A Prospective, Multicenter, Randomized, Trial of Bortezomib/Melphalan/Prednisone (VMP) Versus Bortezomib/Thalidomide/Prednisone (VTP) as Induction Therapy Followed by Maintenance Treatment with Bortezomib/Thalidomide (VT) Versus Bortezomib/Prednisone (VP) in Elderly Untreated Patients with Multiple Myeloma Older Than 65 Years.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3-3 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Albert Oriol ◽  
Joaquin Martinez ◽  
M Teresa Cibeira ◽  
Norma C. Gutiérrez ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Risk Group ◽  
High Risk Group ◽  
Cardiac Events ◽  
Advisory Committees ◽  
To Receive ◽  
Standard Risk

Abstract Abstract 3 In elderly pts with newly diagnosed MM, the VISTA trial has demonstrated that the combination of bortezomib plus melphalan – prednisone (VMP) is significantly superior to MP alone. However, it remains to be elucidated which agent is the optimal partner for bortezomib: an alkylating agent or an immunomodulatory drug. In order to answer this question, Spanish Myeloma Group activated a phase III trial comparing VMP versus VTP (T for thalidomide) as induction therapy. To evaluate if the treatment regimen could be further optimized by decreasing the toxicity while maintaining efficacy, the intensity of both schedules of induction was reduced as compared with the VISTA regimen but supplemented with maintenance therapy. Between April 2005 and October 2008, 260 pts were randomized to receive 6 cycles of VMP vs VTP as induction therapy followed by maintenance with VT vs VP for up to three yrs. In the VMP arm pts received bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, 11; 22, 25, 29 and 32) for one 6-week cycle, followed by once weekly (days 1, 8, 15 and 22) for five 5-week cycles in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. In the VTP arm pts received the same bortezomib and prednisone, but instead of melphalan they received thalidomide at a dose of 100 mg daily. Following the 6 cycles of induction, pts moved into maintenance that consisted in a conventional cycle of bortezomib, 1.3 mg/m2 twice weekly (days 1, 4, 8, 11) administered every three months in combination with either continuous thalidomide, 50 mg daily (VT) or prednisone, 50 mg on alternate days (VP). 253 pts are evaluable for response to induction; 125 were assigned to receive VMP and 128 to VTP. Regarding baseline characteristics, both arms were well balanced. Response rate to induction therapy was similar in both arms: ≥ PR in 81 and 79% of pts treated with VMP and VTP respectively, with a CR rate of 22% vs 27% (p=NS) and CR+nCR of 36% in both arms. Only two pts progressed under induction treatment in each arm. After a median follow-up of 22m (8-40), there weren't significant differences in terms of 2-y TTP (VMP 75% vs VTP 70%), PFS (VMP 71% vs VTP 61%) and OS (VMP 81% vs VTP 84%). 178 pts were randomized to maintenance and 143 are evaluable for efficacy. Overall, maintenance therapy was able to increase the CR rate from 25% (mean obtained after induction therapy) up to 42%, with no significant differences between VT and VP arms (46 and 38%). After a median duration of maintenance of 13 m there is a trend in favour of VT in terms of 1-y TTP (84% vs 71%; p=0.05), without differences in 1-y OS (92% for VT vs 89% for VP). 27 pts presented high-risk cytogenetic abnormalities (CA) ((4;14)t, (14;16)t, del[17p]); the CR rate was similar in this high-risk group as compared with standard risk group (26% vs 25% after induction and 42% after maintenance in both groups). There aren't differences between high-risk and standard-risk pts in the 2-y TTP (74% vs 73%) and 2-y OS (77% vs 81%) from inclusion; however, there is a trend to lower 1 y-TTP from the time to randomization to maintenance for the high-risk group compared to the standard-risk (68% vs 79%) without differences in 1 y-OS (90% vs 93%). Regarding toxicity, during the induction therapy, VMP resulted in higher incidence of ≥G3 neutropenia than VTP (37 vs 21%) and this translated into more ≥G3 infections (7 vs <1%); 8,5% of pts receiving VTP developed ≥G3 cardiac events (cardiac failure (5), atrial fibrillation (2), hypotension (2), heart attack (1) and AV blockage (1)). The incidence of ≥G3 PN was 5% in VMP and 9% in VTP (p=NS). During maintenance therapy, the most relevant ≥G3 toxicities included: cardiac events in 2 pts in VT (supraventricular arritmia (1) and heart attack (1)) vs 1 in VP (cardiac failure); G-I events in 4 pts in VT vs 1 in VP; finally, only one patient in VT arm died during the maintenance therapy due to sepsis. In summary the current results indicate that: 1. both modified induction schedules (VMP and VTP) are highly effective with similar ORR and CR rates, but a clear different toxicity profile (more neutropenia, but less cardiac toxiciety and PN with VMP); 2. maintenance therapy with either VT and VP markedly improve the quality of responses with a good safety profile; and finally 3. the combination of these induction and maintenance schedules seems to overcome the poor prognosis of high-risk CA in elderly MM patients. Disclosures: Mateos: Janssen Cilag: Honoraria, Speakers Bureau; Celgene corporation: Honoraria, Speakers Bureau. Off Label Use: VTP is not approved for the treatment of untreated MM patients. Cibeira:Jansen-Cilag: Honoraria; Celgene: Honoraria. Gutiérrez:Janssen Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen-Cilag: Honoraria; Celgene: Honoraria. de Arriba:Janssen-Cilag: Honoraria; Celgene: Honoraria. San-Miguel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen–Cilag: Honoraria, 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.

