scholarly journals Copy Number Signatures Predict Chromothripsis and Poor Clinical Outcome in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 52-53
Author(s):  
Kylee H Maclachlan ◽  
Binbin Zheng-Lin ◽  
Venkata Yellapantula ◽  
Andriy Derkach ◽  
Even H Rustad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Research Funding ◽  
De Novo ◽  
Data Monitoring ◽  
Signature Analysis ◽  
Independent Data ◽  
Genetics Research ◽  
Manual Curation ◽  
Low Coverage

Chromothripsis is emerging as a strong and independent prognostic factor in multiple myeloma (MM), predicting shorter progression-free (PFS) and overall survival (Rustad BioRxiv 2019). Reliable detection requires whole genome sequencing (WGS), with 24% prevalence in 752 newly diagnosed multiple myeloma (NDMM) from CoMMpass (NCT01454297, Rustad BioRxiv 2019) compared with 1.3% by array-based techniques (Magrangeas Blood 2011). In MM, chromothripsis presents differently to solid cancers. Although the biological impact is similar across malignancies, in MM the structural complexity of chromothriptic events is typically lower. In addition, chromothripsis can occur early in MM development and remain stable over time (Maura Nat Comm 2019). Computational algorithms for chromothripsis detection (e.g. ShatterSeek; Cortes-Ciriano Nat Gen 2018) were developed in solid cancers and are accurate in that setting. Running ShatterSeek on 752 NDMM patients with low coverage WGS from CoMMpass, we observed a high specificity for chromothripsis (98.3%) but poor sensitivity (30.2%). ShatterSeek detected chromothripsis in 64/752 samples (8.5%), with 85% confirmed on manual curation; however, missed 114 cases located by manual curation. This indicates that MM-specific computational methods are required. We hypothesized that a signature analysis approach using copy number variation (CNV) may provide an accurate estimation of chromothripsis. We adapted CNV signature analysis, developed in ovarian cancer (Macintyre Nat Gen 2018), to now detect MM-specific CNV and structural features. The analysis utilizes 6 fundamental CN features: i) absolute CN of segments, ii) difference in CN in adjacent segments, iii) breakpoints per 10 Mb, iv) breakpoints per chromosome arm, v) lengths of oscillating CN segment chains, and vi) the size of segments. The optimal number of categories in each CNV feature was established using a mixed effect model (mclust R package). Using CoMMpass low-coverage WGS, de novo extraction using the hierarchical dirichlet process defined 5 signatures, 2 of which (CNV-SIG 4 and CNV-SIG 5) contain features associated with chromothripsis: longer lengths of oscillating CN states, higher numbers of breakpoints / chromosome arm, and higher total numbers of small segments of CN change. Next, we demonstrate that CNV signatures are highly predictive of chromothripsis (average area-under-the-curve /AUC = 0.9, based on 10-fold cross validation). Chromothripsis-associated CNV signatures are correlated with biallelic TP53 inactivation (p= 0.01) and gain1q21 (p<0.001) and show negative association with t(11;14) (p<0.001). Chromothriptic signatures were associated with shorter PFS, with multivariate analysis after correction for ISS, age, biallelic TP53 inactivation, t(4;14) and gain1q21 producing a hazard ratio of 2.9 (95% CI 1.07-7.7, p = 0.036). A validation set of 29 NDMM WGS confirmed the ability of CNV signatures to predict chromothripsis (AUC 0.87). As WGS is currently too expensive and computationally intensive to employ in routine practice, we investigated if CNV signatures can predict chromothripsis without using WGS. First, we performed de novo signature extraction using whole exome data from 865 CoMMpass samples. CNV signatures extracted without reference to WGS produced an AUC = 0.81 for predicting chromothripsis (in those with WGS to confirm; n =752), and the chromothriptic-signatures confirmed the association with a shorter PFS (HR=7.2, 95%CI 1.32-39.4, p = 0.022). Second, we applied CNV signature analysis to NDMM having either the myTYPE targeted sequencing panel (n= 113; Yellapantula, Blood Can J 2019) or a single nucleotide polymorphism (SNP) array (n= 217). CNV signature assessment by each technology was predictive of clinical outcome, likely due to the detection of chromothripsis. As with WGS, multivariate analysis confirmed CNV signatures to be independently prognostic (myTYPE; p = 0.003, SNP; p = 0.004). Overall, we demonstrate that CNV signature analysis in NDMM provides a highly accurate prediction of chromothripsis. CNV signature assessment remains reliable by multiple surrogate measures, without requiring WGS. Chromothripsis-associated CNV signatures are an independent and adverse prognostic factor, potentially allowing refinement of standard prognostic scores for NDMM patients and providing a more accurate risk stratification for clinical trials. Disclosures Hultcrantz: Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding; Intellisphere LLC: Consultancy. Dogan:Takeda: Consultancy; National Cancer Institute: Research Funding; Roche: Consultancy, Research Funding; Seattle Genetics: Consultancy; AbbVie: Consultancy; EUSA Pharma: Consultancy; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Landgren:Cellectis: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; BMS: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria.

scholarly journals Whole-Genome Sequencing Reveals Evidence of Two Biologically and Clinically Distinct Entities: Progressive Versus Stable Myeloma Precursor Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 47-48
Author(s):  
Bénedith Oben ◽  
Guy Froyen ◽  
Kylee H Maclachlan ◽  
Binbin Zheng-Lin ◽  
Venkata Yellapantula ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Research Funding ◽  
Data Monitoring ◽  
Whole Genome ◽  
Independent Data ◽  
Genetics Research ◽  
Complex Events

