scholarly journals Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 781-781 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Joaquin Martinez-Lopez ◽  
Paula Rodriguez Otero ◽  
Veronica Gonzalez-Calle ◽  
Marta Sonia Gonzalez ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Skin Rash ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Second Primary ◽  
Advisory Committees ◽  
End Point ◽  
Patient Reported ◽  
Risk Of Progression

Introduction: SMM is an asymptomatic and heterogeneous plasma cell disorder. Both Spanish Myeloma and ECOG Groups have demonstrated that pts at high risk of progression to active MM benefit from early treatment with R-based regimens. Our next step was to design this phase 2, single arm trial, focusing on the same population, but with the potential goal of cure, defined by sustained minimal residual disease negativity (MRD-ve) at 5 years after HDT-ASCT. Patients and methods: Ninety SMM pts at high-risk of progression (>50% at 2 yrs), younger than 70 years and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo) or ifonly one criterion was present, pts must >95%of aberrant PCs within the total PCsBM compartment by immunophenotyping plus immunoparesis (Spanish). Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2 twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2 followed by ASCT was given as intensification therapy followed by two KRd consolidation cycles and maintenance with R at dose of 10 mg plus dexamethasone at dose of 20 mg weekly for up to 2 yrs. The primary end-point was to evaluate the MRD-ve rate by next generation flow (NGF) after induction and ASCT and our aim was to increase the MRD -ve rate from 34% (reported in NDMM pts after VTD and ASCT) to at least 50%. Results: Between June 2015 and June 2017, 90 high-risk SMM pts were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM. On February 4th, 2019, 71 pts were already receiving maintenance treatment; 7 pts had finalized the treatment and there were 11 early discontinuations (4 biochemical relapses during maintenance, 2 Informed Consent refusal, 3 adverse events and two deaths). After a median follow-up of 32 months (8-128), 93% of pts remain alive and free of progression and 98% of them alive. In the intent-to-treat pts' population, after induction, the ≥CR rate was 41% and increased to 59% after HDT-ASCT and to 70% after consolidation. In the same analysis, MRD-ve rate was observed in 30% of pts after induction, 52% after HDT-ASCT and 57% after consolidation. If we focus on the 83 pts who completed induction, HDT-ASCT and consolidation, the ≥CR/undetectable MRD rates were 42%/31%, 64%/56% and 76%/63% after each step, respectively. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were reported in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three pts reported hypertension (G2 in two and G3 in one). In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All pts engrafted but one patient developed late graft failure. During consolidation, 2 pts developed G3-4 neutropenia, 3 pts G3-4 infections and 1 pt skin rash. Maintenance treatment is ongoing and one patient had to discontinue due to a second primary malignancy (lung cancer) and other due to sustained thrombocytopenia. Conclusions: The primary end point of the trial was met, and 56% of the pts who completed induction and HDT-ASCT achieved MRD-ve. This "curative strategy for high risk SMM" continues being encouraging and 93% of pts remain alive and progression-free at 30 months and 98% of pts alive. Disclosures Mateos: GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; Takeda: 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; Pharmamar: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Takeda: Consultancy; BMS: Honoraria; Kite Pharma: Consultancy. Oriol:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Takeda: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rosinol Dachs:Janssen, Celgene, Amgen and Takeda: Honoraria. Amor:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Puig:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; The Binding Site: Honoraria. De La Rubia:AMGEN: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. De Arriba:Takeda: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lopez Jimenez:GILEAD SCIENCES: Honoraria, Other: Education funding. Ocio:Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mundipharma: Research Funding; AbbVie: Consultancy; Sanofi: Research Funding; Seattle Genetics: Consultancy; Array Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Pharmamar: Consultancy. Bladé:Jansen, Celgene, Takeda, Amgen and Oncopeptides: Honoraria. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.

scholarly journals Genomic Profiling of Smoldering Multiple Myeloma Classifies Molecular Groups with Distinct Pathogenic Phenotypes and Clinical Outcomes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 723-723
Author(s):  
Shankara Anand ◽  
Mark Bustoros ◽  
Romanos Sklavenitis-Pistofidis ◽  
Robert A. Redd ◽  
Eileen M Boyle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Molecular Classification ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Increased Risk ◽  
Risk Of Progression ◽  
Over Time

