scholarly journals Value of Minimal Residual Disease (MRD) Monitoring Using Real-Time Quantitative PCR in Patients with Acute Promyelocytic Leukemia (APL) Treated with ATRA, ATO, +/- GO

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3851-3851
Author(s):  
Jorge Cortes ◽  
Hagop M. Kantarjian ◽  
Tapan M. Kadia ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Real Time ◽  
Quantitative Pcr ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Real Time Quantitative Pcr ◽  
Risk Patients ◽  
Standard Risk

Background: The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is superior to ATRA plus chemotherapy in the treatment of standard risk patients (pts) with newly diagnosed APL. MRD monitoring has been successfully utilized for the early identification of relapse. Qualitative PCR has been superseded with the more accurate real-time quantitative PCR (RQ-PCR) for MRD detection in APL. Methods: We reviewed pts with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without gemtuzumab ozogamicin (GO). GO was given to High risk pts (WBC >10 × 109/L) and pts with rising WBC. Real-time quantitative RT-PCR (RQ-PCR) was used to measure PML-RARα in bone marrow (BM) and peripheral blood (PB) specimens. We sought to determine the value of MRD monitoring in patients with APL treated with this regimen. Results: A total of 223 pts with APL have been followed from July 2002 to March 2019 with a total of 2007 samples (1622 BM, 385 PB) analyzed with a median number of samples of 8 per pt (range, 1-43). Median follow up is 55.6 months (range, 1-198). MRD positivity decreased over time on therapy; 218 pts (98%) were MRD positive after induction, while only 2 pts (1%) were positive after the first cycle of consolidation. Eight pts (3.5%) had positive MRD (all ≤0.1) during consolidation or after completing treatment but became negative after repeated MRD testing and none of them relapsed. Overall, seven pts relapsed (5 with high risk disease and 2 with low risk) and The median time to relapse after achieving CR was 9.4 months (range, 7.9-79.5).The time to the first relapse was between 7.9-12.4 months except for the pt who relapsed after 79.5 months (low risk pt), Among the high risk pts, molecular relapse preceded hematological relapse by 3.7 weeks (range, 2.1-4.1). There was a correlation between quantitative PCR values on PB and BM samples obtained concomitantly (r2=0.67, p=0.048). Conclusions: MRD monitoring may be useful for early detection of relapse in pts with high risk APL within first year after completion of therapy. Late molecular relapse is very rare and does not justify universal monitoring especially in standard risk patients. These data support the lack of need for MRD monitoring after completion of consolidation in pts with standard risk APL treated with ATRA plus ATO. Table Disclosures Kantarjian: Novartis: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Astex: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding. Kadia:Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding. Jabbour:BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding. Borthakur:Incyte: Research Funding; Merck: Research Funding; Strategia Therapeutics: Research Funding; Janssen: Research Funding; GSK: Research Funding; Agensys: Research Funding; Oncoceutics, Inc.: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Polaris: Research Funding; NKarta: Consultancy; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Cantargia AB: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare AG: Research Funding; Oncoceutics: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Daver:Karyopharm: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Servier: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Agios: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Celgene: Consultancy; Glycomimetics: Research Funding; Otsuka: Consultancy; NOHLA: Research Funding; Sunesis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Novartis: Consultancy, Research Funding. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding.

scholarly journals Efficacy of Induction Thearapy with Lenalidomide, Bortezomib, and Dexamethasone (RVD) in 1000 Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3294-3294 ◽  
Author(s):  
Nisha Joseph ◽  
Vikas A. Gupta ◽  
Craig C Hofmeister ◽  
Charise Gleason ◽  
Leonard Heffner ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Risk Patients ◽  
Standard Risk

Abstract Background : Lenalidomide, bortezomib and dexamethasone (RVD) has been shown to be a well-tolerated and efficacious induction regimen in newly diagnosed myeloma patients. Two large randomized phase III trials show an overall response rate (ORR) >95% (Durie et al, Attal et al) supporting this combination regimen. We have conducted a retrospective analysis utilizing our institutional data of 1000 patients treated with RVD induction therapy at the Winship Cancer Institute of Emory University. Methods: 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 61 years (range 16-83). Other notable patient characteristics include: M/F 54.3%/45.6%; W/AA 56.4%/34%; ISS I and II/III 54%/17%; Isotype IgG/IgA/FLC 59.1%/19%/15.8%; standard risk/high risk 72%/28%. High risk disease was defined as the presence of t(4;14), t(14;16), del(17p), and/or complex karyotype. A total of 835 patients (83.5%) underwent autologous stem cell transplant (ASCT) upfront after attaining at least a partial response with induction therapy, and 165 patients (16.5%) were offered deferred transplant. Among the patients that opted for deferred transplant, 56 of these patients (33.9%) underwent ASCT at first relapse with a median time to transplant of 30 months (3-96). 755 (75.5%) of patients received risk-stratified maintenance therapy following transplant. Evaluation of responses to induction therapy for the entire cohort show an ORR 97.3% with ≥VGPR of 68% post-induction therapy. Response rates 100 days post-transplant show an ORR 98% with 30.7% of patients achieving a sCR. Response rates are summarized in table 1. Median PFS was 63 months for the entire cohort, and 72 months for standard risk patients (61.75-82.25) versus 37 months for the high-risk patients (30.84-43.16), p<0.001. Median OS has not been reached at median of 38 months follow up (Figure 1). Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction. These results illustrate both the activity of this induction regimen with impressive response rates and long-term outcomes in both standard and high risk patients. Disclosures Hofmeister: Adaptive biotechnologies: 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; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Janssen: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Children's Oncology Group (COG) AALL0434: Successful Disease Control without Cranial Radiation in Newly Diagnosed T Lymphoblastic Lymphoma (T-LL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1000-1000 ◽  
Author(s):  
Robert James Hayashi ◽  
Stuart S. Winter ◽  
Kimberly P. Dunsmore ◽  
Meenakshi Devidas ◽  
Brent Wood ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Partial Response ◽  
Board Of Directors ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Patients ◽  
To Receive ◽  
Standard Risk