scholarly journals Mutation Landscape and Prognostic Correlates of ASXL1 Variants in Primary and Secondary Myelofibrosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2578-2578
Author(s):  
Giacomo Coltro ◽  
Paola Guglielmelli ◽  
Giada Rotunno ◽  
Carmela Mannarelli ◽  
Chiara Maccari ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Prognostic Impact ◽  
Driver Genes ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Significant Difference

Abstract Introduction: Myelofibrosis (MF), whether primary (PMF) or secondary (SMF) to polycythemia vera or essential thrombocytemia, is characterized by a complex and partially undeciphered molecular architecture. Besides mutations in driver genes (JAK2, CALR, MPL), somatic mutations in selected myeloid-associated genes have been shown to impact prognosis of MF patients (pts). Among these, ASXL1 mutations (ASXL1MTs) are associated with poor outcomes in myeloid malignancies including PMF, where they are included in the category of "high molecular risk" (HMR) mutations along with EZH2MTs, IDH1/2MTs, and SRSF2MTs (Vannucchi AM, Leukemia 2013). However, a recent study (Luque Paz D, Blood Adv 2021) questioned the value of ASXL1MTs in MF. The current study aimed at further characterizing the prognostic role of ASXL1MTs in MF. Methods: After IRB approval, pts with WHO-defined MF were included in the study. Mutational analysis by targeted NGS was performed as previously described (Guglielmelli P, JCO 2017). All deposited variants were manually curated to assess pathogenicity. In this study, we also used the molecular model proposed by Luque Paz et al. that identifies 4 genetic groups: TP53MT; High-risk (≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1/2); ASXL1MT-only; and "Others". Results: A total of 525 pts were included in the study, including 331 (63%) PMF and 194 (37%) SMF. Median age at diagnosis was 89 (18-90) years, 314 (60%) were male. The median follow-up time was 80 (98% CI, 68-90) months. Overall, 324 (62%) pts were JAK2MT, 126 (24%) CALRMT, 24 (5%) MPLMT, 40 (8%) triple negative (TN), and 11 (2%) double mutated. Among non-driver genes, ASXL1MTs were found in 158 (30%) pts, EZH2MTs in 45 (9%), SRSF2MTs in 37 (7%), NRASMTs in 30 (6%) U2AF1MTs in 27 (5%), TP53MTs and CBLMTs in 25 (5%) each, IDH1/2 MTs in 18 (3%), and KRAS MTs in 15 (3%). Pts in the HMR category were 125 (38%) in PMF and 63 (32%) in SMF. According to the above model, distribution of pts was as follows: TP53MT n=25 (5%), High-risk n=137 (26%), ASXL1MT-only n=64 (12%), and Others n=299 (57%). Pts in the TP53MT and ASXL1MT-only groups were more likely to be diagnosed with SMF compared to pts in the High-risk and Others groups (44% and 48% vs 28% and 38%, respectively). In addition, the High-risk group was enriched in TN pts (16%), while CALRMTs were more common in the ASXL1MT-only and Others compared to the TP53MT and High-risk groups (25% and 27% vs 12% and 18%, respectively). In univariate analysis, the TP53MT and High-risk groups were associated with the worst overall survival (OS), with median values of 38 (14-110) and 55 (45-85) months (P=.0039), respectively (Fig 1A). Albeit remarkably better, the OS of pts in the ASXL1MT-only group was inferior compared to pts in the Others group (median 124 [91-156] vs 193 [142-NR] months; P=.0118) (Fig 1A). We then analyzed separately PMF and SMF cohorts. In the former, the TP53MT and High-risk groups remained associated with the worst OS (median 58 [20-126] vs 55 [36-85] months), although with no significant difference, likely due to the low frequency (4%) of TP53MTs mutations in PMF (Fig 1B). Concurrently, the negative prognostic impact of the ASXL1MT-only group was confirmed in comparison to the Others group (median 103 [78-NR] vs 320 [178-NR] months; P=.0170). In pts with SMF, while the TP53MT group (6%) had by far the worst OS (median 13 [6-NR] months), the OS of the ASXL1MT-only group (median 141 [56-171] months) was comparable to that of the Others group (median 131 [106-NR] months; P=.5188) and not different from the High-risk group (median 58 [45-174] months; P=.3606) (Fig 1C). In a further analysis including only pts in the High-risk group, ASXL1MTs were found in 62% and 63% of patients with PMF and SMF, respectively. In survival analysis, the presence of ASXL1MTs was associated with an increased risk of death only in PMF (median OS 47 [31-73] vs 102 [34-317] months; P=.0240), unlike in SMF (median OS 90 [47-174] vs 25 [16-338] months; P=.3296) (Fig 1D-E). Conclusion: In the current study, we critically re-addressed the prognostic impact of ASXL1MTs by applying a genetic model recently developed by Luque Paz et al. to our cohort of molecularly annotated, WHO-defined MF pts. Overall, our results confirm that ASXL1MTs -even in the absence of other co-occurring high-risk mutations- harbor a negative prognostic impact mainly in PMF. These findings also reinforce the idea that PMF and SMF represent two different biological entities. Figure 1 Figure 1. Disclosures Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Bortezomib, Lenalidomide and Dexamethasone (VRD) Followed By Autologous Stem Cell Transplant for Newly Diagnosed Multiple Myeloma; The Mayo Clinic Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2147-2147
Author(s):  
M Hasib Sidiqi ◽  
Mohammed A Aljama ◽  
Angela Dispenzieri ◽  
Eli Muchtar ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
Advisory Committees ◽  
Post Transplant ◽  
Standard Risk