Abstract Introduction: Multiple Myeloma (MM) is an incurable plasma cell malignancy commonly preceded by the asymptomatic stage smoldering multiple myeloma (SMM). MM is characterized with significant genomic heterogeneity of chromosomal gains and losses (CNVs), translocations, and point mutations (SNVs); alterations that are also observed in SMM patients. However, current SMM risk models rely solely on clinical markers and do not accurately capture progression risk. While incorporating some genomic biomarkers improves prediction, using all MM genomic features to comprehensively stratify patients may increase risk stratification precision in SMM. Methods: We obtained a total of 214 patient samples at SMM diagnosis. We performed whole-exome sequencing on 166 tumors; of these, RNA sequencing was performed on 100. Targeted capture was done on 48 additional tumors. Upon binarization of DNA features, we performed consensus non-negative matrix factorization to identify distinct molecular clusters. We then trained a random forest classifier on translocations, SNVs, and CNVs. The predicted clinical outcomes for the molecular subtypes were further validated in an independent SMM cohort of 74 patients. Results: We identified six genomic subtypes, four with hyperdiploidy (>48 chromosomes, HMC, HKR, HNT, HNF) and two with IgH translocations (FMD, CND) (Table 1). In multivariate analysis accounting for IMWG (20-2-20) clinical risk stages, high-risk (HMC, FMD, HKR) and intermediate-risk (HNT, HNF) genetic subtypes were independent predictors of progression (Hazards ratio [HR]: 3.8 and 5.5, P = 0.016 and 0.001, respectively). The low-risk, CND subtype harboring translocation (11;14) was enriched for the previously defined CD-2 MM signature defined by the B cell markers CD20 and CD79A (FDR = 0.003 ), showed upregulation of CCND1, E2F1, and E2F7 (FDR = 0.01, 0.0004, 0.08), and was enriched for G2M checkpoint, heme metabolism, and monocyte cell signature (FDR = 0.003, 0.003, 0.003, respectively). The FMD subtype with IgH translocations (4;14) and (14;16) was enriched for P53, mTORC1, unfolded protein signaling pathways and plasmacytoid dendritic cell signatures (FDR = 0.01, 0.005, 0.008, respectively). The HKR tumors were enriched for inflammatory cytokine signaling, MYC target genes, T regulatory cell signature, and the MM proliferative (PR) signatures (FDR = 0.02, 0.03, 0.007, 0.02, respectively). The APOBEC mutational signature was enriched in HMC and FMD tumors (P = 0.005), while there was no statistical difference across subtypes in the AID signature. The median follow-up for the primary cohort is 7.1 years. Median TTP for patients in HMC, FMD, and HKR was 3.8, 2.6, and 2.2 years, respectively; TTP for HNT and HNF was 4.3 and 5.2, respectively, while it was 11 years in CND patients (P = 0.007). Moreover, by analyzing the changes in MM clinical biomarkers over time, we found that patients from high-risk subgroups had higher odds of developing evolving hemoglobin and monoclonal protein levels over time (P = 0.01 and 0.002, respectively); Moreover, the absolute increase in M-protein was significantly higher in patients from the high-risk genetic subtypes at one, two, and five years from diagnosis (P = 0.001, 0.03, and 0,01, respectively). Applying the classifier to the external cohort replicated our findings where intermediate and high-risk genetic subgroups conferred increased risk of progression to MM in multivariate analysis after accounting for IMWG staging (HR: 5.5 and 9.8, P = 0.04 and 0.005, respectively). Interestingly, within the intermediate-risk clinical group in the primary cohort, patients in the high-risk genetic subgroups had increased risk of progression (HR: 5.2, 95% CI 1.5 - 17.3, P = 0.007). In the validation cohort, these patients also had an increased risk of progression to MM (HR: 6.7, 95% CI 1.2 - 38.3, P = 0.03), indicating that molecular classification improves the clinical risk-stratification models. Conclusion: We identified and validated in an independent dataset six SMM molecular subgroups with distinct DNA alterations, transcriptional profiles, dysregulated pathways, and risks of progression to active MM. Our results underscore the importance of molecular classification in addition to clinical evaluation in better identifying high-risk SMM patients. Moreover, these subgroups may be used to identify tumor vulnerabilities and target them with precision medicine efforts. Figure 1 Figure 1. Disclosures Bustoros: Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria. Casneuf: Janssen: Current Employment. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Davies: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria. Bergsagel: Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; GSK: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Yong: BMS: Research Funding; Autolus: Research Funding; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria; Amgen: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals Identifying Ultra-High Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3192-3192 ◽  
Author(s):  
Theresia Akhlaghi ◽  
Even H Rustad ◽  
Venkata D Yellapantula ◽  
Neha Korde ◽  
Sham Mailankody ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Ultra High Risk ◽  
Risk Of Progression ◽  
Equity Ownership ◽  
M Spike ◽  
Risk Biomarkers