Abstract Background: COG AALL0434 evaluated the safety and efficacy of a multi agent chemotherapy backbone containing Capizzi based methotrexate/pegaspargase in newly diagnosed T-LL patients. High-risk patients were randomized to receive the COG augmented BFM (ABFM) regimen with or without Nelarabine. This was part of a larger trial including T-Lymphoblastic Leukemia (T-ALL) patients featuring a 2 x 2 pseudo-factorial randomization at the end of induction using the COG ABFM regimen with a randomization of Capizzi MTX/pegaspargase (C-MTX) verses high dose MTX and a randomization with or without Nelarabine (Nel). Methods: AALL0434 enrolled 277 patients with T-LL (2010-2014). Patients were assigned to two risk categories based upon the degree of bone marrow involvement at diagnosis: (≥1%, High Risk, <1% Standard Risk), and the ability to achieve at least a partial response at the end of induction. Patients with prior steroid treatment were assigned to the high risk group. Both groups were treated using the ABFM C-MTX regimen. High-risk patients were randomized to receive or not receive six, 5-day courses of Nel 650 mg/m2/day. No patients received prophylactic cranial radiation and CNS3 patients were ineligible. Response criteria included, Complete Response (CR): disappearance, Complete Response unconfirmed (CRu): >75% reduction, Partial Response (PR): >50% reduction, of all measurable disease, all without new lesions. Results: At the end of induction, 98.9% of the evaluable patients achieved at least a partial response (30.7% CR, 34.7% CRu, 33.5% PR). For all T-LL patients, the 4-year event free survival (EFS) and overall survival (OS) were 87.0 +/- 2.1% and 90.0+/-1.8%. The 4-year Disease Free Survival (DFS) from end of induction was 90.0+/- 2.1%. There was no difference in DFS observed between the high risk and standard risk groups, (p=0.25) or by treatment regimen (p=0.31). Nel did not show an advantage for high-risk T-LL patients, with 4-year DFS 85.0 +/- 5.6% with Nel (N=60) vs 89.0 +/- 4.7% without Nel (N=58) (p=0.28). Neither stage nor tumor response at the end of four weeks of induction therapy resulted in differences in EFS (p= 0.34 and p= 0.22, respectively). Minimal detectable disease (MDD) of the bone marrow at diagnosis (<0.1%, 0.1-0.99%, >1.0%), used to establish the risk assignment for this trial, failed to demonstrate thresholds at diagnosis that resulted in differences in EFS (p=0.27). Relapse involving the CNS only occurred in 4 patients (1.4%). Overall toxicity and neurotoxicity was acceptable and not significantly different than that experienced from the ALL cohort. There was one observed second malignancy and 5 deaths not from progressive disease. Conclusion: COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provides excellent disease control regardless of stage, or the degree of disease involvement of the bone marrow at diagnosis. Nelarabine did not show an improvement in the outcome, although the trial was underpowered to address this specific question. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Bollard:Torque: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neximmune: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Melphalan/Prednisone/Lenalidomide (MPR) Versus High-Dose Melphalan and Autologous Transplantation (MEL200) in Newly Diagnosed Multiple Myeloma (MM) Patients <65 Years: Results of a Randomized Phase III Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3069-3069 ◽  
Author(s):  
Antonio Palumbo ◽  
Federica Cavallo ◽  
Izhar Hardan ◽  
Barbara Lupo ◽  
Valter Redoglia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Patients ◽  
High Dose Melphalan

Abstract Abstract 3069FN2 Background: High-dose chemotherapy with haemopoietic stem-cell improves outcome in multiple myeloma (MM). The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT) in MM patients. Aims: In this prospective randomized study, we compared conventional melphalan-prednisone-lenalidomide (MPR) with tandem high-dose melphalan (MEL200) in newly diagnosed MM patients younger than 65 years. Methods: All patients (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1, 8, 15, 22) (Rd) as induction. As consolidation, patients were randomized to MPR (N=202) consisting of six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); or tandem melphalan 200 mg/m2 MEL200 (N=200) with stem-cell support. All patients enrolled were stratified according to International Staging System (stages 1 and 2 vs. stage 3) and age (<60 vs. ≥60 years). Progression-free survival (PFS) was the primary end point. Data were analyzed in intention-to-treat. Results: Response rates were similar: at least very good partial response (≥VGPR) rate was 60% with MPR vs. 58% with MEL200 (p=.24); the complete response (CR) rate was 20% with MPR vs. 25% with MEL200 (p=.49). After a median follow-up of 26 months, the 2-year PFS was 54% in MPR and 73% in MEL200 (HR=0.51, p<.001). The 2-year overall survival (OS) was similar in the two groups: 87% with MPR and 90% with MEL200 (HR 0.68, p=.19). In a subgroup analysis, MEL200 significantly prolonged PFS in both standard-risk patients without t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 46% in the MPR group vs. 78% in the MEL200 group, HR=0.57, p=.007) and high-risk patients with t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 27% for MPR vs. 71% for MEL200, HR=0.32, p=.004). In patients who achieved CR, the 2-year PFS was 66% for MPR vs. 87% for MEL200 (HR 0.26; p<.001); in those who achieved a partial response (PR), the 2-year PFS was 56% for MPR vs. 77% for MEL200 (HR 0.45; p<.001). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs. 89% (p<.001); G3-4 infections were 0% vs. 17% (p<.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); the incidence of second tumors was 0.5% in MPR patients and 1.5% in MEL200 patients (p=.12). Deep vein thrombosis rate was 2.44% with MPR vs. 1.13% with MEL200 (p=.43). Conclusions: PFS was significantly prolonged in the MEL200 group compared to MPR. This benefit was maintained in the subgroup of patients with standard- or high-risk cytogenetic features. Toxicities were significantly higher in the MEL200 group. This is the first report showing a PFS advantage for ASCT in comparison with conventional therapies including novel agents. These data will be updated at the meeting. Disclosures: Palumbo: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:celgene: Honoraria. Ria:celgene: Consultancy. Caravita Di Toritto:Celgene: Honoraria, Research Funding. Di Raimondo:celgene: Honoraria. Boccadoro:celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Deletion of TP53 (17p13) Is Associated with Poor Outcome for Newly Diagnosed High-Risk Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2982-2982
Author(s):  
Erming Tian ◽  
Joshua Epstein ◽  
Pingping Qu ◽  
Christoph Heuck ◽  
Frits van Rhee ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Chromosome 17 ◽  
University Of Arkansas ◽  
Newly Diagnosed ◽  
Medical Sciences ◽  
Advisory Committees ◽  
Risk Patients

