Evaluation of Re-Intensification of Daratumumab to Weekly or Biweekly Dosing Schedule

Abstract Introduction: Multiple Myeloma (MM) is a hematologic cancer caused by malignant plasma cells. Daratumumab is an immunoglobin G1 kappa human monoclonal antibody that targets CD38 antigen which is a cell surface glycoprotein highly expressed on myeloma cells. Daratumumab is FDA approved as monotherapy and in combination with dexamethasone and lenalidomide, bortezomib or pomalidomide in relapsed/refractory MM. Daratumumab is typically dosed: 16mg/kg weekly (Weeks 1-8), then 16mg/kg biweekly (Weeks 9-24), then 16mg/kg monthly (Weeks 25 and beyond until disease progression). At Dana-Farber Cancer Institute (DFCI), some patients receiving a daratumumab-containing regimen were "re-intensified" upon progression of disease. "Re-intensification" could include (1) re-escalation to weekly dosing from biweekly or monthly dosing or (2) re-escalation to biweekly dosing from monthly dosing or (3) continuation of biweekly or monthly dosing. However, there is a lack of evidence to support the safety and efficacy of daratumumab dose "re-intensification" (Dara-RI) during treatment. We aimed to assess the efficacy and safety of Dara-RI, with or without the addition of other myeloma-agents, in 13 patients with disease progression while on a daratumumab-containing regimen. Method/Results: This is an institutional review board approved, descriptive, retrospective medical chart review of 13 adult patients with MM who received Dara-RI at DFCI from November 2015 to October 2017. The median age was 68 years (range, 53-88). Most patients (8) had IgG Kappa MM (62%) followed by 2 patients (15%) with Lambda Light Chain, 2 patients (15%) with IgA Kappa, and 1 patient (8%) with IgG Lambda. Of the 13 patients, 1 patient continued weekly dosing, 4 patients continued biweekly dosing; 5 patients re-intensified from monthly to biweekly dosing; 1 patient re-intensified from biweekly to weekly; and 2 patients re-intensified from monthly to weekly. Patients were re-intensified at a median of 14 months after starting a daratumumab-containing regimen (range, 4-26). Of the 13 patients, there were 5 patients who had another drug adjustment at the time of Dara-RI. Of note, there were 3 patients who were on a non-FDA approved daratumumab-containing regimen at the time of Dara-RI. At the time of our final analysis, there were 7 patients (54%) who remained on a daratumumab-based regimen. Of these 7 patients, 6 patients continued Dara-RI and 1 patient transitioned from biweekly to monthly daratumumab due to stable disease. Notably, 3 patients had another drug adjustment at the time of Dara-RI. The median length of Dara-RI is 8 months and ongoing (range, 4-12). There were 5 patients (38%) who discontinued their daratumumab-based regimen after Dara-RI. Of these 5 patients, 2 patients had another drug adjustment at the time of Dara-RI. All 5 patients had at least stable disease or partial response to Dara-RI, with exception of one individual who had progressive disease. In addition, all 5 patients who discontinued Dara-RI was within 4 months of starting Dara-RI. Uniquely, one patient had panobinostat added to their Dara-RI regimen after 1 month of re-intensification, but continued with Dara-RI. No patients experienced a dose delay due to adverse effects or were hospitalized after initiation of Dara-RI. Only one patient was prescribed antibiotics for treatment of a cold sore. There were no new hypersensitivity, cardiovascular, hematologic, gastrointestinal, or central nervous system toxicities noted after initiation of Dara-RI. Conclusion: Limitations of this study include other myeloma drug-related adjustments at the time of Dara-RI and the heterogeneous population as well as the retrospective nature of the study. In our experience with 13 patients, Dara-RI appears to be a safe and tolerable alternative regimen for patients who have disease progression on a daratumumab-containing regimen. Disclosures Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Ghobrial:BMS: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy.

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Phase 1/2 Study of Elotuzumab in Combination with Bortezomib in Patients with Multiple Myeloma with One to Three Prior Therapies: Interim Results.

Blood ◽

10.1182/blood.v114.22.3876.3876 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3876-3876 ◽

Cited By ~ 1

Author(s):

Andrzej J Jakubowiak ◽

William Bensinger ◽

David Siegel ◽

Todd M. Zimmerman ◽

Jan M. Van Tornout ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Clinical Response ◽