Abstract Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage to active multiple myeloma (MM), comprised by a heterogenous group of patients with varying rates of progression. While the overall yearly progression rate is 10% the first 5 years, some patients progress at a considerably higher rate. A study from the Mayo Clinic showed that in a subset of 21 patients defined by ≥60% monoclonal bone marrow plasma cells (BMPC), 95% progressed within 2 years. It was subsequently concluded by the International Myeloma Working Group (IMWG) that patients with biomarkers predictive of a 2-year progression rate at 80%, and a median time to progression at 12 months were at ultra-high risk of progression and should be considered to have MM requiring treatment despite being asymptomatic. In 2014, ultra-high risk biomarkers were incorporated in the definition of MM, including BMPC ≥60%, free light chain (FLC) ratio ≥100 and ≥2 focal lesions on magnetic resonance imaging (MRI). While the updated myeloma definition changed the diagnosis of some patients with ultra-high risk SMM to MM, there remain patients classified as SMM progressing at a very high rate. In the present study, we aimed at further identifying ultra-high risk biomarkers predictive of a high rate of progression to active MM. Methods Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2017 were identified and included in the study. Diagnosis of SMM and progression to MM requiring therapy was defined according to the IMWG criteria at the time of diagnosis. Baseline patient and disease characteristics were collected at date of diagnosis with SMM, including pathology reports, laboratory results and imaging data. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Optimal cut-off values for continuous variables were assessed with receiver operating characteristics (ROC) curve. Patients who had not progressed by the end of study or were lost to follow up were censored at the date of last visit. Univariate Cox regression was used to estimate risk factors for TTP with hazard ratios (HR) and 95% confidence intervals (CI). Significant univariate risk factors were selected for multivariate Cox regression. Results A total of 444 patients were included in the study. Median follow-up time was 78 months. During the study period, 215 (48%) patients progressed to active MM, with a median TTP of 72 months. Cut-off points for BMPC, M-spike, and FLC ratio were determined with ROC curves to be 20%, 2 g/dL, and 18, respectively, for predicting high risk of progression. The following factors were associated with significantly increased risk of progression to active MM: BMPC >20%, M-spike >2g/dL, FLC ratio >18, immunoparesis with depression of 1 and 2 uninvolved immunoglobulins respectively, elevated lactate dehydrogenase, elevated beta-2-microglobulin, and low albumin (Table 1). In the multivariate model, BMPC >20% (HR 2.5, 95% CI 1.6-3.9), M-spike >2g/dL (HR 3.2, CI 1.9-5.5), FLC ratio >18 (HR 1.8, CI 1.1-3.0), albumin <3.5 g/dL (HR 3.9, CI 1.5-10.0), and immunoparesis with 2 uninvolved immunoglobulins (HR 2.3, CI 1.2-4.3), predicted a decreased TTP (Table 1). A total of 12 patients had 4 or 5 of the risk factors from the multivariate model, 8 of these did not meet the 2014 IMWG criteria for MM. These patients had a significantly shorter TTP than patients with less than 4 risk factors (median TTP 11 vs 74 months, p<0.0001, Figure 1). At 16 months, 82% of these patients had progressed, and within 2 years, 91% of the patients progressed. Only one patient remained progression free after 2 years, progressing at 31 months. Of patients with less than 4 risk factors, 19% progressed within the first 2 years. Conclusion In addition to baseline BMPC >20%, M-spike >2g/dL, FLC-ratio >18, we found that albumin <3.5g/dL and immunoparesis of both uninvolved immunoglobulins at the time of diagnosis with SMM were highly predictive of a decreased TTP to MM requiring therapy. These biomarkers are readily available and routinely assessed in clinic. Patients with 4 or 5 of these risk factors represent a new ultra-high risk group that progress to active disease within 2 years, further expanding on the definition of ultra-high risk SMM. In accordance with the rationale on ultra-high risk biomarkers as criteria established by the IMWG in 2014, such patients should be considered to have MM requiring therapy. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Lesokhin:Squibb: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Mezzi:Amgen: Employment, Equity Ownership. Khurana:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Werther:Amgen: Employment, Equity Ownership. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding.

scholarly journals Progression Risk-Based Classification of Asymptomatic Waldenström Macroglobulinemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 150-150
Author(s):  
Mark Bustoros ◽  
Romanos Sklavenitis-Pistofidis ◽  
Chia-jen Liu ◽  
Efstathios Kastritis ◽  
Geoffrey Fell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Proportional Hazards ◽  
Risk Group ◽  
Advisory Committees ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Risk Of Progression