Abstract Introduction In multiple myeloma (MM), deletion of chromosome 17 p13 (del17p) is a poor prognostic feature. The percentage of cells carrying an abnormality has been reported to be important with thresholds of 20% being taken generally but thresholds as high as 60% being suggested more recently. We have reported previously in the Total Therapy (TT)-2 trial (NCT00083551) for newly diagnosed (ND) MM that del17p is an adverse prognostic factor (Blood 112: 4235). The TT3 trial (NCT00081939) incorporated Brtezomib into tandem Melphalan-based autotransplants with DT-PACE for induction/consolidation and Thalidomide and Dexamethasone for maintenance to treat patients with newly diagnosed MM. In more recent iterations of these trials following the introduction of novel agents in induction and during maintenance the impact of carrying del17p has not been studied. In particular we have stratified patients into low- or high-risk molecular subgroups based on the GEP-70 (TT4 protocol [NCT00734877] or TT5 protocol [NCT00869232], respectively). We have used interphase FISH (iFISH) to detect the presence of del17p in baseline bone marrow samples. Method The iFISH slides were prepared with bone marrow aspirates after removing erythrocytes. A specific TP53 probe at chromosome 17 arm p13 combined with a control probe for the ERBB3 locus (HER2, 17q12), in different colors, were hybridized to bone marrow cells. Myeloma PCs were identified by restricted Kappa or Lambda immunoglobulin light-chain staining. We investigated role of 20% cutoffs per ≥100 tumor cells for significant deletion of the TP53 probe. Kaplan-Meier analysis was used to estimate the distributions of overall survival (OS) and progression-free survival (PFS) during the follow-ups. OS was calculated from registration until the date of decease. PFS was similarly calculated, but also incorporated progressive disease as an event. Results We examined 709 baseline samples from TT3, 4, and 5 trials with the two probes at chromosome 17. Overall, 66 of 709 patients (9.3%) had deletion of TP53 locus, including 44 of the 591 (7.5%) of low-risk patients and 20 of the 118 (17.0%) high-risk patients (Table). The range of TP53-deleted cells among newly diagnosed patients is 20-99% (median=75%) overall; 35-100% (median=62%) in TT3-low-risk; 30-97% (median=80%) in TT3-high-risk; 21-99% (median=76%) in TT4; and 20-97% (median=81%) in TT5. Deletion of TP53 was associated with significant shorter OS and PFS in HR patients treated on TT3. The 3 year estimated OS of patients for TT3-HR with del17p was 33% compared with 56% for TT3-LR with del17p, and PFS of patients for TT3-HR with del17p was 25% compared with 51% for TT3-LR with del17p (Figure). The comparison of TT4 to TT5 continued showing short OS in HR patients treated on TT5. The 3 year estimated OS of patients for HRMM with del17p was 17% compared with 75% for TT5 patients without deletion (p=0.0008). But, del17p was neutral in LR patients treated on TT4 (Figure). Conclusion Since the introduction of novel agents during various stages of the disease and a focus on HRMM and LRMM defined by GEP70 we show that while TP53 deletion is an adverse prognostic factor for patients with HRMM it is no longer prognostically relevant in LRMM. Table 1. Patients with iFISH results GEP-70 riskLow ≤0.66 High >0.66 Deletion TP53 in 20-59% PCs (n/N [%]) Deletion TP53 in ≥60% PCs (n/N, [%]) Total TT3 (N=329) Low=256 9/329, [2.7%] 9/329, [2.7%] 18/329, [5.5%] High=73 3/329, [0.9%] 9/329, [2.7%] 12/329, [3.7%] TT4 (N=313) Low=313 5/313, [1.6%] 21/313, [6.7%] 26/313, [8.3%] High=0 0 0 0 TT5 (N=67) Low=22 2/67, [3.0%] 0 2/67, [3.0%] High=45 0 8/67, [11.9%] 8/67, [11.9%] Sum (N=709) Low=591 (83.4%) 14/709, [2.0%] 30/709, [4.2%] High=118 (16.6%) 3/709, [0.4%] 17/709, [2.4%] 66/709 (9.3%) Figure 1. Figure 1. Disclosures Tian: University of Arkansas for Medical Sciecnes: Employment. Epstein:University of Arkansas for Medical Sciences: Employment. Qu:Cancer Research and Biostatistics: Employment. Heuck:Millenium: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Consultancy; Foundation Medicine: Honoraria; University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Millennium: Research Funding; Onyx: Research Funding; Novartis: Research Funding. Hoering:Cancer Research and Biostatistics: Employment. Sawyer:University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:Weismann Institute: Honoraria; CancerNet: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Integrative Network Analysis of Newly Diagnosed Multiple Myeloma Identifies a Novel RNA-Seq Based High Riskgene Signature