Board Of Directors ◽

Research Funding ◽

Mononuclear Cells ◽

Phase 1 ◽

Surface Glycoprotein ◽

Advisory Committees ◽

Cell Surface Glycoprotein

Abstract Abstract 3876 Poster Board III-812 Background Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). In mouse xenograft models of MM, elotuzumab demonstrated significantly enhanced anti-tumor activity when combined with bortezomib compared to bortezomib alone (Van Rhee et al., Mol. Cancer Ther., in press, 2009). This phase 1/2 trial will determine the maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK) and clinical response of elotuzumab in combination with bortezomib in patients with relapsed MM following 1-3 prior therapies. Methods The study consists of 4 escalating cohorts of elotuzumab (2.5 mg/kg to 20 mg/kg) administered on Days 1 and 11 and bortezomib (1.3 mg/m2) administered on Days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease at the end of Cycle 2 or 3 also receive oral dexamethasone (20 mg) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each subsequent cycle. Patients with stable disease or better at the end of 4 cycles will continue treatment for 6 or more cycles unless withdrawn earlier due to unexpected toxicity or disease progression. Key entry criteria: age ≥ 18 years; confirmed diagnosis of MM and documentation of 1 to 3 prior therapies; measurable disease M-protein component in serum and/or in urine; and no prior bortezomib treatment within 2 weeks of first dose. Results To date, a total of 16 MM patients with a median age of 64 years have been enrolled in the study. The median time from initial diagnosis of MM was 3.5 years and patients had received a median of 2 prior MM treatments. Patients have been treated in four cohorts; 3 each in 2.5, 5 and 10 mg/kg elotuzumab cohorts, and 7 in the 20 mg/kg elotuzumab cohort. No dose limiting toxicity (DLT) was observed during the first cycle of the study and the MTD was not established. Five SAEs have been reported in four patients in later treatment cycles; two events, chest pain and gastroenteritis, occurring in one patient, were considered elotuzumab-related. Other SAEs include grade 3 sepsis, vomiting, pneumonia and grade 2 dehydration. The most common AEs reported include Grade 1-3 diarrhea, constipation, nausea, fatigue, thrombocytopenia, neutropenia, anemia and peripheral neuropathy. The best clinical response (EBMT criteria) for the 16 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis suggests a serum half-life of 10-11 days at higher doses (10 and 20 mg/kg). Preliminary analysis of peripheral blood mononuclear cells and bone marrow of patients on study indicates that objective responses in the study correlate well with complete saturation of CS1 sites by elotuzumab on bone marrow plasma and NK cells. Conclusions The combination of elotuzumab with bortezomib has a manageable adverse event profile and shows promising preliminary efficacy with ≥PR in 44% and ≥MR in 75% of all enrolled patients. Accrual is ongoing in the expanded 20 mg/kg cohort. Updated safety, efficacy, and PK data will be presented at the meeting. Disclosures: Jakubowiak: Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor Ortho Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bortezomib in combination with elotuzumab for the treatment of relapsed/refractory multiple myeloma. Bensinger:Millennium: Membership on an entity's Board of Directors or advisory committees. Siegel:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Zimmerman:Millennium: Speakers Bureau; Centecor: Speakers Bureau. Van Tornout:BMS: Employment. Zhao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase 2, Multicenter, Nonrandomized, Open-Label Study of Dovitinib (TKI258) in Patients with Relapsed or Refractory Multiple Myeloma with or without t(4;14) Translocation

Blood ◽

10.1182/blood.v120.21.4055.4055 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4055-4055

Author(s):

Christof Scheid ◽

Donna Reece ◽

Meral Beksac ◽

Andrew Spencer ◽

Natalie Callander ◽

...

Keyword(s):