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:KITE: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.

scholarly journals Prognostic and Biologic Significance of Long Non-Coding RNA (lncRNA) Profiling in Cytogenetically Abnormal Acute Myeloid Leukemia (CA-AML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2767-2767
Author(s):  
Dimitrios Papaioannou ◽  
Deedra Nicolet ◽  
Xiaoqing Rong-Mullins ◽  
Krzysztof Mrózek ◽  
Jessica Kohlschmidt ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Group Status ◽  
Advisory Committees ◽  
Expression Levels ◽  
Pathway Analyses

Abstract Introduction: Aberrant expression levels of lncRNAs have been shown to independently associate with outcome of younger and older patients (pts) with cytogenetically normal AML. However, the prognostic and biologic significance of lncRNA expression in CA-AML pts have not been extensively studied. Methods: We performed whole transcriptome profiling (RNA-seq) in 469 pts with de novo CA-AML. Cytogenetic analyses were performed in institutional laboratories and the results were reviewed centrally. All pts were treated on frontline Cancer and Leukemia Group B (CALGB)/Alliance protocols. Results: To evaluate the prognostic significance of lncRNA expression in CA-AML, we analyzed RNA-seq data of 469 pts by applying a machine learning algorithm-based approach. As CA-AML pts constitute a heterogeneous group, we first determined which other clinical and molecular parameters were prognostic [i.e., associated with event-free survival (EFS)] in our dataset. Among the parameters tested, the European LeukemiaNet (ELN) Risk Group status and age group [i.e., younger than 60 years (y) or aged 60 y and older] significantly associated with clinical outcome of CA-AML pts. Next, we individually identified each lncRNA that associated with EFS while adjusting for ELN Risk Group and age group. We conducted random forest analyses to select the prognostic lncRNAs, whose combined expression levels could generate an effective outcome predictor for CA-AML pts. For each step of the random forest analyses, a bootstrap technique was applied; a simple random sample of pts was drawn which served as the training set and the out-of-sample pts were used as the independent validation set. We identified 55 prognostic lncRNAs and used their expression levels to separate our CA-AML cohort into a lncRNA low-risk (n=161) and a lncRNA high-risk (n=308) group. With regard to clinical characteristics, pts in the lncRNA low-risk group were younger (P<.001) and had lower platelet counts (P<.001) and higher white blood cell counts (P=.01) than pts in the lncRNA high-risk group. Concerning cytogenetic abnormalities, pts in the low-risk group more often had core-binding factor translocations or inversions (P<.001) and less often complex karyotypes (P<.001) than pts in the high-risk group. Pts in the lncRNA low-risk group had higher complete remission (CR) rates than pts in the high-risk group (91% vs 48%, P<.001). LncRNA low-risk group status also associated with longer disease-free survival (DFS; 5-y rates 