Abstract Background. Waldenström macroglobulinemia (WM) is a low-grade non-Hodgkin's lymphoplasmacytic lymphoma associated with overproduction of monoclonal IgM protein. It is preceded by an asymptomatic stage, called Smoldering Waldenström Macroglobulinemia (SWM), associated with a high risk of progression to overt disease. Current understanding of progression risk in SWM is based on a few small studies, and it is still unclear how to distinguish the asymptomatic patients who will progress from those who will not. Patients and Methods. We obtained clinical data of all WM patients who had been diagnosed and followed up at Dana-Farber Cancer Institute from 1982 to the end of 2014. Only patients with asymptomatic disease at the time of diagnosis were included in this study to identify risk factors for disease progression. Patients who received chemotherapy for a second cancer, before or after asymptomatic WM diagnosis (n =24), were excluded as chemotherapy might have affected the natural course of disease. Patients who progressed to or were diagnosed later with other types of B-cell lymphoproliferative disorders or Amyloidosis (n =71) and patients with myeloproliferative disorders or thalassemia (n = 4) were all excluded from our cohort. Furthermore, we excluded patients with no morphologic evidence of lymphoplasmacytic infiltration in the bone marrow biopsy (n =37), those without a bone marrow biopsy done at time of diagnosis (n =21), and those who were treated for peripheral neuropathy alone (n =13). Progression was defined based on the Consensus Panel recommendations of the Second International Workshop on WM. Survival analysis was performed using the Kaplan-Meier method and differences between the curves were tested by log-rank test. Effects of potential risk factors on progression rates was examined using Cox proportional-hazards models, with hazard ratios (HRs) and associated 95% confidence intervals (CIs). Results. A total of 439 patients were included in the study. During the 35-year study period and a median follow up of 7.8 years, 317 patients (72.2%) progressed to symptomatic WM. The median time to progression was 3.9 (95% CI 3.2-4.6) years. In the multivariate analysis, IgM ≥ 4,500 mg/dL (adjusted HR 4.65; 95% CI 2.52-8.58; p < 0.001), BM lymphoplasmacytic infiltration ≥ 70% (adjusted HR 2.56; 95% CI 1.69-3.87; p < 0.001), β2-microglobulin ≥ 4.0 mg/dL (adjusted HR 2.31; 95% CI 1.19-4.49; p = 0.014), and albumin < 3.5 g/dL (adjusted HR 2.78; 95% CI 1.52-5.09; p = 0.001) were all identified as independent predictors of disease progression, suggesting those thresholds could be clinically useful for determining high-risk patients. On the other hand, given the continuous nature of these variables, we built a proportional hazards model based on four variables (Bone marrow infiltration percentage, serum IgM, albumin, β2-microglobulin). The model divided the cohort into 3 distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.9 years (95% CI 1.64-2.13), an intermediate-risk group with median TTP of 4.6 years (95% CI 4.31-5.15), and a low-risk group with a median TTP of 8.1 years (95% CI 7.33-8.13)(See Figure). To enhance its clinical applicability, we made the model available as user interface through a webpage and mobile application, where clinicians can enter an individual SWM patient's lab values and get information regarding their risk group and estimated individual risk of progression to symptomatic WM. Conclusion. We have assembled the largest cohort of SWM patients to date, which allowed us to identify four independent predictors of progression to overt disease: BM infiltration ≥ 70%, IgM ≥ 4,500 mg/dL, b2m ≥ 4.0 mg/dL and albumin < 3.5 g/dL. Using those variables in a proportional hazards model, we developed a robust, flexible classification system based on risk of progression to symptomatic WM. This system stratifies SWM patients into low-, intermediate- and high-risk groups and thus has the potential to inform patient monitoring and care. Most importantly, it can help identify high-risk patients who might benefit from early intervention in this rare malignancy. Figure 1. Figure 1. Disclosures Bustoros: Dava Oncology: Honoraria. Kastritis:Takeda: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: 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. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Treon:Johnson & Johnson: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Castillo:Genentech: Consultancy; Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Dimopoulos:Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Ghobrial:BMS: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Celgene: Consultancy.

Lenalidomide/Rituximab Maintenance After Induction With Fludarabine/Rituximab In Combination With Escalating Doses Of Lenalidomide In Previously Untreated Chronic Lymphocytic Leukemia (CLL): The Revlirit CLL5 AGMT Phase I/II Study, Final Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4164-4164 ◽  
Author(s):  
Alexander Egle ◽  
Michael Steurer ◽  
Franz Josef Gassner ◽  
Roland Geisberger ◽  
Thomas Melchardt ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Maintenance Phase ◽  
Study Endpoint ◽  
Primary Study ◽  
Advisory Committees ◽  
Skin Reactions ◽  
Tumor Lysis