Growth Factor ◽

Adverse Events ◽

Disease Progression ◽

Board Of Directors ◽

Stable Disease ◽

Research Funding ◽

Growth Factor Receptor ◽

Study Drug ◽

Advisory Committees ◽

Overall Response

Abstract Abstract 4055 Introduction: Approximately 15% of patients (pts) with multiple myeloma (MM) exhibit a t(4;14) translocation that results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3) in the absence of ligand. This translocation has been strongly linked with a poor prognosis and short survival compared with pts without this translocation. Dovitinib (TKI258) is an RTK inhibitor that has demonstrated in vitro inhibitory activity against FGFR (including FGFR3), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), with IC50values of approximately 10 nM. Tumor growth inhibition was observed in xenograft tumor models of MM treated with dovitinib. This study was designed to evaluate the efficacy and safety of dovitinib in pts with relapsed or refractory MM that is either t(4;14) positive or negative. Patients and Methods: Adult pts who had received at least 2 prior antimyeloma regimens and who had relapsed or were refractory to their last treatment regimen were enrolled in this multicenter, open-label, 2-stage, phase 2 trial. Pts were evaluated for t(4;14) status at the baseline visit and classified according to the result into either a t(4;14)-positive or a t(4;14)-negative group. Dovitinib was administered at a dose of 500 mg/day on a 5-days-on/2-days-off schedule. Response was characterized as per the International Myeloma Working Group (IMWG) criteria. The primary endpoint was extended overall response rate as defined by the rate of pts with best overall response of complete response, very good partial response, partial response, or minor response. Secondary endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. After disease progression, pts had the option to continue treatment with the addition of low-dose dexamethasone (40 mg every 7 days) with M-protein levels at the time of progression considered as the new baseline. Results: A total of 43 pts were enrolled in this study; 26 pts were t(4;14) negative, 13 were t(4;14) positive, and 4 pts had unknown/indeterminate t(4;14) status. Median age was 63 years. Most pts (86%; n = 37) had received ≥ 3 prior lines of therapy. No objective responses were observed in either group of pts. Due to the apparent lack of efficacy, the study did not proceed to stage 2. The following observations are based on the preliminary data. In the t(4;14)-negative group, median duration of exposure to the study drug was 4.0 weeks, and 9 of the 26 pts (35%) had stable disease, 13 (50.0%) had progressive disease, and 4 (15%) were not evaluable. Due to slow enrollment and lack of efficacy among the earlier enrolled t(4;14)-positive pts, enrollment for the t(4;14)-positive group was closed prematurely. Among the 13 enrolled t(4;14)-positive pts, median duration of exposure to the study drug was 8.7 weeks. Best responses were stable disease for 8 pts (62%), disease progression for 3 pts (23%), and unknown for 2 pts (15%). Among both groups, the most common adverse events of any grade, regardless of study drug, were nausea (67%), diarrhea (58%), vomiting (51%), fatigue (47%), thrombocytopenia (33%), and anemia (28%). Most of the nonhematologic events were mild. The most common grade 3/4 adverse events were thrombocytopenia (26%) and anemia (23%). The principal reasons for discontinuation of dovitinib monotherapy were disease progression (72%) and adverse events (19%). Six pts continued on the dovitinib plus dexamethasone regimen; 1 pt is ongoing, and 5 pts discontinued due to disease progression (n = 4) and adverse events (n = 1). Conclusion: Dovitinib was found to have no or minimal single-agent activity in relapsed/refractory myeloma irrespective of t(4;14) status. Although the patient numbers are small, the rate of patients with stable disease during study treatment who may have had a clinical benefit was higher in the t(4;14)-positive group, suggesting that this subgroup may be a candidate to explore combination treatment of dovitinib with other agents, such as proteasome inhibitors. Gastrointestinal toxicity, while mostly mild, remains a challenge, and timely monitoring and supportive care during dovitinib treatment may alleviate these symptoms. Dovitinib may be a promising agent for combination therapies to improve prognosis of patients with t(4;14)-positive MM. Disclosures: Scheid: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Reece:Millennium Pharmaceuticals: Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Spencer:Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria. Callander:Millennium Pharmaceuticals: Research Funding. Sonneveld:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding. Kalimi:Novartis Pharmaceuticals: Employment. Cai:Novartis: Employment. Shi:Novartis: Employment, Equity Ownership. Scott:Novartis: Employment. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

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Crowdsourced High-Risk Classifiers for Multiple Myeloma Patients Commonly Identify PHF19 As a Robust Progression Biomarker

Blood ◽

10.1182/blood-2019-127362 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4370-4370

Author(s):

Michael J Mason ◽

Carolina D. Schinke ◽

Christine Eng ◽

Fadi Towfic ◽

Fred Gruber ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

High Risk ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Multiple myeloma (MM) is a hematological malignancy of terminally differentiated plasma cells residing within the bone marrow with 25,000-30,000 patients diagnosed in the United States each year. The disease's clinical course depends on a complex interplay chromosomal abnormalities and mutations within plasma cells and patient socio-demographic factors. Novel treatments extended the time to disease progression and overall survival for the majority of patients. However, a subset of 15%-20% of MM patients exhibit an aggressive disease course with rapid disease progression and poor overall survival regardless of treatment. Accurately predicting which patients are at high-risk is critical to designing studies with a better understanding of myeloma progression and enabling the discovery of novel therapeutics that extend the progression free period of these patients. To date, most MM risk models use patient demographic data, clinical laboratory results and cytogenetic assays to predict clinical outcome. High-risk associated cytogenetic alterations include deletion of 17p or gain of 1q as well as t(14;16), t(14;20), and most commonly t(4,14), which leads to juxtaposition of MMSET with the immunoglobulin heavy chain locus promoter, resulting in overexpression of the MMSET oncogene. While cytogenetic assays, in particular fluorescence in situ hybridization (FISH), are widely available, their risk prediction is sub-optimal and recently developed gene expression based classifiers predict more accurately rapid progression. To investigate possible improvements to models of myeloma risk, we organized the Multiple Myeloma DREAM Challenge, focusing on predicting high-risk, defined as disease progression or death prior to 18 months from diagnosis. This effort combined 4 discovery datasets providing participants with clinical, cytogenetic, demographic and gene expression data to facilitate model development while retaining 4 additional datasets, whose clinical outcome was not publicly available, in order to benchmark submitted models. This crowd-sourced effort resulted in the unbiased assessment of 171 predictive algorithms on the validation dataset (N = 823 unique patient samples). Analysis of top performing methods identified high expression of PHF19, a histone methyltransferase, as the gene most strongly associated with disease progression, showing greater predictive power than the expression level of the putative high-risk gene MMSET. We show that a simple 4 feature model composed of age, stage and the gene expression of PHF19 and MMSET is as accurate as much larger published models composed of over 50 genes combined with ISS and age. Results from this work suggest that combination of gene expression and clinical data increases accuracy of high risk models which would improve patient selection in the clinic. Disclosures Towfic: Celgene Corporation: Employment, Equity Ownership. Dalton:MILLENNIUM PHARMACEUTICALS, INC.: Honoraria. Goldschmidt:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Research Funding; Amgen: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; MSD: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; John-Hopkins University: Research Funding. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Ortiz:Celgene Corporation: Employment, Equity Ownership. Trotter:Celgene Corporation: Employment, Equity Ownership. Dervan:Celgene: Employment. Flynt:Celgene Corporation: Employment, Equity Ownership. Dai:M2Gen: Employment. Bassett:Celgene: Employment, Equity Ownership. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Shain:Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Munshi:Abbvie: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Celgene Corporation, Janssen: Research Funding; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses. Walker:Celgene: Research Funding. Thakurta:Celgene: Employment, Equity Ownership.