49% vs 12%, P<.001), overall survival (OS; 5-y rates: 58% vs 14%, P<.001) and EFS (5-y rates: 45% vs 6%, P<.001). With regard to the accuracy of outcome prediction, the lncRNA risk classification had a C-index of 0.73, which compares favorably with other prognostic classifiers of AML pts. In multivariable analyses, lncRNA low-risk status was an independent marker for higher CR rates, as well as for longer DFS, OS and EFS (P<.001 in all comparisons), after adjusting for other covariates. Finally, we examined the prognostic value of the lncRNA risk classification within the Favorable and Intermediate ELN Groups of our dataset, for which lncRNA risk groups had adequate pt numbers. Among pts in ELN Favorable Group, lncRNA low-risk pts (n=128) had higher CR rates (P=.003) and longer DFS (P<.001), OS (P<.001) and EFS (P<.001) than lncRNA high-risk pts (n=32). Similarly, in the ELN Intermediate Group (n=85), lncRNA low-risk group status (n=28) associated with higher CR rates (P=.01), longer OS (P=.01) and EFS (P=.005) and a trend for longer DFS (P=.08). To gain biological insights, we examined the molecular pathways regulated by the 55 prognostic lncRNAs. To minimize the confounding effects of differences in the concurrent cytogenetic abnormalities, we restricted these analyses to the ELN Favorable Group. We identified approximately 900 transcripts that were differentially expressed between lncRNA low- and high-risk pts. DAVID pathway analyses showed enrichment of genes involved in the processes of phosphorylation, acetylation and RNA-binding. Ingenuity pathway analyses of up-stream regulators identified aberrant activity of homeobox genes such as MEIS1, HOXA9 and HOXA10 in the lncRNA low-risk group and other transcription factors such as MYC, FOSB and JUN in the high-risk group. Conclusion: We conclude that lncRNA profiling provides meaningful prognostic and biologic information in CA-AML pts. Disclosures Kolitz: Magellan Health: Consultancy, Honoraria. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Stone:Cornerstone: Consultancy; Astellas: Consultancy; Orsenix: Consultancy; Merck: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Novartis: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Fujifilm: Consultancy; Ono: Consultancy; Jazz: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy; AbbVie: Consultancy; Agios: Consultancy, Research Funding. Uy:Curis: Consultancy; GlycoMimetics: Consultancy. Wang:Amgen: Consultancy; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau. Stock:Jazz Pharmaceuticals: Consultancy.

A Randomized Comparison Of Maintenance Therapy With Subcutaneous Rituximab For 2 Years Versus Until Progression In Patients With Indolent Non-Hodgkin’s Lymphoma: Interim Safety Data From The Mabcute Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3052-3052 ◽  
Author(s):  
Simon Rule ◽  
Javier Briones ◽  
Angelo Michele Carella ◽  
Olivier Casasnovas ◽  
Wolney Gois Barreto ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Hodgkin’S Lymphoma ◽  
Safety Analysis ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
To Receive