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3285-3285
Author(s):  
Alessandro Lagana ◽  
Deepak Perumal ◽  
David Melnekoff ◽  
Ben Readhead ◽  
Brian Kidd ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
Kaplan Meier ◽  
Risk Patients ◽  
Equity Ownership

Abstract High-risk Multiple Myeloma (MM) is characterized by unresponsiveness to multiple therapies, rapid disease progression and short overall survival, and may be significantly different from relapsed MM, where aggressiveness is usually a result of drug-resistance associated to clonal selection. Several gene expression-based signatures have been proposed in the past years, however the identification of high-risk patients at diagnosis still represents a challenge. Next generation high-throughput sequencing technologies have enabled a deeper insight into cancer genomes and transcriptomes at an unprecedented level of detail. MMRF CoMMpass is a longitudinal, prospective observational study, started in 2011, that aims to collect and analyze sequencing and clinical data from >1,000 MM patients at initial diagnosis and at relapse. CoMMpass is a real world observational study and, as such, reflects the therapeutic heterogeneity seen across patient populations and provides a unique opportunity to correlate molecular profiles, genomic alterations and clinical characteristics of MM with treatment outcome. Here we present a network approach to identify high-risk myeloma patients developed using next generation sequencing data from 450 patients in the IA7 release of CoMMpass. We generated MMNet, an integrated network model of newly diagnosed myeloma based on RNA-seq, Whole-Exome (WXS) and Whole-Genome (WGS) data correlated with clinical outcomes. MMNet consisted of 37 modules of coexpressed genes, that were further characterized by functional enrichment analysis and correlation with clinical traits and genomic alterations, i.e. somatic mutations and copy number alterations inferred from WGS and WXS data. A total of 89 progression/death events have been reported for the cohort within the second year since the beginning of the study. Cox regression analysis identified a module of co-expressed genes whose over-expression was significantly correlated with early relapse (<2yr) (HR 1.75, 95%CI = 1.169-2.614, p=0.005). The module was also associated to stage III R-ISS, high clonality (>4 clones) and high mutational burden, as well as higher percentage of plasma cells in both bone marrow and peripheral blood, which are traits associated with high-risk disease. Module expression was also up regulated in patients with mutations in TP53 and MAX, 13q deletion and 1q amplification. We further narrowed down the signature to 286 genes (the MMNet-286 signature) strongly correlated with time to Event Free Survival (EFS) (r = -0.81, p = 0). This gene-set was significantly enriched for several pathways including Cell Cycle, DNA repair and Homologous Recombination (q < 0.01). Cox regression analysis showed that the two clusters induced by MMNet-286 discriminated between lower and higher risk patients with respect to EFS (HR = 2.22, 95% CI = 1.505-3.295, p = 4.007e-5) (Fig. 1). The prognostic value of MMNet-286 was confirmed on two independent datasets: Broyl-2010 (HR = 1.76, 95% CI = 1.182-2.642, p = 0.005) and Shaughnessy-2006 (HR = 2.65, 95% CI = 1.746-4.031, p = 2.03e-6) (Fig. 2 and 3). The Broyl-2010 dataset consisted of 275 samples from newly diagnosed myeloma patients included in the HOVON65/GMMG-HD4 trial (GSE19784). The Shaughnessy-2006 dataset consisted of 559 samples from newly diagnosed patients pre-TT2 and -TT3 treatments (GSE2658). Comparison of MMNet-286 with previous high risk signatures and disease classes revealed an overlap of five genes with the UAMS-70 signature, twelve genes with the EMC-92 signature and fifteen genes with the set of up-regulated genes in the UAMS PR class, for which the coexpression module was enriched. In Conclusion, our results demonstrate the advantages of employing integrated network models to identify prognostic features based on next generation sequencing data from large cohort of patients. Applications of the MMNet-286 signature include the generation of a prognostic assay (i.e. NanoString) for the identification of high-risk patients. Future work will aim at validation of the signature in larger cohorts from CoMMpass and other studies. Figure 1 Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 1. Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 2 Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 2. Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 3 Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Figure 3. Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Disclosures Chari: Novartis: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen Inc.: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus, Inc.: Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding. Barlogie:Signal Genetics: Patents & Royalties. Dudley:GlaxoSmithKline: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Ayasdi, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership; Ontomics, Inc.: Equity Ownership; AstraZeneca: Speakers Bureau; NuMedii, Inc.: Patents & Royalties; Personalis: Patents & Royalties.

scholarly journals Long-Term Carfilzomib for High-Risk Patients with Newly Diagnosed Multiple Myeloma: A Pooled Analysis of Two Phase 1/2 Studies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3240-3240
Author(s):  
Roberto Mina ◽  
Alessandra Larocca ◽  
Maria Teresa Petrucci ◽  
Gianluca Gaidano ◽  
Stelvio Ballanti ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Board ◽  
Induction Phase ◽  
Advisory Committees ◽  
High Risk Patients ◽  
Risk Patients ◽  
Standard Risk