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Assessing the Immune Tumour Microenvironment (iTME) Using Multiplex Immunoflourescence Histochemistry (mIHC) Demonstrates Close Proximity of Cytotoxic T-Cells to Plasma Cells (PC) in Patients with Newly Diagnosed Multiple Myeloma (NDMM)

Blood ◽

10.1182/blood-2021-150471 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4705-4705

Author(s):

Slavisa Ninkovic ◽

Louise E. Purton ◽

Simon J Harrison ◽

Hang Quach

Keyword(s):

T Cells ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Cytotoxic T Cells ◽

Expression Patterns ◽

Cell Segmentation ◽

Advisory Committees ◽

Checkpoint Receptors

Abstract Aim: A dysfunctional iTME facilitates disease progression in MM. Studies have demonstrated the association between the spatial distribution of immune cells and progression of various cancers. Using mIHC we aim to describe quantitative and qualitative changes in CD3+CD8+ T-cells (T cytotoxic) in patients with MGUS, ND and relapsed/refractory MM (RRMM) and assess spatial proximity to PCs. Method: Formalin-fixed, paraffin-embedded trephine sections from pts with MGUS (n=32), NDMM (n=65) and RRMM (n=59) were sequentially stained for CD138, CD3, CD8 and checkpoint receptors (CPs) Tim3, Lag-3 and PD-1 (Figure 1). Halo® image analysis platform was used for cell segmentation and phenotyping, facilitating enumeration of T cytotoxic populations and analysis of proximity to PCs. Descriptive statistics and ordinary one-way ANOVA were applied as appropriate. Results: Patient demographics, disease characteristics, treatment (including prior therapies, where applicable), best response, duration of response, median progression free (PFS) and overall survival (OS) will be presented for all cohorts. There was no difference in BM cellularity or total number of nucleated cells assessed across the cohorts (p=0.16 and p=0.25). PC % was higher in the ND and RRMM compared to MUGS cohort (p<0.001). The average distance between T cytotoxic and PCs was similar between the cohorts (p=0.38), but a higher proportion of T cytotoxic were within 50μm of a PC in the ND cohort (p=0.0036, 90.8±15.8% (ND) vs. 77.6±19.5% (MGUS) and 80.1±25.9% (RR)). The % of unique PCs with a single T cytotoxic within 100μm is higher in patients with MGUS and RRMM than NDMM (p=0.0007). There was no difference in the %CD3+, %CD3+CD8+ or %CD3+ cells expressing CD8 (p=0.22, p=0.62, p=0.48). CP expression on T cytotoxic was similar (Tim3 p=0.46, Lag-3 p=0.35; PD-1 p=0.54) with no difference in dual or triple CP expression. Sub-analyses assessing CP expression patterns and T cytotoxic/PC proximity within individual cohorts based on response to treatment/disease progression are to follow. Conclusion: The infiltration of cytotoxic T cells into tumours is a critical factor in immunotherapy efficacy. Here we clearly demonstrate the feasibility of mIHC to describe the spatial context of the iTME and we plan to implement it for predictive value in future studies of immunotherapies in patients with MM. Figure 1: Bone marrow FFPE trephine section stained with mIHC using the Opal TM workflow demonstrating plasma cells (CD138, green), T cells (CD3, yellow; CD8, pink) and checkpoint receptors (PD-1, orange; Lag-3, magenta; Tim3, light blue) with colocalisation of some signals. Disclosures Harrison: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: 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, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria. Quach: Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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CLL Intraclonal Fractions Defined By Time Since Cell Birth/Division Promote a Leukemia-Supportive, Immune-Tolerant Microenvironment By Distinct Mechanisms

Blood ◽

10.1182/blood-2018-99-119843 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1836-1836

Author(s):

Shih-Shih Chen ◽

Xiao J. Yan ◽

Thomas M. Herndon ◽

Clare C. Sun ◽

Priyadarshini Ravichandran ◽

...