Abstract Background Rituximab is part of the standard induction and maintenance therapy for most patients with first-line or relapsing indolent non-Hodgkin's lymphoma (iNHL). However, the optimal duration of maintenance is still to be defined. The MABCUTE trial is designed to evaluate the efficacy and safety of maintenance therapy with subcutaneous (SC) rituximab until disease progression (PD). Patients with relapsed or refractory iNHL, who respond to induction and an initial 2 years' maintenance therapy, are randomized to receive additional maintenance therapy or observation. Here we report the findings of a planned interim safety analysis in the first 231 patients enrolled in the trial. Methods MABCUTE (NCT01461928) is an ongoing multicenter, randomized, parallel-group, phase IIIb study that started in December 2011. Eligible patients were aged ≥18 years with relapsed or refractory CD20+ iNHL (histologically confirmed) following ≥1 line of immunotherapy and/or chemotherapy and/or radiotherapy. Patients were scheduled to receive induction therapy consisting of rituximab every 3–4 weeks for 8 cycles (intravenous [IV] 375 mg/m2 in cycle 1 then SC 1400 mg in cycles 2–8) and 6–8 cycles of standard chemotherapy. Patients who achieved a complete or partial response (CR/PR) continued into standard maintenance (rituximab SC 1400 mg every 8 weeks for 24 months). Upon completion of standard maintenance, patients in sustained CR/PR will be randomized to receive additional maintenance (rituximab SC 1400 mg every 8 weeks) until PD, or observation. Results At data cut-off (January 16, 2013), the safety population consisted of 216 patients who had received ≥1 dose of rituximab SC: 70 (32%) had completed induction therapy, 122 (57%) were receiving induction therapy, and 24 (11%) had discontinued induction therapy. A total of 58 (27%) patients had continued into standard maintenance, with 2 patients having subsequently discontinued maintenance therapy. Patients had a median age of 64.5 years (range, 20–90). At screening, the most common types of iNHL were follicular NHL (n=131, 61%), marginal zone lymphoma (n=41, 19%), and Waldenström's macroglobulinemia (n=31, 14%). The most commonly used chemotherapy regimens were bendamustine (n=137, 63%), CHOP (n=31, 14%) and CVP (n=21, 9.7%). During therapy, AEs occurred in 174 (81%) patients (Table), grade 3 or higher AEs in 70 (32%) patients and serious AEs (SAEs) in 44 (20%) patients. Administration-related reactions (ARRs) were reported by 61 (28%) patients after 1 dose of rituximab IV and by 89 (41%) patients after a median (range) of 5 (1–11) doses of rituximab SC. The majority of ARRs were mild to moderate and transient, and expected with the change in the route of administration. Overall, 25 patients had grade 4 hematological events, most commonly neutropenia (22 patients). Only 4 cases of neutropenia lasted >14 days and these resolved without interruption to treatment. One patient had a grade 4 non-hematological event (thrombosis and pulmonary embolism that resolved after 12 days). Among the 26 patients who discontinued study treatment, reasons given were AEs (n=8; skin reactions [3], neutropenia [2], general health problems [2], and oseophagitis [1]), patient or investigator request (n=6), PD (n=5), death (n=2), and other (n=5). One patient died of bronchopneumonia and sepsis due to leucopenia and 1 died of myocarditis; neither was considered by the investigator to be related to the study drug. Conclusions Rituximab SC is associated with ARRs that are transient and mainly mild to moderate in severity. The incidence and intensity of other hematological and non-hematological toxicities are within the expected range for rituximab SC or IV administration. No new safety signals or concerns associated with rituximab SC were identified during induction and maintenance therapy in this interim safety analysis, as confirmed by the Independent Data Monitoring Committee. Rituximab SC appears to be well tolerated and the study continues. Disclosures: Rule: Pharmacyclics, Inc: Consultancy; J&J: Consultancy; F. Hoffmann-La Roche: Consultancy. Off Label Use: Rituximab, administered as an IV infusion, is approved for use in a number of hematologic indications. The data presented here assess a subcutaneous approach to rituximab administration in patients with indolent Non-Hodgkin’s Lymphoma. Briones:Celgene: Membership on an entity’s Board of Directors or advisory committees; Takeda: Membership on an entity’s Board of Directors or advisory committees; Novartris: Membership on an entity’s Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria. Casasnovas:F. Hoffmann-La Roche: Consultancy, Research Funding. Pocock:F. Hoffmann-La Roche: Honoraria. Osborne:F. Hoffmann-La Roche: Employment. Smith:F. Hoffmann-La Roche: Employment. Zaja:F. Hoffmann-La Roche: Consultancy.

Induction Therapy with “3+7” Chemotherapy Plus ATRA Followed by Consolidations with Three Courses of Idarubicin Alone and Maintenance Therapy with ATRA in Newly Diagnosed Acute Promyelocytic Leukemia (APL) Has An Excellent Leukemia-Free Survival but Minimal Toxicity in Low and Intermediate Risk Groups.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2072-2072
Author(s):  
Moon-Young Choi ◽  
Yeung-Chul Mun ◽  
Se Hoon Park ◽  
Eun Kyung Cho ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
Relapse Rate ◽  
Induction Therapy ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Low Risk ◽  
Intermediate Risk ◽  
Newly Diagnosed