Introduction Multiple myeloma (MM) is consistently preceded by an asymptomatic expansion of clonal plasma cells, clinically recognized as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). Here, we present the first comprehensive whole-genome sequencing (WGS) analysis of patients with MGUS and SMM. Methods To characterize the genomic landscape of myeloma precursor disease (i.e. SMM and MGUS) we performed WGS of CD138-positive bone marrow mononuclear samples from 32 patients with MGUS (N=18) and SMM (N=14), respectively. For cases with low cellularity resulting in low amounts of extracted DNA (N=15), we used the low-input enzymatic fragmentation-based library preparation method (Lee-Six et al, Nature 2019). Myeloma precursor disease samples were compared with 80 WGS of patients with MM. All WGSs (N=112) were investigated using computational tools available at the Wellcome Sanger Institute. Results After a median follow up of 29 months (range: 2-177), 17 (53%) patients with myeloma precursor disease progressed to MM (13 SMM and 4 MGUS). To interrogate the genomic differences between progressive versus stable myeloma precursor disease we first characterized the single base substitution (SBS) signature landscape. Across the entire cohort of plasma cell disorders, all main MM mutational signatures were identified: aging (SBS1 and SBS5), AID (SBS9), SBS8, SBS18, and APOBEC (SBS2 and SBS13). Interestingly, only 2/15 (13%) stable myeloma precursor disease cases showed evidence of APOBEC activity, while 14/17 (82%) and 68/80 (85%) patients with progressive myeloma precursor disease (p=0.0058) and MM (p=0.004), respectively, had APOBEC mutational activity. The two stable cases with detectable APOBEC were characterized by a high APOBEC3A:3B ratio, a feature which defines a group of MAF-translocated MM patients whose pathogenesis is characterized by intense and early APOBEC activity (Rustad et al Nat Comm 2020) and is distinct from the canonical ~1:1 APOBEC3A:3B mutational activity observed in most cases. When exploring the cytogenetic landscape, no differences were found between progressive myeloma precursor disease and MM cases. Compared to progressors and to MM, patients with stable myeloma precursor disease were characterized by a significantly lower prevalence of known recurrent MM aneuploidies (i.e. gain1q, del6q, del8p, gain 8q24, del16q) (p<0.001). This observation was validated using SNP array copy number data from 78 and 161 stable myeloma precursor disease and MM patients, respectively. To further characterize differences between progressive versus stable myeloma precursor disease, we leveraged the comprehensive WGS resolution to explore the distribution and prevalence of structural variants (SV). Interestingly, stable cases were characterized by low prevalence of SV, SV hotspots, and complex events, in particular chromothripsis and templated insertions (both p<0.01). In contrast, progressors showed a genome wide distribution and high prevalence of SV and complex events similar to the one observed in MM. To rule out that the absence of key WGS-MM defining events among stable cases would reflect a sample collection time bias, we leveraged our recently developed molecular-clock approach (Rustad et al. Nat Comm 2020). Notably, this approach is based on pre- and post-chromosomal gain SBS5 and SBS1 mutational burden, designed to estimate the time of cancer initiation. Stable myeloma precursor disease showed a significantly different temporal pattern, where multi-gain events were acquired later in life compared to progressive myeloma precursor disease and MM cases. Conclusions In summary, we were able to comprehensively interrogate for the first time the whole genome landscape of myeloma precursor disease. We provide novel evidence of two biologically and clinically distinct entities: (1) progressive myeloma precursor disease, which represents a clonal entity where most of the genomic drivers have been already acquired, conferring an extremely high risk of progression to MM; and (2) stable myeloma precursor disease, which does not harbor most of the key genomic MM hallmarks and follows an indolent clinical outcome. Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; EUSA Pharma: Consultancy; National Cancer Institute: Research Funding; AbbVie: Consultancy. Landgren:Pfizer: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Merck: Other; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Binding Site: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Merck: Other; Seattle Genetics: Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Bolli:Celgene: Honoraria; Janssen: Honoraria.

scholarly journals The Genomic Complexity of Multiple Myeloma Precursor Disease Can be Predicted Using Copy Number Signatures on Targeted Sequencing and SNP Array Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Kylee H Maclachlan ◽  
Binbin Zheng-Lin ◽  
Venkata Yellapantula ◽  
Even H Rustad ◽  
Benjamin Diamond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Copy Number ◽  
Research Funding ◽  
Snp Array ◽  
Targeted Sequencing ◽  
Data Monitoring ◽  
Independent Data ◽  
Genetics Research ◽  
Chromosome Arm