Abstract INTRODUCTION: High-risk cytogenetic abnormalities, such as del(17p), t(4;14), and/or t(14;16), are associated to an unfavorable prognosis. Several trials investigating current approved regimens have shown that high-risk multiple myeloma (MM) patients have shorter progression-free survival (PFS) and overall survival (OS) as compared to standard-risk patients. Carfilzomib, a second generation proteasome inhibitor, demonstrated to be able to improve the survival of high-risk MM patients in the relapse setting. Here we present a pooled analysis of two phase 1/2 studies to investigate the role of carfilzomib in high-risk, newly diagnosed (ND) MM patients. METHODS: Transplant ineligible patients with NDMM enrolled in the IST-CAR 561 and IST-CAR 506 studies were pooled together and analyzed. All patients received 9 28-day induction cycles of carfilzomib, either 70 mg/m2 once weekly (IST-CAR 561) or 36 mg/m2 twice weekly (IST-CAR 506), combined with weekly cyclophosphamide (300 mg/m2) and dexamethasone (40 mg) (CCyd). After the induction phase, patients proceeded to maintenance with single-agent carfilzomib until progressive disease or intolerable toxicity. The primary objective was to compare response to treatment, PFS, PFS-2 and OS in standard versus high-risk FISH, defined by the presence of del(17p), t(4;14), and/or t(14;16). A 15% cut-off point was used for detection of translocation [t(4;14) and t(14;16)] and 10% for detection of del(17p). RESULTS: 121 NDMM patients were enrolled in the IST-CAR 561 (n=63) and in the IST-CAR 506 (n=58) study. Cytogenetic data were available in 94 patients: 37 (31%) had high-risk chromosomal abnormalities by FISH, including 10% of patients with t(4;14), 3% with t(14;16) and 18% with del(17p), while 57 patients (47%) were classified as standard-risk. After the induction phase, no difference in terms of overall response rate (ORR; 86% vs. 92%; p=0.52) and at least near complete response (39% vs. 41%; p=1) was observed between standard and high-risk patients. After a median follow-up of 39 months, median PFS from enrollment was NR in standard-risk patients and 27.8 months in high-risk ones (HR: 0.76; p=0.38) (Figure 1); at 3 years, 52% and 43% of patients, respectively, were alive and free from progression. The PFS benefit for the comparison between standard and high-risk patients was more pronounced in patients who received once weekly carfilzomib at 70 mg/m2, (median: NR vs. 39.6 months; HR: 0.78, p=0.63) as compared to those treated with twice weekly carfilzomib at 36 mg/m2 (median: NR vs. 24.2 months; HR: 0.52, p=0.12). Median PFS-2 from enrollment was NR in standard-risk patients and 44.1 months in high-risk ones (HR: 0.66; p=0.26), without significant differences in the once weekly (median, NR vs. 39.6; p=0.27) and the twice weekly group (median; NR vs. 44.1; p=0.63). Median OS from enrollment was NR in standard-risk patients and 47.5 months in high-risk ones (HR:0.71; p=0.36) (Figure 1). In patients who received once weekly carfilzomib, median OS was NR and 47.5 months (HR:0.66, p=0.48) in standard and high-risk patients, respectively, while median OS in the twice weekly group was NR in standard-risk patients and 44.1 months (HR:0.73; p=0.55) in high-risk ones. CONCLUSION: In transplant ineligible patients with NDMM, carfilzomib combined with cyclophosphamide and dexamethasone as initial treatment mitigated the poor prognosis of high-risk FISH in terms of PFS, PFS-2 and OS. The median PFS of high-risk patients treated with CCyd compares favorably with those reported with current standard of care. As compared to twice weekly carfilzomib at 36 mg/m2, once weekly carfilzomib, at the dose of 70 mg/m2, confirmed to be effective in high-risk patients. These data support the use of carfilzomib for the treatment of high-risk NDMM patients. Figure 1. Figure 1. Disclosures Larocca: Janssen-Cilag: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Petrucci:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Gaidano:AbbVie: Other: Advisory Board; Janssen: Other: Advisory Board, Speakers Bureau. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Offidani:Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caravita di Toritto:Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Amgen: Other: Advisory Board; Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding; Takeda: Other: Advisory Board. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.

scholarly journals The Prognostic Power of Gene Expression Profiling with Cytogentics and Routinely Acquired Serum Markers: SKY92 Combined with Revised ISS

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Rowan Kuiper ◽  
Mark van Duin ◽  
Martin H Van Vliet ◽  
Erik H Van Beers ◽  
Berna Berna Beverloo ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Risk ◽  
Ensembl Gene ◽  
Private Company ◽  
Advisory Committees ◽  
High Risk Patients ◽  
Risk Patients ◽  
Standard Risk