Abstract Abstract 2072 Poster Board II-49 Backgrounds Currently, there are many efforts to design risk-adapted strategies in newly diagnosed acute promyelocytic leukemia (APL) by modulating treatment intensity and those seem to be an efficient approach to minimize treatment-related morbidity and mortality (TRM) while maintain the potential in cure for each relapse-risk group. We had postulated that maintaining of Ara-C during induction therapy might have acceptable toxicities yet obtaining good CR in newly diagnosed APL, and idarubicin alone during consolidation periods might have excellent LFS and OS with low relapse rate. Patients and Methods Eighty six patients with newly diagnosed APL were enrolled in the “multicenter AML-2000 trial” after informed consents were obtained during the period of January 2000 to July 2007. For remission induction therapy, patients received oral ATRA (45mg/m2/d, maintained until CR) combined with idarubicin (12mg/m2/d, D1-D3) plus Ara-C (100mg/m2/d, D1-D7). After CR achievement, patients received 3 monthly consolidation courses consisting of idarubicin (12mg/m2/d, D1-D3) alone and maintenance therapy with ATRA (45mg/m2/d, D1-D15, every 2 month) alone had continued for 2 years. Total patients were divided into low-risk, intermediate-risk and high-risk groups according to a predictive model for relapse risk (Sanz score) based on pretreatment WBC and platelet count and the treatment outcomes were compared in the different risk groups. Results The median age of our cohort was 40 years old (range; 6-80) and median follow-up was 27 months (range; 1-90). The distribution of patients in the 3 risk groups was as follows ; 28 (32.6%) patients in low-risk, 40 (46.5%) in intermediate-risk and 18 (20.9%) in high-risk. Overall, CR was achieved in 78 (90.7%) of 86 patients. The CR rate according risk groups was 96.4% in low-risk, 87.5% in intermediate-risk, and 88.9% in high-risk group and there was no significant statistical difference among the different risk groups. During induction therapy, 48 (55.8%) patients experienced grade 3-4 treatment-related toxicity (TRT), mostly fever and infection (38.8% of all patients) and 6 (7.0%) patients died of treatment-related complications. During 3 consolidation courses, 25 (29.1%) of 78 patients experienced grade 3-4 TRT in 1st course, 27 (36.0%) of 75 patients in 2nd course, and 14 (28.0%) of 50 patients in 3rd course. Overall, 3 (3.5%) patients died of treatment-related complications in CR. The incidence of TRT and treatment-related mortality (TRM) during induction or consolidation therapy showed no significant statistical difference among the different risk groups. The relapse occurred in 6 (7.0%) patients; 2 cases in intermediate-risk and 4 cases in high-risk. However, none had relapsed in low risk group, 5 patients of relapsed patients relapsed during consolidation courses and only one patient, however, relapsed during maintenance therapy. The overall survival (OS) and leukemia-free survival (LFS) rate at 7 years in all of patients was 76.7% and 83.5%, respectively. The OS rate at 7 years was 92.9% in low-risk, 78.6% in intermediate-risk and 53.6% in high-risk group (P:0.04) and the LFS rate at 7 years was 96.4%, 83.4% and 62.2% respectively, showing the significant difference between 3 different risk groups (P:0.046). Conclusions This study indicates that our protocol composed of induction therapy with “3+7” chemotherapy plus ATRA followed by consolidations with three courses of idarubicin alone and maintenance therapy with ATRA alone yields a high CR rate and low relapse rate but minimal acceptable toxicities. Despite of adding Ara-C during induction therapy, we did not find much significant toxicities but having good CR rates, and despite of not adding any additional low/intermediate dose chemotherapies(ie, 6MP), we were able to observe significantly high relapse rate in low and intermediate risk group with excellent LFS and OS. Meanwhile, in high-risk group, the relapse rate was significantly higher than other risk groups and most of the relapses occurred in the middle of consolidation courses. This data suggests that our consolidation therapy composed of anthracycline alone may be not enough to minimize risk of relapse in high-risk group in contrast with the low and intermediate-risk groups. More intensive consolidation therapy combined with other effective, but get tolerable chemotherapies or hematopoietic stem cell transplantation in first CR or the combination of arsenic trioxide or others in front-line therapy should be considered in the patients with high-risk of relapse. Disclosures: No relevant conflicts of interest to declare.