Introduction Current clinical models for predicting the progression from myeloma precursor disease (smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS)) to multiple myeloma (MM) are based on tumor burden, and not designed to capture heterogeneity in tumor biology. With the advent of whole genome sequencing (WGS), complex genomic change including the catastrophic event of chromothripsis has been detected in a significant fraction of MM patients. Chromothripsis is associated with other features of aggressive biology (i.e. biallelic TP53 deletion and increased APOBEC activity), and in newly diagnosed MM (NDMM), patients harboring chromothripsis have a shorter progression free survival (PFS) (Rustad BioRxiv 2019). Chromothripsis has also been demonstrated in SMM which later progressed to MM (Maura Nat Comm 2019) and our preliminary results indicate that the absence of chromothripsis is associated with stable precursor disease (Oben ASH 2020). We have demonstrated that chromothripsis can be accurately predicted in NDMM using copy-number variation (CNV) signatures on both WGS and whole exome sequencing (Maclachlan ASH 2020). As with WGS, CNV signature analysis in less comprehensive assays (e.g. targeted sequencing panels and single nucleotide polymorphism (SNP) arrays) demonstrated that chromothripsis-associated CNV signatures are associated with shorter PFS. The aim of this study was to define the landscape of CNV signatures in myeloma precursor disease, and to compare the results with CNV signatures in NDMM. Methods CNV signature analysis uses 6 fundamental features: i) breakpoint count per 10 Mb, ii) absolute CN of segments, iii) difference in CN between adjacent segments, iv) breakpoint count per chromosome arm, v) lengths of oscillating CN segments, and vi) the size of segments (Macintyre Nat Gen 2018). The number of subcategories for each feature (which may differ between cancer and assay types) was established using a mixed effect model (mclust R package). For both targeted sequencing (myTYPE panel; (n=19, 4 MGUS, 15 SMM) and SNP array (n=78, 16 MGUS, 62 SMM), de novo CNV signature extraction was performed by hierarchical dirichlet process, running the analysis together with NDMM samples for reliable signature detection. Results Our analysis identified 4 and 6 CNV signatures from myTYPE and SNP array data respectively, with the extracted signatures being analogous to those from WGS, which are highly predictive of chromothripsis (Maclachlan ASH 2020). Compared with NDMM (myTYPE; n=113; SNP array; n=217), precursor samples contained significantly fewer breakpoints / chromosome arm (myTYPE; p= 0.0003, SNP; p <0.0001), fewer breakpoints / 10 Mb (both; p <0.0001), shorter lengths of oscillating CN (myTYPE; p= 0.013, SNP; p= 0.018), fewer jumps between CN states (myTYPE; p= 0.0043, SNP; p < 0.0001), lower absolute CN (myTYPE; p= 0.0059, SNP; p < 0.0001) and fewer small segments of CN change (myTYPE; p= 0.0007, SNP; p= 0.0008). Chromothripsis-associated CNV signatures were significantly enriched in NDMM compared to precursor disease (p<0.0001), with only 8.2% of precursors having a significant contribution from these signatures (NDMM; 38.7%). Overall, every CNV feature consistent with chromothripsis was measured at a significantly lower level in precursors than NDMM. As <5% of the precursors have progressed to MM, and given that we see heterogeneity in the pattern of CNV abnormalities both between MM and precursor disease, and within patients with precursor disease, we are currently investigating the role of CNV abnormalities in relation to clinical progression. As an interim measure; restricting analysis to patients with clinical stability >5 years (n=11), we observed chromothripsis-associated signatures to be absent in all samples. Conclusion All individual CN features comprising chromothripsis-associated CNV signatures are significantly lower in stable myeloma precursor disease compared with NDMM when assessed by targeted sequencing and SNP array, along with a lower contribution from chromothripsis-associated signatures. Given the adverse impact of chromothripsis in MM, these data show great promise towards the future refinement of risk prediction estimation in myeloma precursor disease. Our ongoing work involves extending CNV analysis into larger datasets, including precursor patients who subsequently progressed to MM. Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Dogan:Roche: Consultancy, Research Funding; Physicians Education Resource: Consultancy; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; EUSA Pharma: Consultancy; AbbVie: Consultancy; National Cancer Institute: Research Funding. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Landgren:Amgen: Consultancy, Honoraria, Research Funding; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Binding Site: Consultancy, Honoraria; Adaptive: Consultancy, Honoraria; Merck: Other; Pfizer: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Binding Site: Consultancy, Honoraria; Karyopharma: Research Funding; Merck: Other; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding.

scholarly journals The Role of 18f-FDG-PET/CT in Characterizing Depth of Response in High Risk Smoldering Multiple Myeloma Patients Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-12
Author(s):  
Elizabeth Hill ◽  
Neha Korde ◽  
Candis Morrison ◽  
Alexander Dew ◽  
Ashley Carpenter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Clinical Trials ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Data Monitoring ◽  
Independent Data ◽  
Genetics Research ◽  
Pet Ct

Introduction A direct association exists between minimal residual disease (MRD) negativity and prolonged survival in multiple myeloma (MM) (Landgren et al, BMT 2016). 18F-fluoro-deoxy-glucose (FDG) positron emission tomography-computed tomography (PET/CT) is a recommended monitoring technique for patients with MM as persistence of FDG uptake after induction therapy, prior to maintenance, is an independent risk factor for progression. Therefore PET/CT and MRD detection in the bone marrow are complementary prognostic tools prior to initiation of maintenance therapy. In patients with smoldering multiple myeloma (SMM), the presence of a focal FDG-avid lesion without underlying osteolytic lesion on PET/CT is associated with rapid progression to MM. However, little is known about the prognostic value of PET/CT for SMM patients receiving treatment. Herein, we show that treatment of high risk (HR)-SMM with carfilzomib, lenalidomide, and dexamethasone with lenalidomide maintenance (KRd-R) leads to sustained remissions detected on PET/CT imaging. Methods Trial design including key results for KRd-R in HR-SMM (NCT01572480) has been submitted to the meeting separately (abstract ID: 136148). As part of the study design, all eligible patients had bone marrow biopsies with multicolor flow cytometry (MRD sensitivity, 10-5) and whole-body PET/CT performed at baseline and at key time points, including achievement of complete response (CR) or completion of KRd induction (8 cycles), after 1 and 2 years of -R maintenance, and annually thereafter. PET/CTs were evaluated by nuclear medicine radiologists blinded to flow cytometry and considered positive if at least one focal hypermetabolic (above background reference) lesion and/or heterogenous bone marrow involvement were present, as defined by the IMWG (Hillengass et al. Lancet Oncol 2019). Results As of data cutoff, 46 patients had completed at least 8 cycles of therapy and had 2 sequential PET/CTs performed. By the end of induction therapy, no patient developed progressive disease and the overall response rate was 100%. Approximately 72% of patients with baseline negative PET/CTs remained negative, 11% of patients had resolution of previous focal/heterogenous FDG avidity, 15% of patients had decrease or stable focal/ heterogenous lesions, and 2% developed new focal lesions. Table 1 shows the results at subsequent time points of one and two years of maintenance therapy. Throughout this time period, one patient developed a lytic lesion after 1 year of maintenance therapy. However, 3 patients had either resolution or decrease in focal/heterogenous lesions. Specifically, after 8 cycles of combination therapy, 33 patients (70.2%, 95% CI 55.9 - 81.4%) had a response of MRD negative CR based on bone marrow flow cytometry and 26 patients (55.3%; 95% CI 41.2-68.6%) had a negative PET/CT in addition to MRD negative CR (Table 2). Conclusions It is important to evaluate the tools used in MM response assessment specifically in the SMM population as more studies report results of treatment in this population. MRD information can be used as a biomarker to evaluate the efficacy of different treatment strategies. This study demonstrates an exceptionally high rate of concordance between MRD negativity by flow cytometry and negative PET/CT after 8 cycles of KRd. However, 15% of patients were MRD negative yet had positive findings on PET/CT. While these lesions were not biopsy proven, some resolved during maintenance therapy. Further follow-up is needed to determine whether early MRD negativity in bone marrow with negative PET/CT correlates to longer overall survival and decreased progression to MM compared to those patients with a positive PET/CT. The use of PET/CT imaging may increase our understanding in assessing depth response to treatment in HR-SMM patients and be an important outcome predictor. Disclosures Korde: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other.