Background Updating prognostic models for multiple myeloma is important in the context of changing treatment options. Previously we have described the value of the prognostic marker SKY92, which identifies high-risk multiple myeloma patients, as well as the value of the combined SKY92-ISS marker. With the introduction of revised ISS, it is of interest to evaluate the value of the updated combination of SKY92 with R-ISS. Within the HOVON87/NMSG18 trial, stratification into 3 groups was described: high-risk: 11% SKY92 high-risk (HR) + R-ISS II-III, low-risk: 15% SKY92 standard risk (SR) + R-ISS I and intermediate risk (74%, other). The 3-year PFS rates were 54% (95%CI: 38-77%), 27% (95%CI: 21-37%) and 7% (95%CI: 1-46%) for SKY-RISS I, II and III, respectively (p &lt; 0.001). The 3-yr OS rates for SKY-RISS I to III were 88%, 66% and 26% (p=6×10-7). Here we describe the validation of SKY92-RISS in the CoMMpass dataset. Methods SKY92 was determined using RNA-seq data available from the CoMMpass dataset. Briefly, the SKY92 score was obtained as a weighted summation of the expression given by the available Ensembl gene IDs, corresponding to the probe sets of the SKY92 classifier. Renormalization of the original SKY92 discovery data (HOVON65/GMMG-HD4) allowing a direct remodeling between the Affymetrix probe-set expressions (i.e. SKY92) and RNAseq Ensembl gene IDs. Only Ensembl gene IDs with an average log2 expression &gt;8 were used. Revised ISS status was determined as described. For optimal comparison to the discovery cohort of the HOVON87/NMSG18 trial, the analysis was limited to 93 patients older than 65 years in the CoMMpass data set, that did not receive transplant, and for whom RNA-Seq at diagnosis, R-ISS and follow-up data were available. Results The median follow-up is 41 months. SKY92 identified 24 high-risk patients (24/93: 26%). The 3-yr PFS and OS rates of standard-risk patients were 49% and 80% respectively, compared to 23% and 44% for high-risk, resulting in a significant log rank test (p &lt; 0.005). The R-ISS classified patients into the low-risk R-ISS I (24% of patients), intermediate-risk R-ISS II (63%) and high-risk R-ISS III (13%). The 3-yr PFS rates were 76% (RISS I), 33% (RISS II) and 33% (RISS III); for OS: 100% (RISS I), 68% (RISS II) and 33% (RISS III; PFS, p = 0.07; OS, p &lt; 0.001). SKY92 and R-ISS were independent prognostic factors in terms of OS and PFS. The SKY-RISS classification resulted in 20% low-, 61% intermediate- and 18% high-risk patients (Figure 1). The 3-yr PFS rates were 81% (95%CI: 64-100%), 42% (95%CI: 30-59%) and 12% (95%CI: 3-44%; p &lt; 0.001) and 3-yr OS rates were 100% (95%CI: 100-100%), 77% (95%CI: 66-89%) and 32% (95%CI: 16-61%; p &lt;0.001). Out of 69 patients classed as standard risk using the SKY92 classifier (80% 3-yr OS rate), 17 and 52 were classified as SKY-RISS I and II, respectively, resulting in a 3-yr survival rate of 100% and 74%, respectively. In contrast, out of 24 SKY92 HR patients (44% 3 yr OS rate), 5 were classified as SKY-RISS II (100% alive at 3 years) with the remainder true high-risk patients (32% alive at 3 years). Out of 12 RISS III patients (3-yr OS, 33%), 5 were classified as SKY-RISS II (3-yr OS: 60%) and 7 as SKY-RISS III (3-yr OS: 14%). Conclusion This study demonstrates the value of gene expression profiling - SKY92 - alongside revised ISS. They form a solid combination, improving on either marker separately. Both models combined clearly identified more high-risk patients correctly, whilst also placing low risk patients into a more appropriate risk category. This was shown in the discovery set and was subsequently applied to an independent set, confirming the validity and usability of the SKY-RISS. Disclosures Kuiper: SkylineDx: Current Employment, Current equity holder in private company. Van Vliet:SkylineDx: Current Employment, Current equity holder in private company. Van Beers:SkylineDx: Ended employment in the past 24 months. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; 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. Broijl:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

scholarly journals Efficacy and Safety of Carfilzomib at 56mg/m2 with Cyclophosphamide and Dexamethasone (K56Cd) in Newly Diagnosed Multiple Myeloma Patients Followed By ASCT or K56Cd Consolidation: Initial Results of the Phase 2 Cardamon Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 861-861 ◽  
Author(s):  
Kwee Yong ◽  
Rakesh Popat ◽  
William Wilson ◽  
Gavin Pang ◽  
Richard Jenner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Patients ◽  
Standard Risk