Bortezomib-Based Induction Treatments Improve Outcomes of Newly Diagnosed Multiple Myeloma Patients with High-Risk Cytogenetic Abnormalities

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 781-781 ◽  
Author(s):  
Michele Cavo ◽  
Sara Bringhen ◽  
Carolina Terragna ◽  
Paola Omedè ◽  
Giulia Marzocchi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Plasma Cells ◽  
Risk Group ◽  
High Risk Group ◽  
Newly Diagnosed ◽  
Negative Group ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities

Abstract Abstract 781 Aim of the present study was to evaluate the impact of bortezomib-based induction treatments on clinical outcomes of newly diagnosed multiple myeloma (MM) patients with unfavorable cytogenetic abnormalities. For this purpose, we analyzed 590 bortezomib-treated patients who were screened at diagnosis for the presence of del(13q), t(4;14) and del(17p) by fluorescence in situ hybridization (FISH) on highly purified bone marrow plasma cells. Patients were stratified into the following 3 groups based on 1) the absence of any cytogenetic abnormality (n=261, or 44%) or 2) the presence of del(13q) alone (n=175, or 30%) or 3) positivity for t(4;14) and/or del(17p) (n=154, or 26%). In the great majority of the patients, loss of 17p was detected in more than 70% of bone marrow plasma cells, a finding which precluded a comparison with patients carrying del(17p) in a lower percentage of plasma cells. After diagnosis, 218 patients received induction therapy with bortezomib-thalidomide-dexamethasone (VTD), while the remaining 372 patients were treated with bortezomib-melphalan-prednisone (VMP) (n=181) or VMP plus thalidomide (VMPT) (n=191). The median number of bortezomib infusions (1.3 mg/m2) actually received was 24. Baseline characteristics of the 3 groups of patients were comparable, with the exception of a higher frequency of ISS stage 3 among patients with t(4;14) and/or del(17p) as compared with the cytogenetic-negative group (29% vs 17%, respectively; p=0.003). The rates of absence or presence of del (13q), t(4;14) and/or del(17p) were comparable among patients receiving VTD or VMP or VMPT treatments. Best CR to overall treatment protocols was 39% for the cytogenetic-negative group and 44% for high-risk patients carrying t(4;14) and/or del(17p). With a median follow-up of 27.5 months, median PFS was 40.5 months for patients without cytogenetic abnormalities as compared with 34 months for the high-risk group (p=0.7), while it was not reached after 38 months in the group with del(13q) alone (p not statistically significant for comparison with the other two groups). Overall, the frequency of events was 31% for patients without cytogenetic abnormalities or with del(13q) alone in comparison with 38% for those with high-risk cytogenetic profiles (p=0.15). Median OS was not reached in any of the 3 groups. Forty-month projected OS rates were 89% for the cytogenetic-negative group, 81% for the group with del(13q) alone (p=0.6) and 77% for the high-risk group (p=0.003 for comparison between this latter and the cytogenetic-negative group). Patients with t(4;14) and/or del(17p) had a shorter OS after relapse in comparison with the cytogenetic-negative group (20-month projected rates: 60% vs 76%, respectively; p=0.01). To more carefully evaluate the prognostic relevance of high-risk cytogenetic abnormalities, we stratified patients in the high-risk group into the following 3 subgroups: 1) t(4;14)-positive but del(17p)-negative (84 patients); 2) del(17p)-positive in the absence of t(4;14) (54 patients); t(4;14)-positive and del(17p)-positive (16 patients). Median PFS was not reached after 40 months for patients with t(4;14) alone, while it was 33 months for patients with del(17p) alone (p=0.1) and was 18.5 months for those who carried both these abnormalities (p=0.0008 for comparison between these latter patients and t(4;14)-positive patients). Overall, the frequency of events was 30% and 41% for patients carrying either t(4;14) or del(17p), respectively (p=0.13), while it was as high as 69% for patients with both these abnormalities. The 40-month projected OS rates for these 3 subgroups were 79%, 82% and 64%, respectively (p not significant). In conclusion, the present analysis of a large series of newly diagnosed MM patients receiving bortezomib-based induction treatments showed that: 1) del(13q) alone had no adverse effect on both PFS and OS; 2) the presence of t(4;14) and/or del(17p) did not adversely influence PFS, but was associated with a shorter OS, due at least in part to a worse outcome after relapse; 3) in comparison with t(4;14), del(17p) alone did not predicted for shorter PFS and OS, possibly as a result of the relatively long-term exposure to bortezomib); 4) the presence of both del(17p) and t(4;14) was likely to confer a particularly dismal clinical outlook, a finding which needs to be confirmed in larger series of patients. Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib-based treatment for newly diagnosed multiple myeloma. Petrucci:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:NOVARTIS: Honoraria; CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Palumbo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, no.