scholarly journals Initial Whole Genome Sequencing of Plasma Cell Neoplasms in First Responders and Recovery Workers Exposed to the World Trade Center Attack of September 11, 2001

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-51
Author(s):  
Benjamin Diamond ◽  
Kylee H Maclachlan ◽  
Andriy Derkach ◽  
Venkata Yellapantula ◽  
Even H Rustad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Plasma Cell ◽  
Research Funding ◽  
First Responders ◽  
Data Monitoring ◽  
Independent Data ◽  
Mutational Signatures ◽  
Mutational Signature ◽  
Plasma Cell Neoplasms

PURPOSE : The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. A higher incidence of multiple myeloma (MM) and precursor disease has been reported among first responders to the WTC disaster compared to the unexposed population (Landgren, 2018). To expand on prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole genome sequencing (WGS) of WTC first responders and recovery workers who were diagnosed with a plasma cell disorder after the attack. PATIENTS AND METHODS: We performed WGS of 9 CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after exposure to the WTC disaster: 4 monoclonal gammopathy of undetermined significance (MGUS), 2 smoldering multiple myeloma (SMM), 2 MMs, and 1 patient with plasma cell leukemia (PCL). Eight patients (88%) were first responders and one was a recovery worker. Peripheral blood mononuclear cells were used as normal match. Median coverage for tumor and normal samples was 50.9X (range 47-76) and 37X (range 35-41), respectively. The landscape of genomic drivers and complex structural events was compared to 752 MM patients enrolled in the CoMMpass trial with available whole exome and low-coverage long-insert WGS data (IA15; NCT01454297). To characterize the mutational signature landscape we combined the WTC cohort with 110 whole genomes from 56 patients with multiple myeloma and myeloma precursor disease (Rustad et al. 2020; Landau et al. 2020) and we ran our three-step workflow: de novo extraction (i.e. sigprofiler), assignment, and fitting (i.e. mmsig). To exclude contribution of any environmental agents in the WTC debris with known mutational signatures (Kucab et al., 2019), we ran our fitting algorithm mmsig in each post-WTC case, including and forcing the extraction of these mutational signatures. RESULTS: No significant differences were observed in comparing the post-WTC driver and mutational signatures landscape with 110 previously published WGS from 56 patients with MM and the CoMMpass WGS cohort (n=752). Likewise, we did not observe any new or distinct mutational signatures among WTC-exposed patients. Following forced extraction of 5 mutational signatures associated with environmental agents detected in the WTC debris (e.g. PAHs), we did not find significant contributions from any of these described environmental mutational signatures. To reconstruct the temporal activity of each mutational process we divided all single nucleotide variants into subclonal and clonal. Clonal mutations were further subdivided into duplicated (acquired before a chromosomal gain) and unduplicated (Rustad et al. 2020). WTC-exposed patients had differing patterns in mutational signature timelines of AID and APOBEC activity. Overall, the mutational signature activity over time in post-WTC plasma cell dyscrasia reflects what has been previously observed in multiple myeloma without WTC-exposure (Rustad et al., 2020). Finally, leveraging constant activity of the clock-like single base substitution mutational signatures 1 and 5 over time and our molecular time workflow (Rustad et al., 2020), we estimated the age at which each evaluable patient acquired a tumor-initiating chromosomal gain and found that they were windowed to both pre- and post-WTC exposure across neoplasms (Figure 1). In some cases, clonal multi-chromosomal gain events were acquired decades before both the diagnosis and the WTC exposure. Specifically, of 6 patients with large clonal chromosomal gains, 1 MM case, 1 SMM, and 1 MGUS showed evidence of a pre-existing clone prior to WTC exposure, two MGUS showed evidence of multi-gain events following the exposure, and one MM case had a 1q gain in the same time window as the attack. CONCLUSIONS: Post-WTC plasma cell neoplasms had similar genomic landscapes to non-exposed cases. Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy. The existence of pre-malignant clonal entities at time of WTC exposure may therefore be relevant for future WTC-related study. Figure 1 Disclosures Hultcrantz: Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding; GSK: Research Funding. Shah:Physicians Education Resource: Honoraria; Celgene/BMS: Research Funding. Iacobuzio-Donahue:BMS: Research Funding. Papaemmanuil:Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Illumina: Consultancy, Honoraria; Kyowa Hakko Kirin: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Prime Oncology: Consultancy, Honoraria; MSKCC: Patents & Royalties. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; stelexis: Current equity holder in private company; Janssen: Research Funding; Medpacto: Research Funding. Dogan:National Cancer Institute: Research Funding; EUSA Pharma: Consultancy; Takeda: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Physicians Education Resource: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy. Landgren:Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Seattle Genetics: Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding.

