previously published in adult DLBCL. Correlation of molecular features and event free survival (EFS) was performed using Kaplan-Meier curves. RESULTS Histologically, 33 were DLBCL, 20 LBCL-IRF4 and 8 high grade B-cell lymphomas, not otherwise specified (HGBCL). Nodal disease was present in 57%, mainly in the cervical region. COO distribution was: 68% GCB, 18% ABC and 13% unclassified. Most of LBCL-IRF4 cases were GCB-COO (73%). The IRF4 translocation was demonstrated in 16 out of 19 cases diagnosed as LBCL-IRF4 and an IGH rearrangement was seen in the other 3. Five cases carried MYC-breaks (3 DLBCL and 2 HGBCL) and two cases carried BCL6-breaks (1DLBCL and 1HGBCL). BCL2 rearrangements were absent. CN analysis detected alterations in 46/51 cases with recurrent gains (〉15%) of 1q, 2p16, 11q, trisomies 7 and 12, and recurrent losses (〉10%) of 1p36, 6q21-q22, 15q24, 17p13 and 19p13. Recurrent homozygous deletions were observed at 19p13/CD70 (6 cases), 9p13/CDKN2A (3 cases) and 13q14/RB1 (2 cases). Alteration patterns suggestive of chromothripsis were found in 10% (5/51) of the cases. No ABC-DLBCL related alterations such as 3p21-p14, 6q21-q25, 9p21.3 and 17p13 losses were seen. Targeted sequencing detected a total of 434 variants in 44 of 47 cases (mean 9.2 mutations/case). A pipeline for selection of driver mutations revealed a total of 270 mutations (62%) with potential functional effect. Recurrent mutations found in 〉15% of the cases affected IRF4, SOCS1, PIM1, CARD11, ACTB and CCND3 genes. In comparison to adult DLBCL, pediatric and young adult cases had significantly lower incidence of MYD88 (5 cases), CREBBP,TP53 (3 cases each) and TNFRSF14 (2 cases) mutations which are strongly associated with the definition of established mutational clusters in adult DLBCL. In our cohort, the morphological subtypes displayed different molecular profiles. IRF4 variants (some cases with 〉7 variants) and mutations in NF-kB pathway (CARD11, CD79B and MYD88-non L265P) were found specifically in the LBCL-IRF4 subgroup, whereas mutations in GCB related genes such as SOCS1 and EZH2 were particularly seen in cases with DLBCL diagnosis. All 49 patients with available follow-up received chemotherapy as first line treatment (41% containing Rituximab). Variables significantly associated with poor EFS in univariate analysis were age 〉18 years, ABC-COO, Stage IV, high genetic complexity (chromothripsis and/or 〉10 CN alterations), 2p16/REL gain/amplification, 9p21.3/CDKN2A homozygous deletions, MYC rearrangements and mutations in MYC, TP53 and DDX3X genes. CONCLUSION Despite pediatric/young-adult LBCL having overlapping features with adult disease our findings suggest that LBCL in young age have specific molecular mechanisms and highlight potential key drivers of these lymphomas in this age group. Disclosures No relevant conflicts of interest to declare.

Description: Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma–related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age 〉18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.