Keyword(s):

T Cells ◽

Cell Division ◽

T Cell ◽

Disease Progression ◽

Board Of Directors ◽

Stable Disease ◽

Research Funding ◽

Advisory Committees ◽

Immune Tolerant

Abstract Chronic lymphocytic leukemia (CLL) cells actively participate in the formation of the tumor microenvironment (TME). The interplay of CLL cells and leukemia-supporting cells such as Th2 cells and regulatory T cells (Tregs) promotes a leukemia-supportive, immune-tolerant TME. In these supportive/tolerogenic niches of lymph nodes (LN) and bone marrow (BM), CLL cells slowly proliferate, and the rate of proliferation correlates with disease progression. However, how these dividing/recently-divided cells and other intraclonal CLL fractions interact with non-neoplastic cells to shape the TME to support growth and accelerate disease is unclear. To address these questions, matched LN and PB samples collected at day 13 after 2H2O ingestion from treatment-naïve patients (7 with stable disease and 7 with active disease) were sorted to determine in vivo growth rates of CLL cells within the proliferative fraction (PF, CXCR4DimCD5Bright), resting fraction (RF, CXCR4BrightCD5Dim) and intermediate fraction (IF, CXCR4IntCD5Int). In LN, PF cells had the highest 2H-DNA levels, and only the growth rate of PF but not IF or RF cells correlated with disease aggressiveness. In the PB, PF cells also had the highest growth rate; however, all 3 fractions (PF, IF, RF) had 2H-DNA levels that correlated with disease aggressiveness. Thus, PF cells from patients with aggressive clinical course undergo quicker transitions to the IF and then to the RF which might promote faster tissue homing and disease progression. Indeed, more PF cells from active than stable disease patients were found in the spleen (SP) and BM and less remained in PB, 18 hours post-injection into NSG mice. Gene expression profiling (GEP) was then performed on RF, IF, and PF from 7 paired PB and LN samples. GEP signatures of the PF from PB and LN were similar, consistent with 2H2O data that the PF are recent emigrants from TME. These GEP also inferred enhanced cell proliferation (CCND2, CDK2AP1), adhesion and motility (FERMT3, CD49d, CD11a, CD21), antigen presentation (CD1C), and promotion of T-cell trafficking (CCL3, CCL4) in LN CLL cells within the PF but not the IF or RF. Thus, CLL cells within the three intraclonal fractions might promote distinct biologic functions. To test this, we studied T cell responses stimulated by the CXCR4/CD5 fractions in vitro and in vivo. In an antigen-driven allo-MLR, the whole clone of CLL cells triggered the division of normal T cells, but PF induced the highest level of T-cell division that is ≥ 3 times more than any other fraction. Similarly, in an autologous polyclonal CD4 T cell response stimulated by anti-CD3/28 Dynabeads and IL-2, T-cell division was suppressed by unseparated CLL cells and each fraction. However, the least suppression was seen in T cells co-cultured with PF cells compared to those cultured alone or with IF or RF. In both settings, PF cells induced significantly more IL-4+ T cells, and RF cells triggered more Tregs. Similar numbers of Th1 cells were seen in all cultures. The RF and IF, but not the PF, produced the immunosuppressive cytokine IL-10. Finally, when dividing cases based on disease aggressiveness, significantly more T-cell division was triggered by PF and RF from active patients than stable patients; the percentages of Th1 and Th2 cells however were similar. These results were confirmed in vivo; in NSG mice injected with autologous T cells together with the PF, IF or RF sorted from 2 sets of active versus stable disease patients, PF from all 4 cases induced the highest levels of CLL B and T cell expansion in SP and BM, and RF from active but not stable disease patients triggered the growth of CLL T and B cells. In summary, CLL disease progression correlates with the rate of CLL cell division, and the rapidity that CLL cells home to the TME. The intraclonal fractions of CLL clones exhibit distinct biologic properties that can be further differentiated based on disease aggressiveness. This appears especially relevant for the development of a leukemia-supportive, immune-tolerant TME contributed by all 3 CXCR4/CD5 fractions, albeit by different mechanisms. The PF creates this by superior antigen presentation capacity and skewing T cell function to an immunosuppressive Th2 phenotype. For the IF and RF, this is done by inducing IL-10 secretion and amplifying Tregs. Together, these findings suggest the possibility of targeting specific subpopulations in CLL clones with distinct immunoregulatory modalities as a novel form of therapy. Disclosures Chen: Beigene: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding. Wiestner:Pharmacyclics LLC, an AbbVie Company: Research Funding. Rai:Cellectis: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees. Chiorazzi:Janssen, Inc: Consultancy; AR Pharma: Equity Ownership.