scholarly journals Monotherapy Activity with the First CD20-Targeted Immunotoxin, MT-3724, in Subjects with Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4098-4098
Author(s):  
Paul A. Hamlin ◽  
Vasile Musteata ◽  
Mamia Zodelava ◽  
Steven I Park ◽  
Christine Burnett ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Data Monitoring Committee ◽  
Data Monitoring ◽  
Independent Data ◽  
Safety And Efficacy ◽  
Peripheral Edema ◽  
Monitoring Committee

Background: The near ubiquity and persistence of CD20 expression in B-cell malignancies provides a strong rationale for novel CD20-directed therapies. MT-3724 is a novel engineered toxin body comprised of an anti-CD20 single chain variable fragment genetically fused to Shiga-like toxin A subunit, which forces internalization of CD20-bound MT-3724, irreversibly inactivating ribosomes and triggering apoptosis. As MT-3724 competes with rituximab (RTX) for the same CD20 binding domain, undetectable or low (< 500 ng/mL) RTX levels (RTX-neg) allow potential response to MT-3724. We present final safety and efficacy results from dose escalation to maximum tolerated dose (MTD) in Non-Hodgkin Lymphoma (NHL) subjects (subj) and dose expansion in RTX-neg DLBCL subj. Methods: In Part 1, MT-3724 dose was escalated in 21 subj with B-cell NHL according to the 3+3 design based on ≤1 subj exhibiting DLT during Cycle 1 (28 days) in 6 sequential dose cohorts (5, 10, 20, 50, 75, and 100 μg/kg/dose IV over 2 hours 3 times per week for 2 of 4 consecutive weeks) for up to 5 cycles. In Part 2, the safety and efficacy of MT-3724 was further evaluated in 6 RTX-neg subj with DLBCL. Tumor response was assessed by the International Working Group Response Criteria for Clinical Trials (Cheson 2007). Results: Twenty-seven subj with NHL (DLBCL:16, composite DLBCL/Follicular Lymphoma (FL): 3, FL: 6, Mantle Cell Lymphoma: 2 were enrolled. Seventeen (63%) were female, mean age was 65 yrs (34-78). Performance status was ECOG 0: 44%, 1: 44%, 2: 11%; median follow-up was 50 (11-372) days; median cycles 2 (1-11). The most common AEs (%) of all grades were peripheral edema (63), fatigue (41), diarrhea (41), myalgia (41), muscle weakness (33), insomnia (30); 27 subj had AEs (%) with related causality, the most common were: peripheral edema (41), myalgia (33), fatigue (26). The most common related grade (G) ³3 AEs included neutropenia, myalgia, and infections (all 11%); There were 9 related SAEs among 6 subj. One subj died on study from disease progression. MT-3724 was not tolerated at 100 µg/kg/dose (DLTs: G3 pneumonia, G2 ileus). After 2 obese (BMI >35) subj treated at 75 µg/kg/dose in the expansion cohort had G2 capillary leak syndrome (CLS), the MTD was set at 50 µg/kg/dose with a 6000 mg/dose cap. Innate immune responses such as CLS or manifestations thereof (hypotension, hypoalbuminemia, peripheral edema) were noted with increasing frequency with higher doses of MT-3724. No cases of >G2 CLS have been observed. Of the 13 RTX-neg DLBCL subj, 5 (38%) responded across the range of 5 to 50 μg/kg/dose. All responses were partial responses (PRs) including 1 subj with composite DLBCL/FL post autologous stem cell transplantation (SCT) who had a complete metabolic response of a large mesenteric mass and proceeded to allogeneic SCT. Three subj had stable disease (SD) including two with 49% and 47% tumor reductions, one of whom had FL transformed from DLBCL post autologous SCT; another 5 had progressive disease. Given a limited prescribed period of treatment with MT-3724, duration of response cannot be calculated, however, generally the tumor burden in responders decreased with repeat treatment. Among the responders, mean age was 61 (50-76) yrs, and the median number of prior lines of NHL therapy received was 3 (1-8). Subj with detectable baseline RTX levels did not benefit from MT-3724. Of all 20 subj measured, 6 developed anti-drug antibodies (ADAs) during the first cycle of therapy; 5 developed ADAs at a later timepoint; 6 did not develop ADAs. ADAs were observed in all subj who showed a response, and in 4 of 5 subj with SD. Increasing MT-3724 dose was associated with a dose-dependent peripheral B-cell depletion, evidenced by decreasing CD19+ cells. Conclusions MT-3724 is the first CD20 targeted immunotoxin to enter clinical trials. Safety events were mostly mild-moderate, and DLTs were in line with the mechanism of action of MT-3724. A tolerable dose and schedule have been identified: 50 μg/kg/dose up to a maximum of 6000 μg/dose infused over 1 hour on days 1, 3, 5, 8, 10, and 12 of a 21-day cycle. A 38% objective response rate has been observed with monotherapy in a heavily pretreated, RTX-neg DLBCL population; of these subj, 5 were treated at 50 ug/kg (MTD) and 3 of whom responded. The development of ADAs did not preclude benefit of MT-3724. An ongoing phase 2 monotherapy study to confirm efficacy and safety in RTX-neg subj with DLBCL (NCT02361346) is open for recruitment. Disclosures Musteata: Institute of Oncology: Employment; Arensia EM: Other: Principal Investigator. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Burnett:Molecular Templates, Inc.: Employment. Dabovic:Molecular Templates, Inc.: Employment. Williams:Molecular Templates, Inc.: Employment. Higgins:Molecular Templates, Inc.: Employment, Equity Ownership. Persky:Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy.