Introduction: Carfilzomib (20/36mg/m2) triplets with Lenalidomide-Dexamethasone (KRd), or Cyclophosphamide-Dexamethasone (KCd) are safe and effective in patients with newly diagnosed multiple myeloma(NDMM). The higher dose of 56mg/m2 is effective as a doublet with Dexamethasone in the relapsed setting, but there is limited data on this dose in triplet combinations in the frontline setting. Aim: The CARDAMON study evaluated KCd with bi-weekly carfilzomib (56mg/m2) as induction in NDMM patients, and the benefit of ASCT versus K56Cd consolidation followed by carfilzomib maintenance. Co-primary endpoints were major response (≥VGPR rate) to 4 induction cycles of K56Cd, and 2-year PFS for ASCT versus K56Cd consolidation. Here we report interim analysis of the first primary endpoint of ≥VGPR rate to K56Cd induction. Methods: Transplant eligible ND patients received 4 x 28d cycles of K56Cd (carfilzomib:20/56mg/m2, IV d1, 2, 8, 9, 15, 16, cyclophosphamide 500mg orally d1, 8, 15 and dexamethasone 20mg d1, 2, 8, 9, 15, 16). Responding patients with a successful stem cell harvest (PBSCH) were randomised to autologous stem cell transplant (ASCT) or 4 more cycles of K56Cd as consolidation, followed by 18 months carfilzomib maintenance (K56 days 1, 8, 15) for both arms. Trial recruitment completed in July 2019. Response was assessed by IMWG criteria; all patients had MRD testing by multi-parameter flow cytometry (10-5) after PBSCH. Adverse risk genetics was any one of t(4;14), t(14;16), t(14,20) or del(17p). Results: 281 pts were registered between 06/2015 and 07/2019; we report outcomes for 252 patients who either completed induction or came off study before end of induction. Median age was 58yrs(33-74), 91% ECOG 0-1, 45.2% ISS I, 24.7% adverse risk (48.5% when including 1p/1q+). Best response at end of induction or after PBSCH (n=250) was: ≥VGPR 59.2%, ORR 87.6%. ≥VGPR rate in adverse risk patients was 53.4% vs 61.9% in standard risk(SR), (p=0.25), ORR was similar: adverse risk, 87.9% vs standard risk, 88.1%. Post-PBSCH, 24.1% of patients were MRD-negative (patients who were withdrawn due to insufficient induction response or toxicity and those with an inconclusive result were grouped with the MRD-positive). Of 19 patients in sCR/CR, 9 were MRD-negative(47.4%) while 40/110 (36.4%) of VGPR patients were MRD-negative. MRD-negative rates in adverse and standard risk patients were 22.8% and 24.7% respectively. 10 patients progressed during or at end of induction, and 12 were withdrawn for toxicity. There were 4 deaths during induction, one from myocardial infarction, the other 3 from cardiac arrest, associated with bronchopneumonia and sepsis. During induction, 114 serious adverse events (SAEs) were reported in 72/252 patients, notable ones were thrombotic microangiopathy (2), grade 3 cardiac ischaemia (4), infection (16.3%, mainly lung), renal impairment (6), G3 hypertension (3), thromboembolism(2). Specific guidance for hypertension management was incorporated. 25% of patients are currently reported to have received a dose modification during induction. Full details of adverse events and dose intensity will be presented at the meeting. Conclusion: K56Cd is an effective induction regimen in NDMM patients, and has equivalent MRD negative rates in adverse and standard risk disease. The SAE profile is in keeping with published safety data with carfilzomib. Disclosures Yong: Sanofi: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Autolus: Consultancy; Janssen: Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Popat:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria; Takeda: Honoraria, Other: travel, accommodations, expenses. Ramasamy:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; NAPP Pharmaceuticals Ltd.: Research Funding; Janssen-Cilag Ltd.: Research Funding; Oncopeptides and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chapman:Takeda: Honoraria. Benjamin:Allogene: Research Funding; Gilead: Honoraria; Novartis: Honoraria; Pfizer: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Servier: Research Funding; Eusapharm: Consultancy. Owen:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel/ meeting support. OffLabel Disclosure: Carfilzomib is used with cyclophosphamide as 1st line treatment for myeloma

Validation of the EMC92/SKY92 Signature in HOVON-87/Nmsg-18: Gene Expression Based Prognostication Is Applicable in Elderly Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2967-2967
Author(s):  
Mark van Duin ◽  
Rowan Kuiper ◽  
Martin van Vliet ◽  
Annemiek Broijl ◽  
Leonie de Best ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Univariate Analysis ◽  
Low Risk ◽  
Advisory Committees ◽  
Hazard Ratios ◽  
Risk Patients ◽  
Standard Risk

Abstract Improved prognostication is required for multiple myeloma (MM). So far, marker development has been based on clinical trials with a study population predominantly younger than 65 years. However, the median age of newly diagnosed MM patients is 66 years old. Based on gene expression profiles of the HOVON-65/GMMG-HD4 dataset, we previously developed the EMC92 prognostic signature, consisting of 92 probe sets for improved prognostication in MM. The EMC92 was validated in the MRC-IX, TT2, TT3 and APEX datasets. These studies were mostly aimed at younger patients with a median age of 57 years. The EMC92 signature was subsequently developed for clinical use as part of the MMprofiler, and termed the SKY92 signature. To assess the validity of the SKY92 signature in older MM patients, we used the HOVON-87/NMSG-18 study, in which induction therapy with melphalan, prednisone and thalidomide, followed by thalidomide maintenance, was compared with melphalan, prednisone and lenalidomide, followed by lenalidomide maintenance (MPT-T vs. MPR-R). The median age of all patients included in this trial was 73 years, with 34% of patients 76 years or older. The median follow up of the patients still alive was 39 months. Of 143 patients both gene expression profiling and clinical data were available (median age 73; 30% ≥76; n=83 MPT-T; n=60 MPR-R). The MMprofiler was used to obtain SKY92 scores, classifying a patient as high risk or standard risk (MMprofiler- CE IVD assay, performed according to the manufacturers' instructions for use at the SkylineDx reference lab, Rotterdam, The Netherlands). The association between survival and the SKY92 signature was evaluated using Cox regression analysis. Kaplan-Meier curves were constructed for visualization. Using the SKY92 signature 22/143 patients were identified as high risk (15.4%). The median overall survival (OS) for high risk patients was 21 months, compared to 53 months for standard risk patients (hazard ratio (HR): 2.9 (95% confidence interval (CI): 1.6-5.4; p=5.6 x 10-4)). The median progression free survival (PFS) in the high risk and standard risk groups were 12 months and 23 months, respectively (HR: 2.2 (95% CI: 1.4-3.7; p=1.2 x 10-3)). In this subset of 143 patients, deletion of 17p (del17p) and gain of 1q (gain1q) were also adversely associated with OS in a univariate analysis. Including SKY92, del(17p) and gain(1q) in a multivariate model demonstrated that SKY92 and del(17p) remained significantly associated with OS (subset of 143 (n=101) with all data known; Table 1). We previously developed the combination of ISS with SKY92: low risk (ISS I-SKY92 standard risk (SR)), intermediate-low (ISS II-SKY92 SR), intermediate-high (ISS III-SKY92 SR) and high risk (ISS I-III, SKY92 high risk; Kuiper et al., ASH 2014, #3358). The Cox model for this combined marker has a p-value for the likelihood ratio test of p=3 x 10-3 for OS (Figure 2) and p=0.016 for PFS. In conclusion, the SKY92 signature (MMprofiler) is a useful prognostic marker to identify a high-risk subgroup in the elderly population. Figure 1. Performance of the SKY92 signature in the HOVON-87/NMSG-18 study. Red line indicates high risk patients (n=22), blue line indicates standard risk patients (n=121). PFS (A); OS (B). Figure 1. Performance of the SKY92 signature in the HOVON-87/NMSG-18 study. Red line indicates high risk patients (n=22), blue line indicates standard risk patients (n=121). PFS (A); OS (B). Table 1. SKY92 in relation to FISH markers in the HOVON-87/NMSG-18 (Hazard ratios (HR), 95% confidence intervals (CI) and p-values (2-sided; p) for Cox proportional hazards analysis). The multivariate analysis (bottom) was performed using the markers significant in the univariate analysis (top). Bold: p<0.05, pos: positive, neg: negative and na: not available. Table 1. SKY92 in relation to FISH markers in the HOVON-87/NMSG-18 (Hazard ratios (HR), 95% confidence intervals (CI) and p-values (2-sided; p) for Cox proportional hazards analysis). The multivariate analysis (bottom) was performed using the markers significant in the univariate analysis (top). Bold: p<0.05, pos: positive, neg: negative and na: not available. Figure 2. Combining ISS with SKY92. Groups are defined in the text. Hazard ratios of the individual groups are given relative to the low risk group. Figure 2. Combining ISS with SKY92. Groups are defined in the text. Hazard ratios of the individual groups are given relative to the low risk group. Disclosures Kuiper: SkylineDx: Employment. van Vliet:SkylineDx: Employment. Broijl:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. de Best:SkylineDx: Employment. van Beers:SkylineDx: Employment. Bosman:SkylineDx: Employment. Dumee:SkylineDx: Employment. van den Bosch:SkylineDx: Employment. Waage:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Zweegman:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Research Funding.