Abstract Introduction Lenalidomide has shown encouraging activity in monotherapy trials in CLL, but tumor lysis and tumor flare presented obstacles in development. We and others previously presented first data on combinations of lenalidomide with standard treatment regimens in CLL. As reported at ASH 2011 we combined Lenalidomide safely and efficaciously with the combination of Fludarabine and Rituximab, achieving early reduction of tumor load without tumor lysis or tumor flare and with high response rates. We also uncovered a patient population unable to tolerate higher Lenalidomide doses and marked by an exhausted T cell subset, measured pre-treatment. We now report final results of this trial, including the maintenance phase. Study design In induction Lenalidomide was combined with Fludarabine (40mg/m2 po d1-3 q28d) and Rituximab (375mg/m2 iv d4 cycle 1; 500mg/m2 iv d1 cycles 2-6, q28d). In cycle 1 Lenalidomide was added day 7-21 at 2.5 mg. Toxicity permitting, Lenalidomide dose was escalated to 5, 10, 15, 20 and 25mg day 1-21 over cycles 2-6. Subsequent maintenance treatment was two-monthly Rituximab at 375mg/m2 and Lenalidomide at the last dose tolerated in combination in a 28 day cycle without interruption for 6 months. The main goal of this treatment phase was to establish safety and efficacy as a secondary endpoint to the study. Results Patient characteristics of 45 recruited patients were previously reported: median age was 66 years and at least one molecular high risk feature was present in 64% of patients. No systematic toxicity determining an MTD in induction, the primary study endpoint, was found. The median daily dose in cycle 6 was 15mg in 40 evaluable patients, with 3 patients receiving the last cycle without lenalidomide. Toxicity and efficacy of the induction regimen were reported previously. Maintenance treatment was started in all 40 patients finishing induction. Three patients that finished without lenalidomide received only Rituximab. The median starting dose for all 40 patients was 15mg daily and 70% started with 10mg upwards. In total, 46% needed dose reductions, with prolonged neutropenia being the main reason, but 47% received doses above 10mg up to cycle 6 of maintenance. Interestingly, 9/13 patients receiving 25mg as maintenance were able to receive the treatment uninterrupted for 6 months, suggesting that a biologically select group may tolerate very high doses. As alluded to the major toxicity was neutropenia with 45% and 27% reaching G3 and G4, respectively. Surprisingly this did not translate into a relevant signal for infections. Grade 3, but no G4 infections, were observed in 5% of patients and all other G3/4 toxicities remained below 5%. Compared to the reported incidence of skin reactions in induction, we did not observe a significant signal in the maintenance phase. Improvement of response from PR after induction to CR at the end of maintenance was observed in 25%. The overall best response in ITT to the regimen during induction and maintenance was CR in 67% and PR in 29%. Median follow up of the study is now 35 months, at which point PFS is 89% and observed median PFS is currently 46 months. Exploratory analyses show no significant influences of age>65, mutation state or CD38 risk on PFS, but undetectable MRD after induction and high risk cytogenetics showed borderline effects (both p=0.08), the latter (2 cases with del17p and 9 with del11q) being driven by relapses in patients with del11q with a median PFS of 42 months in this group. Conclusions A combination of Lenalidomide with FR followed my maintenance with Lenalidomide and Rituximab proved clinically feasible. While initial dose-finding was complicated by highly individual levels of tolerance to lenalidomide in the combination (with skin toxicity being a major problem), the main toxicity in maintenance was neutropenia. Although the important myelotoxicity did not translate into a rate of infection above that expected after induction treatment, our judgment is, that a more moderate approach to dosing may be warranted in maintenance, since a majority of patients had to be dose-adjusted. Finally, the PFS observed with this induction and maintenance regimen seems encouraging by comparison with other first line regimens. While the exploratory nature of the trial clearly limits this conclusion, we further explore combination approaches with lenalidomide. Disclosures: Egle: Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding. Off Label Use: Lenalidomide in CLL. Pleyer:Celgene: Honoraria, Research Funding. Fridrik:Roche: Honoraria. Thaler:Roche: Honoraria, Research Funding. Greil:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding.

scholarly journals Identifying a Gene Expression (GEP)-Based Model Predicting for Progression from AMM to Cmm Requiring Therapy in S0120 Patients Treated at Mirt

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2078-2078
Author(s):  
Rashid Z Khan ◽  
Christoph Heuck ◽  
Adam Rosenthal ◽  
Caleb K Stein ◽  
Joshua Epstein ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Effect ◽  
M Protein ◽  
Proliferation Index ◽  
Q Value ◽  
Advisory Committees ◽  
Cut Point ◽  
Risk Of Progression