Duration of Post-Autologous Hematopoietic Cell Transplant Anemia and Thrombocytopenia Are Associated with Prolonged Hospital Length-of-Stay for Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Binbin Zheng-Lin ◽  
Nirupama Krishnamurthi ◽  
Benjamin Diamond ◽  
Kylee H Maclachlan ◽  
Francesco Maura ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Research Funding ◽  
Demographic Data ◽  
Hospital Length Of Stay ◽  
Data Monitoring ◽  
Cell Transplant ◽  
Independent Data ◽  
Hematopoietic Cell Transplant ◽  
Post Transplant ◽  
Grade Iii

BACKGROUND: Anemia, neutropenia, and thrombocytopenia are expected complications of autologous hematopoietic cell transplant (AHCT) for multiple myeloma (MM). However, prolonged cytopenias may predispose patients to other infectious, cardiovascular, and/or hematological toxicities. Various factors have been implicated in the length of post-AHCT cytopenias including stem cell dose, marrow microenvironment, and clonal hematopoiesis. We hypothesize that the length of post-transplant anemia, neutropenia, and thrombocytopenia may negatively impact hospital length-of-stay (LOS) and in-hospital complications. METHODS: This is a single-center observational study of MM patients who underwent AHCT. Patients were part of a larger cohort with detailed single nucleotide polymorphism (SNP) array cytogenetic data. Exclusion criteria were concurrent amyloidosis and tandem transplant. Demographic data, comorbidities, cytogenetic features (presence of TP53 deletion, and translocation status of MMSET, CCDN3, CCDN1, MAF, and MAFB), therapy line, peri-transplant laboratory values, and clinical outcome were collected retrospectively. LOS was calculated from transplant day -2 to hospital discharge. Predictive factors for LOS were calculated with multiple linear regression. Multiple logistic regression was then used to calculate associating factors for in-hospital complications. Grade III and IV post-transplant cardiovascular, infectious, and hematological complications were collected following the Common Terminology Criteria for Adverse Events (CTCAE). Post-transplant anemia was defined as sustained hemoglobin (Hb) &lt;8 g/dL despite transfusions. The cutoffs for neutropenia and thrombocytopenia were absolute neutrophil count (ANC) &lt;1.5 K/uL, and platelet (PLT) count &lt;50 K/uL, respectively. RESULTS: 158 AHCT cases of MM patients were identified. 95 patients received AHCT as frontline treatment, 35 patients were transplanted in the salvage setting, and 14 patients received both frontline and subsequent-line transplant. The most commonly used conditioning regimen was melphalan 200 mg/m2 in 123 cases, followed by melphalan 140 mg/m2 in 23 patients. 50.6% (80/158) developed grade III anemia with a median onset of 9 days after transplant (IQR 5-11 days) and median length of 2 days (IQR 1-6 days). Neutropenia had higher incidence of 96.8% (153/158) with an earlier onset of 5 days (IQR 5-6 days) and median length of 5 days (IQR 2-7 days). Grade III thrombocytopenia occurred in 98.1% (155/158), with median onset of 7 days (IQR 5-7 days) and a median duration of 8 days (IQR 6-10 days). When comparing patients who received frontline transplant vs subsequent line transplants, no statistical significance was observed between onset or length of cytopenias (p=0.40). Median LOS was 16 days (IQR 15-19 days). The most frequent post-AHCT complications in our cohort were neutropenic fever (N=27), followed by engraftment syndrome (N=12), pneumonia (N=4), urinary tract infection (N=2), cellulitis (N=2), and bacteremia (N=1). Cardiovascular events were uncommon (N=3) and included pericarditis, new onset atrial fibrillation, and new onset supraventricular tachycardia. Pulmonary embolism (N=1) and deep vein thrombosis (N=3) were recorded. No major bleeding was observed. Longer LOS was independently associated with post-AHCT anemia (p=0.03) and thrombocytopenia (p=0.0005). Notably, LOS and in-hospital complication rates were not significantly associated with demographic data, pre-existing comorbidities, pre-transplant cytopenias, or cytogenetic abnormalities. CONCLUSION: In our cohort, longer duration of post-transplant anemia and thrombocytopenia were statistically associated with longer hospital LOS, but not with post-transplant complications. Prospective validation in an independent cohort is warranted. Disclosures Landgren: Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Merck: Other; Seattle Genetics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding. Chung:Genentech: Research Funding.

Chromosome 1q Amplification Is Associated with a History of Prior Malignancies Among Patients Newly Diagnosed with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2193-2193
Author(s):  
Elizabeth B Lamont ◽  
Andrew J. Yee ◽  
Stuart L. Goldberg ◽  
Andrew D Norden
Keyword(s):  
Prostate Cancer ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Usual Care ◽  
Real World ◽  
Research Funding ◽  
Newly Diagnosed ◽  
History Of ◽  
Equity Ownership ◽  
Prior Malignancy