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Phase III Intergroup Study of Lenalidomide Versus Placebo Maintenance Therapy Following Single Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Multiple Myeloma: CALGB 100104

Blood ◽

10.1182/blood.v116.21.37.37 ◽

2010 ◽

Vol 116 (21) ◽

pp. 37-37 ◽

Cited By ~ 22

Author(s):

Philip L. McCarthy ◽

Kouros Owzar ◽

Kenneth C. Anderson ◽

Craig C. Hofmeister ◽

David Duane Hurd ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Disease Progression ◽

Board Of Directors ◽

Stable Disease ◽

Interim Analysis ◽

Research Funding ◽

Phase Iii ◽

Cell Transplant ◽

Advisory Committees

Abstract Abstract 37 The primary objective of CALGB 100104 was to determine if maintenance lenalidomide would prolong time to progression (TTP) after single AHSCT for multiple myeloma. Eligibility included: Stage I-III multiple myeloma, ≤ 1 year from diagnosis, ≥ 2 months of induction with stable disease or better and age < 70 years. AHSCT regimen was melphalan 200 mg/m2. Patients (pts) with stable disease or better were randomized double-blinded at day 100–110 post-AHSCT to lenalidomide or placebo, after stratification by diagnostic β2-microglobulin (β2M) level and prior thalidomide or lenalidomide therapy. Starting dose was 10 mg/day, escalated to 15 mg/day after 3 months and continued until disease progression. Drug was stopped and dose reduced according to the development of toxicity. Drug was held for ≥ Gr 3 toxicity, restarted at resolution to ≤ Gr 2 and de-escalated by 5 mg or maintained as tolerated at 15, 10, 5 mg daily or 5 mg daily for 21 of 28 days per month. All pts required some form of anticoagulation including aspirin, warfarin or heparin compounds. There was no consolidation therapy. Results: 568 pts were enrolled before AHSCT (04/15/05-07/03/09) from 47 centers. Of 108 pts (19%) not randomized, reasons were: progressive disease/no response 16%, adverse events (AEs) 5%, died during therapy 2%, refusal 26 %, other disease 1%, other therapy 4 %, other reasons 33%, unknown 14%. Pt characteristics in the lenalidomide arm and placebo arm respectively were: median age (range) 58 (29-70) and 57 (39-70); male gender 48% and 52%; β2M >2.5 mg/L, 28% and 27%. For 554 pts with complete data, induction regimens were thalidomide based (27%), lenalidomide based (22%), bortezomib based (20%), bortezomib and thalidomide based (12%), bortezomib and lenalidomide based (9%), dexamethasone based (4%), lenalidomide and thalidomide (3%), lenalidomide, thalidomide and bortezomib (1%), other (1%) and missing (1%); hence 74% of pts received either lenalidomide or thalidomide prior to enrollment. The primary endpoint of the study, TTP was met in a planned protocol interim analysis in the 3rd quarter of 2009 and the study results were released on 12/17/09. This updated 3rd interim analysis for TTP includes further events up until 12/17/09 after which study pts were un-blinded. This interim analysis is based on 460 randomized pts with approximately 33% of the required number of events (progression or death before progression) observed. The median follow-up is 17.5 months from ASHCT. The number of events among 231 pts randomized to lenalidomide was 44 compared to 91 among 229 pts randomized to placebo. The one-sided unadjusted P-value was <0.0001. Pts receiving lenalidomide experienced a 61% reduction in the risk of disease progression or death when compared to pts receiving placebo. The estimated hazard ratio was 0.39 (95% CI,0.27-0.56 p < 0.0001). The preliminary estimated median TTP is 42.3 months for the lenalidomide arm and the estimated median TTP is 21.8 months for the placebo arm. Deaths in the lenalidomide and placebo arms were 19 and 28 respectively (p=0.13) and as of this analysis, there is no difference between these two arms. Significant improvements in TTP were observed in the lenalidomide maintenance arm regardless of β2M level or prior thalidomide or lenalidomide induction therapy. For 389 reported pts, the post-randomization, hematologic AEs were Gr 3 (32%), Gr 4 (13%) and Gr 5 (0) for the lenalidomide arm and Gr 3 (6%) Gr 4 (4%) and Gr 5 (0) for placebo (p=0.0001). The non-hematologic AEs were Gr 3 (30%), Gr 4 (3%) and Gr 5 (1%) for the lenalidomide arm and Gr 3 (19%), Gr 4 (3%), and Gr 5 (2%) for placebo (p=0.0048). Comparing lenalidomide versus placebo post-randomization pooled Gr 3–5 AEs, there were significantly more episodes of thrombocytopenia (11% versus 3%, p=0.01), neutropenia (44% vs 8%, p<0.0001) anemia (5% vs 1%, p=0.0082) and all infections (16% vs 3%, p<0.0001) with lenalidomide. There were no significant differences in incidence of fatigue, neuropathy, rash and thromboembolism. A minority of patients discontinued therapy due to AEs (12%, 28 of 231 on lenalidomide vs 2%, 5 of 229 on placebo) and for other reasons (13%, 29 of 231 on lenalidomide vs 6%, 14 of 231 on placebo). Conclusions: Long term administration of lenalidomide is feasible. When compared to placebo controls, lenalidomide initiated at day 100–110 post-AHSCT in multiple myeloma patients significantly delays TTP. Disclosures: McCarthy: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide maintenance therapy for myeloma following autologous hematopoietic cell transplant. Anderson:Millenium: Consultancy, Honoraria; Celgene: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Merck: Consultancy; Bristol Myers Squibb: Consultancy; Acetylon: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Hurd:Celgene: Research Funding. Giralt:Celgene: Honoraria, Speakers Bureau; Millenium: Honoraria, Speakers Bureau. Stadtmauer:Celgene: Speakers Bureau. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Vij:Celgene: Honoraria, Speakers Bureau. Callander:Millenium: Research Funding. Maziarz:Millenium: Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees. Martin:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Novartis: Speakers Bureau. Qazilbash:Celgene: Speakers Bureau. Shea:Millenium: Consultancy, Research Funding.