Abstract Background: The definition of high risk smoldering multiple myeloma (HR-SMM) is in flux. There are several models using serologic, bone marrow and radiologic data that predict for time to progression (TTP) to clinical myeloma (CMM). Lenalidomide and Dexamethasone in HR-SMM is reported to delay onset of end organ damage and improve overall survival, stressing the clinical utility of early intervention. We previously reported a GEP70 based score cutoff (<-0.26), when applied to the S0120 population, that improved the predictive power (R2) of standard clinical variables by 11%. The combination of GEP70 score >-0.26, serum M spike ≥3g/dL, and involved SFLC >25 mg/dL identified a subset of patients with 67% risk of progression at 2 years. With longer follow up, we now examine whether unique gene probe sets can be identified at the AMM stage that portend an earlier time to therapy (TTT). Patients and Methods: We identified 105 patients with AMM who had baseline GEP data on our S0120 protocol, after IRB approval for retrospective data review, and evaluated each of 54,675 Affymetrix gene probes for their potential to predict TTT. Probes were ranked by their q-values; we found 40 probes with q-value < 0.05 and 7 probes with q-value < 0.01; the top probe had a q-value of 0.00066. Scores based on the number of significant probes at these cut-points were computed by subtracting the sum of the expressions of the up-regulated probes from the sum of the expressions of the down-regulated probes, then dividing by the total number of probes. Results: In the GEP40 model, an optimal cut-point for risk of progression was identified at 7.05. The 3-year TTT probability was 83% with scores >=7.05 and only 11% for patients with values under this threshold (Figure 1A; p<0.0001). TTT probabilities also differed markedly when examined by score quartiles, attesting to a gene dose effect (Figure 1B). For the Q1 subset of 26 patients, only 4% required therapy in 3 years. Univariate Cox analysis for TTT yielded age>65 (HR: 2.3), Albumin<3.5g/dl (HR: 3.7), M-protein>3g/dl (HR: 4.99), BM plasmacytosis>=10% (HR: 12.2), GEP70>-0.26 (HR: 3.4), GEP40>=7.05 (HR: 16.41), GEP proliferation index > -0.26 (HR: 2.8), GEP PR subgroup (HR: 9.4) and GEP PolyPC >11.6 (HR: 0.22) to be significant. In the multivariate model, GEP40>=7.05 was the most significant (HR: 13.7), followed by SFLC>10mg/dl and M-protein>3g/dl. GEP40 score positively correlated with proliferation index (R: 0.804), and showed no correlation with GEP polyPC score (R: -0.156). Next, we used recursive partitioning on data from 72 patients and identified 23 patients with GEP40 score >=7.05 of whom 22 suffered TTT by 3 years (87%). Among the remaining 49 patients with GEP40 <7.0325, a further cut-point of age >59 years identified 24 patients, of whom 11 suffered progression with a 3 year TTT estimate of 25%. In the 25 patients with GEP40 <7.0325 and age <59 years, no patient progressed to CMM, with a 3 year TTT estimate of 0%. The GEP7 and GEP1 models, at optimal cut-offs, yielded equivalent positive and negative predictive values compared to the GEP40 model, albeit with less power. Conclusion:Gene expression profiling can readily identify a subset of AMM patients who are high risk for progression to CMM. Further refinement of GEP based risk scoring can be achieved by combining clinical and correlative variables to select the super HR-SMM for intervention trials. Figure 1a Figure 1a. Figure 1b Figure 1b. Disclosures Zangari: Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. Van Rhee:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Dhodapkar:Celgene: Research Funding. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Outcomes of Lenalidomide Retreatment with Novel Triplet Regimens in Multiple Myeloma Patients Progressing on Lenalidomide-Based Maintenance Therapy: A Single Center Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3198-3198
Author(s):  
Chutima Kunacheewa ◽  
Lei Feng ◽  
Elisabet E. Manasanch ◽  
Qaiser Bashir ◽  
Krina K. Patel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Maintenance Therapy ◽  
Retrospective Analysis ◽  
Board Of Directors ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Single Center ◽  
Advisory Committees ◽  
Treatment Groups

INTRODUCTION Several phase 3 randomized studies have validated the use of novel 3-drug regimens with lenalidomide (LEN) and dexamethasone (Rd) in combination with carfilzomib (ASPIRE), elotuzumab (ELOQUENT-2), ixazomib (TOURMALINE-MM1), and daratumumab (POLLUX) in relapsed and/or refractory multiple myeloma (MM) with ≥ 1 line of prior therapy. However, these studies notably excluded patients (pts) who were LEN-refractory since the control arm in these studies received Rd. In practice though, many MM pts at first relapse for which these LEN-based triplets are often utilized are progressing on low-dose LEN maintenance therapy, and their outcomes have not been well characterized in the context of these pivotal trials that excluded such pts. In this single-center retrospective analysis, we report the outcomes of LEN-retreatment with a novel LEN-based triplet in pts progressing on LEN-based maintenance therapy, and compare to a smaller, similar cohort of pts treated with a pomalidomide (POM)-based regimen. METHODS MM pts progressing on LEN-based maintenance therapy between 1/1/2015 and 6/30/2018 at MD Anderson Cancer Center after autologous stem cell transplant (ASCT) who were then treated with a LEN-based triplet or POM-based therapy were eligible for this study. Post-maintenance LEN-based triplet regimens included Rd in combination with bortezomib (VRd), carfilzomib (KRd), elotuzumab (ERd), ixazomib (IRd), and daratumumab (DRd). Disease response and progression were assessed by International Myeloma Working Group response criteria. The Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS), and cohorts were compared by log-rank test. Pts who had not progressed were censored at the time of last disease evaluation prior to any change in therapy or data cut-off of 6/23/2019. RESULTS A total of 88 pts with a median of 1 prior line of therapy were eligible for the study. Baseline characteristics and prior treatment history are summarized in the Table. 66 pts received a LEN-based triplet, and 22 pts received a POM-based regimen after disease progression on LEN-based maintenance. A similar proportion of pts had high-risk cytogenetics (del 17p, t(4;14), and/or t(14;16)) in the LEN-based (21%) and POM-based (18%) post-maintenance treatment groups. The most common LEN-based maintenance regimens included LEN monotherapy (66%), ixazomib and LEN (14%), and elotuzumab and LEN (10%). Median PFS after ASCT on LEN-based maintenance was 26.0 months, and similar between the LEN-based (25.7 months) and POM-based (29.1 months) post-maintenance treatment groups, suggesting enrichment of pts with early progression on LEN-based maintenance in this analysis. In pts retreated with LEN-based therapy, the median LEN dose increased from 10 mg during maintenance therapy to 25 mg in the post-maintenance regimen. The overall response rate (ORR, ≥ PR) to LEN-based retreatment was 56% (≥ VGPR 33%) and median duration of response (DOR) was 11.7 months (95% CI 9.23 - NA). In comparison, the ORR and DOR with POM-based treatment were 73% (≥ VGPR 41%) and 19 months (95% CI 7.88 - NA), respectively. At a median follow-up time of 20.5 months, median PFS and OS were 13.6 and 40 months, respectively, with LEN-based retreatment versus 21.4 months (P 0.7) and not reached (P 0.6) with POM-based therapy. There was no significant difference in PFS or OS between LEN-based triplet regimens (VRd, KRd, ERd, IRd, and DRd). In the LEN-based retreatment group, high-risk cytogenetics did not significantly impact PFS (10.1 vs. 13.6 months, P 0.9), although OS was worse (22.5 vs. 42.8 months, P 0.003). However, pts who progressed on LEN-based maintenance ≥3 years after ASCT had a significantly better median PFS with LEN-based retreatment compared to pts who progressed <3 years after ASCT (median not reached vs. 9.9 months, P 0.001, Figure). CONCLUSION In pts progressing on LEN-based maintenance therapy, retreatment with a LEN-based novel triplet to maximize LEN dose intensity and synergy with other novel agents can lead to deep and durable responses in select pts, particularly in those with a more indolent disease course and longer (≥3 years) PFS after ASCT. However, ORR and PFS may favor switching to a POM-based regimen over LEN-based retreatment in this patient population, and warrants further investigation in studies evaluating optimal sequencing strategies in relapsed and/or refractory MM. Disclosures Manasanch: Sanofi: Research Funding; Quest Diagnostics: Research Funding; Merck: Research Funding; Skyline Diagnostics: Research Funding; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Kaufman:Janssen: Other: travel/lodging, Research Funding. Iyer:Novartis: Research Funding; Genentech/Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Arog: Research Funding; Seattle Genetics, Inc.: Research Funding; Incyte: Research Funding. Thomas:Xencor: Research Funding; BMS: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Qazilbash:Bioclinical: Consultancy; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Genzyme: Other: Speaker. Lee:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy.