Background: Over the past 20 years, observational data from usual care clinical oncology settings has been leveraged to inform estimates of cancer treatment-associated benefits and risks among patients not treated on clinical trials. Increasing genomic testing to inform treatment decisions in usual care settings now meaningfully augments traditional observational data, positioning it to provide insights beyond clinical care into tumor biology. We studied patients with newly diagnosed multiple myeloma (MM), comparing cytogenetic test patterns according to history of prior malignancy. Methods: In this retrospective cohort study, we identified 2,380 patients from the COTA real-world database (RWD) who were newly diagnosed with MM in the years 2010-2018. The COTA RWD is a de-identified composite of both abstracted electronic health record and administrative data pertaining to patients receiving their cancer care at one of COTA's clinical oncology practice partners. Among these patients, 1769 (74%) had evidence of MM-associated cytogenetic testing with fluorescent in-situ hybridization (FISH) within the 120 days surrounding their date of diagnosis. The 1,769 patients form the analytic cohort. We compared patients' FISH results for t(4;14), deletion(17p), t(14;16), deletion(13), t(14;20), t(6;14), t(11;14), deletion (1p), and amplification(1q) according to their history of prior malignancy. Results: Within the cohort, 263 prior malignancies were identified in 241 patients (14%, 241/1,769). Two-hundred and twenty-one patients (92%) had one prior malignancy, 28 (7.9%) had two prior malignancies, and one (<1%) had four prior malignancies. The most common prior malignancies were prostate (n=50), breast (n=19), melanoma (n=14), skin (n=13), and cervix (n=6). Amplification of the long arm of chromosome one (amp(1q)) was noted in 31% of patients (75/241) with a prior malignancy vs. 24% of patients (370/1,528) without (chi2 test p=0.02). Overall 25% of patients had amp(1q). No other translocations, amplifications, deletions were associated with prior cancers. A non-parametric test for trend revealed a strong positive association between patients' malignancy count (range 0-4) and amp1q (p<0.01). MM patients with prior lymphomas and prior melanomas also had high rates of amp(1q), though these were not significantly different from patients without these prior malignancies. In a multivariable logistic regression model that adjusted for patient demographic attributes, other known potentially collinear MM poor prognostic factors (i.e., revised ISS stage, IgA sub-type, lambda light chains) and adjusted standard errors for clustering of patients within treatment settings, a history of prostate cancer remained clinically and statistically significantly positively associated with amp(1q) (OR 2.1, 95% CI: 1.9-2.2) as did history of two or more prior malignancies (OR 2.8, 95% CI: 2.3-3.3). Of note, amp(1q) was positively associated with IgA subtype (OR 1.5, 95% CI: 1.3-1.6) and the presence of lambda subtype (OR 1.3, 95%CI: 1.3-1.4). Conclusions: Using RWD, we found that newly diagnosed MM patients with histories of prostate cancer and those with two or more prior malignancies were more likely to have amp(1q), a poor prognostic marker in MM. Gains in 1q have previously been identified among patients with prostate and lymphoid cancers, but to our knowledge this is the first study to identify an association with a prior history of cancer, especially prostate cancer, and amp(1q) in MM. This relationship is worth further exploration of whether there is a common pathway associated with for example risk of prostate cancer and amp(1q) in MM. Clinical trials are less likely to answer this question as patients with prior malignancies are often excluded from enrollment. Overall, the results reported suggest that RWD is an efficient and comparatively inexpensive tool to support research in cancer biology through hypothesis generating and testing analyses of linked real-world phenotypic and genotypic data. Disclosures Lamont: COTA: Employment. Yee:Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy. Norden:COTA: Employment, Equity Ownership.

Updated Outcomes of Fludarabine/Melphalan/Bortezomib (Flu/Mel/Vel) Conditioning for Upfront Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5885-5885
Author(s):  
Taiga Nishihori ◽  
Claudio Anasetti ◽  
Rachid Baz ◽  
Jose L Ochoa-Bayona ◽  
Kenneth H. Shain ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Advisory Committees ◽  
Allogeneic Hct ◽  
Genetics Research ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors

Abstract Background: Multiple myeloma remains incurable despite impressive array of available novel agents and therapeutic strategies. Allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative option for patients with multiple myeloma but it is limited by its toxicities. We previously reported initial result of a phase 2 study of upfront allogeneic HCT in myeloma patients achieving at least very good partial response (VGPR) after initial therapy (Nishihori, et al. ASH 2013 abstract 3390) and here we report more mature results after a median follow up of 3 years. Methods: Twenty seven myeloma patients received allogeneic HCT between 01/2010 and 02/2015 at Moffitt Cancer Center (NCT 00948922). Eligible patients were age ≤ 60, achieving first ≥ VGPR or complete response (CR), and have 8/8 HLA-matched related or unrelated donors. Conditioning regimen consisted of fludarabine 30 mg/m2 for 4 days (days -6, -5, -4, and -3) and melphalan 70 mg/m2 for 2 days (days -4 and -3) followed by a single dose of bortezomib 1.3 mg/m2 on day -3 (Flu/Mel/Vel regimen). GVHD prophylaxis was initially left to the discretion of physicians but later modified to only tacrolimus/methotrexate. No maintenance therapy was prescribed after allogeneic HCT. Results: The median age at transplant was 50 (range, 25-58) years. Disease status at the time of allogeneic HCT was VGPR (n=17: 63%) and CR/stringent CR (n=10: 37%). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched related donors (n=14) or HLA-matched unrelated donors (n=13). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus plus either methotrexate (n=19: 70%), or mycophenolate mofetil (n=4), or sirolimus (n=4). All patients achieved neutrophil engraftment with a median of 15 (range, 11-19) days. Platelet engraftment was achieved with a median of 17 (range, 13 - 35) days and 2 patients did not recover platelets. The cumulative incidences of grades II-IV and grades III-IV acute GVHD at day 100 were 63.6% (95% confidence interval (CI): 43.1-81.1) and 19.6% (95%CI: 5.4-39.9), respectively. The cumulative incidence of moderate to severe chronic GVHD was 56.4% (95%CI: 36.3-75.5) at 1-year. The cumulative incidences of transplant-related mortality at day 100, 1 year and 2 years were 7.4% (95%CI: 0.8-20.0), 11.1% (95%CI: 2.7-25.4), and 11.1% (95%CI: 2.7-25.4), respectively. Progression-free survival estimates at 1, 2, and 3 years were 74.1% (95%CI: 53.2-86.7), 65.1% (95%CI: 43.3-80.2), and 65.1% (95%CI: 49.9-87.5), respectively. With a median follow up of 39 months for surviving patients, overall survival estimates at 1, 2 and 3 years were 85% (95%CI: 64.9-94.1), 75.4% (95%CI: 52.6-88.3), and 69.1% (95%CI: 53.8-93.5), respectively. Conclusions: The results of the this phase 2 trial of upfront allogeneic HCT with fludarabine/melphalan/bortezomib (Flu/Mel/Vel) conditioning are promising and provide the rationale for reasonable potentially curative option to younger and fit patients who are eligible for upfront intensive consolidation strategy. This approach may be potentially valuable for those with high-risk myeloma and a multicenter study is currently being conducted (BMT CTN protocol 1302:NCT02440464). Disclosures Nishihori: Novartis: Research Funding; Signal Genetics: Research Funding. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Karyopharm: Research Funding; Bristol-Myers Squibb: Research Funding; Signal Genetics: Research Funding. Shain:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Alsina:Signal Genetics: Consultancy; Novartis: Research Funding; Takeda/Millennium: Research Funding; Amgen/Onyx: Consultancy, Speakers Bureau.