Use of Gene Expression Profiling May Predict Clinical Outcomes in Newly Diagnosed Multiple Myeloma Patients in a Standard of Care Setting

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5390-5390
Author(s):  
Catherine M Claussen ◽  
Tammy Chuang ◽  
Jatin Shah ◽  
Hans Lee ◽  
Nina Shah ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Clinical Outcomes ◽  
Expression Profiling ◽  
Research Funding ◽  
Complete Response ◽  
Low Risk ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Patients

Abstract Introduction: Multiple myeloma (MM) is characterized by malignant plasma cell (PC) proliferation. Gene expression profiling (GEP) of CD138+ bone marrow PC has emerged as a new way to identify patients with worse clinical outcomes so that an individualized treatment approach can be undertaken in the clinic. The majority of data with GEP come from clinical trials. We aimed to evaluate the use of GEP in a standard clinical setting. Methods: We retrospectively searched our database of newly diagnosed MM patients with GEP completed prior to initial treatment. 35MM patients from April 2014 until June 2015 were identified and included in our analysis. GEP was performed through MyPRS® (Signal Genetics, Little Rock, AR). Fisher's exact test was used to evaluate the associations between complete response status and other categorical variables. The Wilcoxon rank sum test was used to evaluate the difference in continuous variables between patients that achieved a complete remission after 6 months of initial treatment and those who did not. Responses were assessed using IMWG criteria. Results: Median age was 60 (38-76). Patients presented with lytic lesions (60%), anemia (80%), kidney dysfunction (11%) and hypercalcemia (20%). All patients with known initial therapy were treated with bortezomib (n=29) or carfilzomib (n=1) based therapy. 10 patients had upfront autologous stem cell transplant. 18 patients had available response at 6 months. 37% (n=13) of patients were characterized as high risk by GEP, of which 46% (n=6) had the proliferation (PR) subtype. Most low risk patients had hyperdiploidy (HY) subtype (n=12, 55%). Patients with high risk GEP presented more often with complex karyotypes whereas low risk GEP patients most often had normal or hyperdiploid karyotypes. FISH abnormalities that are usually present in high risk myeloma were also present in patients classified as GEP low risk (Table 1). At 6 months after diagnosis, lower baseline total protein, serum M-spike, serum free light chain ratio and serum kappa light chain levels were significantly associated with achieving a stringent complete response (sCR) (p<0.05). High risk patients were more likely to achieve a CR (n= 6/10, 60%) than low risk patients (n=5/16, 31%) at 6 months. Despite this, high risk patients seemed more likely to lose CR and relapse or die. Within one year of diagnosis, one patient relapsed after achieving a VGPR (high risk, PR subtype) and one patient died due to MM progressive disease after achieving an sCR (high risk, CD-1 subtype) (Table 1). Conclusion: In a standard clinical setting, GEP seems to identify MM patients that are at higher risk of adverse clinical outcomes early after diagnosis. GEP may be an adjunct to cytogenetics/FISH in MM risk stratification, as high risk FISH abnormalities were also found in low risk GEP patients. Larger studies with longer follow up may help address the particular role of GEP in the individualized treatment of MM. Figure 1. Figure 1. Disclosures Orlowski: Array BioPharma: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding.

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