scholarly journals Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 797-797
Author(s):  
Talha Badar ◽  
Mark R. Litzow ◽  
Rory M. Shallis ◽  
Jan Philipp Bewersdorf ◽  
Antoine Saliba ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Research Funding ◽  
Univariate Analysis ◽  
Advisory Board ◽  
Novel Therapies ◽  
Advisory Committees ◽  
Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p &lt;0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p&lt;0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p&lt;0.001) and alloHCT in CR1 (p&lt;0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p&lt;0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. &lt; 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

scholarly journals Primary Plasma Cell Leukemia Outcomes Remain Dismal Despite Novel Agents and Hematopoietic Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 266-266
Author(s):  
Sagar Patel ◽  
Saulius K. Girnius ◽  
Binod Dhakal ◽  
Lohith Gowda ◽  
Raphael Fraser ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Disease Status ◽  
Cell Leukemia ◽  
Advisory Committees ◽  
Primary Plasma Cell Leukemia ◽  
Equity Ownership

Background Primary plasma cell leukemia (pPCL) is a rare plasma cell neoplasm with a high mortality rate. There have been improvements in multiple myeloma (MM) outcomes with novel induction agents and use of hematopoietic cell transplantation (HCT) with maintenance, but similar progress has not been reported for pPCL. We examined the outcomes of pPCL patients receiving novel agents with autologous (autoHCT) or allogeneic (alloHCT) approaches as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) in the modern era. Methods From 2008 to 2015, 348 pPCL pts underwent HCT (N = 277 - autoHCT and 71 - alloHCT) with 45% and 48% having research level data available, respectively. Cumulative incidences of non-relapse mortality (NRM) and relapse/progression (REL), and probability of progression-free survival (PFS) and overall survival (OS) were calculated. Cox multivariate regression was used to model survival after autoHCT only. Median follow-up in autoHCT and alloHCT was 48 and 60 months, respectively. Results AutoHCT Cohort Median age was 60 years and 93% received HCT within 12 months of diagnosis with 76% after a single line of induction (Table 1). 35% had high risk cytogenetics. 23% received bortezomib, doxorubicin, cisplatin, cyclophosphamide, and etoposide (VDPACE). Moreover, 40% received bortezomib (BTZ) and immunomodulatory drug (IMIID)-based triplets. Disease status at HCT was VGPR or better in 47%. 27% received maintenance therapy. At 4 years post-HCT, NRM was 7% (4-11%), REL 76% (69-82%), PFS 17% (13-23%), and OS 28% (22-35%) (Figures 1A, 2A, 2B). Disease status ≥VGPR at HCT and Karnofsky Performance Score &gt;90 significantly predicted superior OS in multivariate analysis. AlloHCT Cohort Median age was 53 years and 89% received HCT within 12 months of diagnosis (Table 1). 61% received a single alloHCT, while 39% used auto-alloHCT tandem approach. 42% had high-risk cytogenetics. 61% received total body irradiation with 44% receiving myeloablative conditioning. Use of VDPACE was higher at 41% in this cohort. VGPR status at HCT was similar (48%), while maintenance was used less often (12%). Grade II-IV acute GVHD occurred in 30% and chronic GVHD in 45%. At four years post-HCT, NRM was 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%) (Figures 1A, 1B, 2A, 2B). There were no differences in outcomes based on type of HCT. A comparison of post-HCT outcomes of CIBMTR pPCL patients from 1995 to 2006 showed that PFS and OS outcomes are inferior despite lower NRM in this modern cohort (Mahindra et al. Leukemia. 2012). In addition, analysis of SEER (1995-2009) and CIBMTR databases showed that use of HCT increased from 12% (7-21%) in 1995 to 46% (34-64%) in 2009. Conclusion More newly diagnosed pPCL patients are receiving modern induction regimens translating into a higher proportion receiving HCT, but without significant further benefit post-HCT. Post-HCT relapse remains the biggest challenge and further survival in pPCL will likely need a combination of targeted and cell therapy approaches. This study provides a benchmark for future HCT studies for pPCL. Disclosures Girnius: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dhakal:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria. Shah:University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Bioclinical: Consultancy; Autolus: Consultancy; Genzyme: Other: Speaker. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