scholarly journals Minorities Do Not Have Worse Outcomes for Diffuse Large B Cell Lymphoma (DLBCL) If Optimally Managed

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 425-425
Author(s):  
Bei Hu ◽  
Tommy Chen ◽  
Danielle Boselli ◽  
Rupali Bose ◽  
James T. Symanowski ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Research Funding ◽  
De Novo ◽  
Private Insurance ◽  
Insurance Coverage ◽  
Cancer Center ◽  
Advisory Committees

BACKGROUND: DLBCL is the most common and a potentially curable non-Hodgkin lymphoma. Multiple previous studies have shown that minority populations have worse outcomes compared to Caucasians (Tao L, Blood 2014; Griffiths R, BMC Cancer 2010; Koroukian et al, Cancer, 2010, Shenoy PJ Cancer 2010). Moreover, it has been reported that uninsured and Medicaid insured patients with DLBCL have inferior survival compared to privately insured patients (Han X, Cancer 2014; Koroukian et al, Cancer 2010;). It has also been well established that minorities are underrepresented in clinical trials (Gerrero S, Sci Rep 2018; Kwiatkowski K, Cancer 2013). We present the baseline characteristics, treatment paradigms and outcomes of Caucasian (C) and non-Caucasian (NC) patients with de novo DLBCL treated at a single academic hybrid cancer center. METHODS: We collected demographic, disease, insurance coverage, treatment characteristics, and treatment outcomes for patients with de novo DLBCL who presented between January 2016 and January 2019 at Levine Cancer Institute, Charlotte, North Carolina. Patient race, C or NC were self-reported. Insurance was categorized as Government (Medicaid or Medicare), Private, or Uninsured. We used the Revised International Prognostic Index (R-IPI) to risk stratify patients. Double-hit lymphomas (DHL) were defined as having the MYC translocation with either BCL2 or BCL6 translocation on fluorescent in situ hybridization. Treatments included standard chemoimmunotherapies, stem cell transplantation and clinical trials including chimeric antigen receptor therapies (CART). Outcomes of overall survival (OS) and progression free survival (PFS) were calculated using the Kaplan Meier method and compared with log rank test. Demographic data was compared using Fisher's Exact tests. RESULTS: One hundred and ninety-six consecutive patients with de novo DLBCL were included in the analysis [155 (79%) = C, 41 (21%) = NC] (Table). The NC group was predominantly African American (71%) followed by Hispanic (15%). Prognostic scores (R-IPI) and the incidence of DHL were similar between C and NC. The median age at diagnosis in the NC group was lower than in C. There were significant differences in insurance coverage between the 2 groups (p=0.012). The C group did not have any uninsured patients and had more patients with private insurance (33%) compared to the NC group (7% uninsured and 27% with private insurance). The most common frontline treatment was RCHOP (C=66%, NC=70%) followed by dose adjusted REPOCH (C=12%, NC=15%). Median follow up was 31.6 months. There was no difference in OS and PFS between the 2 groups (Figure 1). OS at 2 years from date of diagnosis was 81% for C and 84% for NC, p=0.852. Two-year PFS from time of diagnosis were similar for both groups: 61% for C and 63% for NC, p=0.999. Similar numbers of patients in both groups developed relapsed or refractory (R/R) disease after frontline therapy. Median number of treatments was 2 for both groups, p=0.582. For patients who developed R/R DLBCL, the 2-year OS was 60% for C and 63% for NC, p=0.590. Similar proportions underwent stem cell transplantation: 11% for C and 20% for NC, p= 0.186. Clinical trial enrollment was comparable: 11% for C and 12% for NC, p=0.785. CONCLUSION: Unlike previous population-based studies that have shown racial disparities with superior outcomes for Caucasians and for patients with private insurance, our single center experience demonstrates similar survival outcomes between Caucasians and non-Caucasians diagnosed with de novo DLBCL, despite differences in insurance coverage favoring Caucasians. In the R/R setting, similar proportions of both groups underwent stem cell transplantation and enrolled on clinical trials. The likely explanation is that our safety net cancer center, with extensive nurse navigator support and access to standard treatments, stem cell transplants and cutting-edge clinical trials may abrogate the inferior outcomes in minority populations that have been previously reported. Disclosures Symanowski: Immatics: Consultancy; Eli Lilly: Consultancy; Carsgen Therapeutics: Consultancy; Boston Biomedical: Consultancy. Park:Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Gilead: Speakers Bureau; Teva: Consultancy, Research Funding; G1 Therapeutics: Consultancy; Seattle Genetics: Research Funding, Speakers Bureau. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees; Best Practice-Br Med J: Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia. Jacobs:Genentech: Speakers Bureau; AstraZeneca: Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; AbbVie: Consultancy, Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau. Ghosh:TG Therapeutics: Consultancy, Honoraria, Research Funding; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Genentech: Research Funding; AstraZeneca: Honoraria, Speakers Bureau; Forty Seven Inc: Research Funding.

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