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Higher Intensity of Cell Surface Glucose-Regulated Protein 78 (csGRP78) Expression Is Seen in Patients with Early Progressive Disease/Mortality in a Cohort of Relapsed, Refractory Multiple Myeloma Patients Treated with Carfilzomib, Thalidomide and Dexamethasone

Blood ◽

10.1182/blood-2019-128190 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4376-4376

Author(s):

Slavisa Ninkovic ◽

Simon Harrison ◽

Lenny Straszkowski ◽

Giulia Quattrocchi ◽

Wee-Joo Chng ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Surface ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Response To Therapy ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Cell Surface Grp78

Background: GRP78, an endoplasmic reticulum stress-inducible molecular chaperone, is up-regulated at times of cellular stress to limit proteotoxicity and promote cell survival. Translocation of GRP78 to the cell surface (csGRP78) is emerging as a critical step providing tumour cells with a survival advantage. Here we quantified, monitored and correlated plasma cell (PC) csGRP78 expression in patients (pts) with relapsed/refractory multiple myeloma (RRMM) treated with carfilzomib, thalidomide and dexamethasone (KTd). Method: Patients enrolled in the single arm, multicentre, phase II Australasian Leukaemia & Lymphoma Group MM018/Asian Myeloma Network 002 study were treated with KTd as described previously (Quach et al. Blood 2018 132:1955). Formalin-fixed, paraffin-embedded BM trephine sections collected at baseline (n=29), after 6-months (mo) of KTd (n=19) and at time of disease progression (PD; n=5) were stained for CD138 and GRP78 by multiplex immunofluorescence histochemistry using the OpalTM workflow. Membrane expression of CD138 and GRP78 was extracted using inForm® software, compared across timepoints and correlated to disease characteristics and treatment outcomes. Descriptive statistics, paired/unpaired two-tailed t-test, Pearson's or Spearman's correlation were applied as appropriate. Results: Correlative BM biopsies were collected for 29 pts [male = 18, mean age = 65.0 years (range 41.9-83.2), 2 median prior lines of therapy (range 1-3)] at baseline, 21 pts after 6 months of KTd (7 had PD/died prior to cycle 6, 1 came off study due to grade 4 AE after 5 cycles) and 5 pts at time of PD. There was no difference in the number of fields, BM cellularity (%) or number of nucleated cells (NCs) assessed at baseline and 6mo (p=0.927, 0.331 and 0.491 respectively). PC burden (%; mean±SD) reduced significantly following 6mo KTd (28.3±28.1 vs. 2.12±2.37; p=0.0007). The number of plasma cells expressing csGRP78 (% of all NCs) was reduced following 6mo KTd treatment (27.04±26.83 vs. 2.05±2.32; p=0.0007) while the % of CD138-ve BM cells expressing csGRP78 (% of all NCs; mean±SD) increased (62.61±27.55 vs. 87.46±10.11; p=0.0005). Globally, there was a trend for reduced intensity of csGRP78 expression after 6mo KTd (H-score 70.79±62.16 vs. 53.53±51.45; p=0.2073). There was no correlation between baseline BM NC GRP78 H-score and baseline paraprotein level, involved/uninvolved serum free light chain ratio or depth of response to KTd. Pts with early (<6mo) disease progression/mortality (n=7) had a significantly higher baseline H-score (136±78.8 vs. 75.1±65.2; p=0.049). There was a separation of survival curves, but no significant difference regarding risk of early PD/mortality based a baseline H-score >75th percentile of the cohort (>152); p=0.1472 (Figure 1). Conclusion: Here we demonstrate that cell surface expression of GRP78 is prominent in both the plasma cells and cells of the tumour microenvironment in patients with RRMM and persists in the TME cells in patients on treatment. Early (<6mo) disease progression or mortality is associated with higher baseline intensity of global cell surface GRP78 expression. Additional studies are being performed to evaluate the promise of cell surface GRP78 expression on plasma cells as a potential biomarker of response to therapy. Disclosures Harrison: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding. Quach:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees.