scholarly journals Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1589-1589
Author(s):  
Fabian Frontzek ◽  
Marita Ziepert ◽  
Maike Nickelsen ◽  
Bettina Altmann ◽  
Bertram Glass ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
High Dose ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: 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; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

scholarly journals A Phase II Single Arm Study of Nivolumab As Maintenance Therapy after Autologous Stem Cell Transplantation in Patients with Hodgkin Lymphoma at Risk of Relapse or Progression

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2455-2455
Author(s):  
Carlos Bachier ◽  
Henning Schade ◽  
Behyar Zoghi ◽  
Aravind Ramakrishnan ◽  
Nirav N. Shah
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Residual Disease ◽  
Refractory Disease ◽  
Advisory Committees ◽  
Extranodal Disease

Abstract Introduction: Autologous stem cell transplants (ASCT) are standard of care for patients with primary refractory or recurrent Hodgkin lymphoma (HL). While transplant results in cure for some patients, others relapse and succumb from their disease. Studies have found high expression of programmed death ligand 1 (PD-L1) in HL cells. The anti-PD-1 monoclonal antibody, nivolumab, has been safe and efficacious in the treatment of relapsed, refractory HL (Ansell et al. 2015). We evaluated the safety and efficacy of nivolumab maintenance therapy post-ASCT in high risk for relapse Hodgkin disease. Methods: Patients with HL with high risk of residual disease following ASCT ( high risk defined as refractory disease, relapse &lt;12 months, or relapse ≥12 months with extranodal disease after frontline therapy) received nivolumab (240 mg IV every 2 weeks) starting 45-180 days post-transplant for a maximum of 6 months of treatment. Patients were followed for AEs through 100 days after the last dose of drug. PET-CT response assessments were performed 1-3 month, 6 month, and 12 month post-ASCT. The primary objective was to evaluate the safety and tolerability of nivolumab as maintenance therapy early after ASCT. The secondary objective was to evaluate progression-free survival (PFS) at 12 months post-transplant. Results: To date, 37 patients were enrolled; median age 36 years; 25 patients (68%) male. The median number of prior systemic regimens was 2 (range 2-4). 25 patients (68%) had relapsed disease, and 12 patients (32%) had primary refractory disease. 18 patients (49%) had extranodal disease at relapse, 6 patients (16%) had B-symptoms at relapse, and 11 patients (30%) had residual disease after salvage, including 10 patients (27%) of whom had 2-3 prior salvage therapies. 22 patients (60%) had received prior brentuximab, and 3 patients (8%) had received prior nivolumab or pembrolizumab. 36 patients received ASCT and 1 patient received tandem ASCT. At the time of data cutoff, 28 patients (76%) had discontinued nivolumab treatment, 22 patients (60%) because they had completed the 6-month treatment course, 4 patients (11%) due to an adverse event (AE) (1 patient each with pain, pneumonitis, rhabdomyolysis, or hypothyroidism), and 2 patients (5%) due to disease progression. The median duration of treatment was 22.1 weeks. 17 patients (46%) experienced a treatment-related AE (TRAE), of which 5 patients (14%) experienced a ≥Grade 3 TRAE. The most common (≥5%) TRAEs were diarrhea, fatigue, bone pain, neutrophil count decreased, pruritus, rash, and vomiting. 2 patients experienced a treatment-related serious AE (pneumonitis, rhabdomyolysis). There were no treatment-related deaths. With a median follow up of 9.2 months, the median PFS and overall survival (OS) have not been reached. The 6 month PFS is 92.1% and the 12-month OS is 100%. There were no differences in OS when stratified based on prior treatment. Conclusions: The use of nivolumab maintenance early after ASCT is safe and tolerable in this high risk patient population. Early efficacy data is promising, but data need to mature to determine the 12 month PFS. Figure 1 Figure 1. Disclosures Bachier: CRISPR: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Shah: Umoja: Consultancy; Incyte: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy.

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