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Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-117871 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 804-804 ◽

Cited By ~ 7

Author(s):

Mark Bustoros ◽

Chia-jen Liu ◽

Kaitlen Reyes ◽

Kalvis Hornburg ◽

Kathleen Guimond ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

High Risk ◽

Disease Progression ◽

Board Of Directors ◽

Rna Sequencing ◽

Research Funding ◽

Response Rate ◽

Advisory Committees ◽

Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: 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. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

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Dynamic Epigenetic Landscapes Define Multiple Myeloma Progression and Drug Resistance

Blood ◽

10.1182/blood-2020-142872 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Rafael Renatino-Canevarolo ◽

Mark B. Meads ◽

Maria Silva ◽

Praneeth Reddy Sudalagunta ◽

Christopher Cubitt ◽

...

Keyword(s):

Gene Expression ◽

Drug Resistance ◽

Disease Progression ◽

Board Of Directors ◽

Research Funding ◽

Chromatin Accessibility ◽

Refractory Disease ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Genome Wide

Multiple myeloma (MM) is an incurable cancer of bone marrow-resident plasma cells, which evolves from a premalignant state, MGUS, to a form of active disease characterized by an initial response to therapy, followed by cycles of therapeutic successes and failures, culminating in a fatal multi-drug resistant cancer. The molecular mechanisms leading to disease progression and refractory disease in MM remain poorly understood. To address this question, we have generated a new database, consisting of 1,123 MM biopsies from patients treated at the H. Lee Moffitt Cancer Center. These samples ranged from MGUS to late relapsed/refractory (LR) disease, and were comprehensively characterized genetically (844 RNAseq, 870 WES, 7 scRNAseq), epigenetically (10 single-cell chromatin accessibility, scATAC-seq) and phenotypically (537 samples assessed for ex vivo drug resistance). Mutational analysis identified putative driver genes (e.g. NRAS, KRAS) among the highest frequent mutations, as well as a steady increase in mutational load across progression from MGUS to LR samples. However, with the exception of KRAS, these genes did not reach statistical significance according to FISHER's exact test between different disease stages, suggesting that no single mutation is necessary or sufficient to drive MM progression or refractory disease, but rather a common "driver" biology is critical. Pathway analysis of differentially expressed genes identified cell adhesion, inflammatory cytokines and hematopoietic cell identify as under-expressed in active MM vs. MGUS, while cell cycle, metabolism, DNA repair, protein/RNA synthesis and degradation were over-expressed in LR. Using an unsupervised systems biology approach, we reconstructed a gene expression map to identify transcriptomic reprogramming events associated with disease progression and evolution of drug resistance. At an epigenetic regulatory level, these genes were enriched for histone modifications (e.g. H3k27me3 and H3k27ac). Furthermore, scATAC-seq confirmed genome-wide alterations in chromatin accessibility across MM progression, involving shifts in chromatin accessibility of the binding motifs of epigenetic regulator complexes, known to mediate formation of 3D structures (CTCF/YY1) of super enhancers (SE) and cell identity reprograming (POU5F1/SOX2). Additionally, we have identified SE-regulated genes under- (EBF1, RB1, SPI1, KLF6) and over-expressed (PRDM1, IRF4) in MM progression, as well as over-expressed in LR (RFX5, YY1, NBN, CTCF, BCOR). We have found a correlation between cytogenetic abnormalities and mutations with differential gene expression observed in MM progression, suggesting groups of genetic events with equivalent transcriptomic effect: e.g. NRAS, KRAS, DIS3 and del13q are associated with transcriptomic changes observed during MGUS/SMOL=>active MM transition (Figure 1). Taken together, our preliminary data suggests that multiple independent combinations of genetic and epigenetic events (e.g. mutations, cytogenetics, SE dysregulation) alter the balance of master epigenetic regulatory circuitry, leading to genome-wide transcriptional reprogramming, facilitating disease progression and emergence of drug resistance. Figure 1: Topology of transcriptional regulation in MM depicts 16,738 genes whose expression is increased (red) or decreased (green) in presence of genetic abnormality. Differential expression associated with (A) hotspot mutations and (B) cytogenetic abnormalities confirms equivalence of expected pairs (e.g. NRAS and KRAS, BRAF and RAF1), but also proposes novel transcriptomic dysregulation effect of clinically relevant cytogenetic abnormalities, with yet uncharacterized molecular role in MM. Figure 1 Disclosures Kulkarni: M2GEN: Current Employment. Zhang:M2GEN: Current Employment. Hampton:M2GEN: Current Employment. Shain:GlaxoSmithKline: Speakers Bureau; Amgen: Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; AbbVie: Research Funding; Takeda: Honoraria, Speakers Bureau; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive: Consultancy, Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siqueira Silva:AbbVie: Research Funding; Karyopharm: Research Funding; NIH/NCI: Research Funding.

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