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 Impact of Cytogenetics on Outcomes of Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Continuous Lenalidomide Plus Low-Dose Dexamethasone in the First (MM-020) Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 730-730 ◽  
Author(s):  
Herve Avet-Loiseau ◽  
Cyrille Hulin ◽  
Lofti Benboubker ◽  
Meletios A. Dimopoulos ◽  
Andrew Belch ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Risk Group ◽  
Risk Groups ◽  
High Risk Group ◽  
Continuous Treatment ◽  
Duration Of Treatment ◽  
Advisory Committees ◽  
Reduced Risk

Abstract Introduction: Cytogenetic abnormalities in patients (pts) with multiple myeloma (MM) are of prognostic importance and can be associated with poor outcomes (Bergsagel, Blood, 2011). The FIRST trial is a pivotal phase 3 study with the largest data set in transplant-ineligible pts with newly diagnosed MM (NDMM). This subanalysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible pts with NDMM continuously treated with lenalidomide plus low-dose dexamethasone until disease progression (Rd continuous). Methods: Transplant-ineligible pts with NDMM were randomized to 1 of 3 treatment arms: Rd continuous, Rd18 (Rd for 18 cycles [72 weeks]), or melphalan-prednisone-thalidomide (MPT; for 12 cycles [72 weeks]). Cytogenetics were assessed using fluorescence in situ hybridization. Pts were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. High-risk cytogenetics included del(17p), t(4;14), and t(14;16); all other pts were categorized as non-high risk. The primary endpoint was progression-free survival (PFS; primary comparators were Rd continuous vs MPT), and key secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Results: A total of 762 of 1623 pts from the intent-to-treat population had validated cytogenetic profiles, with 142 pts in the high-risk group and 620 pts in the non-high-risk group. Baseline characteristics were well balanced across cytogenetic risk groups (Table 1). The median follow-up for OS was 40.2 months for the 762 pts in this analysis (data cutoff, March 03, 2014). In the non-high-risk group, median duration of treatment was 19.4 months with Rd continuous and 16.6 months with both Rd18 and MPT. In the high-risk group, median duration of treatment was 10.0 months with Rd continuous, 8.2 months with Rd18, and 12.0 months with MPT. Rd continuous treatment resulted in a 24% reduced risk of death or progression compared with MPT and an even greater 32% reduced risk in pts without high-risk cytogenetics (Table 2). In non-high-risk pts, median PFS was 31.1 months with Rd continuous compared with 21.2 and 24.9 months with Rd18 and MPT, respectively (Figure). However, in high-risk pts, the observed numerical median PFS favoring Rd18 is mainly due to small pt numbers influenced by long runners (n = 5), and the greatly overlapping 95% CIs from all 3 arms show the difference is likely to be minimal. Rd continuous treatment resulted in a 28% reduced risk of death vs MPT overall and a 34% reduced risk in pts without high-risk cytogenetics. OS was similar across treatment arms for high-risk pts. ORRs in all cytogenetic risk groups favored Rd continuous vs MPT. In pts with high-risk cytogenetics, higher-quality responses were also observed with Rd continuous vs MPT treatment. Similar results were seen with Rd continuous compared with Rd18, although OS and ORR benefits overall and in pts without high-risk cytogenetics were not as pronounced. In all 3 treatment arms, adverse events were consistent across cytogenetic risk groups. Conclusions: Rd continuous treatment resulted in PFS and OS benefits vs MPT in pts with validated cytogenetic profiles. This was largely due to PFS and OS improvements in pts without high-risk cytogenetics. In the high-risk group, the longest PFS was observed with Rd18 treatment and OS was similar across treatment arms. Despite being on the continuous vs fixed duration treatment arm, high-risk pts on Rd continuous received a shorter duration of treatment than those on MPT, which may explain why PFS favored MPT vs Rd continuous. Higher response rates were observed with Rd continuous vs MPT, regardless of cytogenetic risk, and greater quality responses were observed in pts with high-risk cytogenetics. The safety profile of Rd continuous was manageable and consistent between cytogenetic risk groups. Results support Rd continuous as a standard treatment option for pts with NDMM who are ineligible for transplant, especially those without high-risk cytogenetics. Additional PFS and OS benefits may be achieved in pts with high-risk cytogenetics when Rd continuous is used as a backbone for combination therapy with a novel agent. Promising activity in pts with high-risk cytogenetic abnormalities has been demonstrated using this approach (Lonial et al, N Engl J Med, 2015; Stewart et al, N Engl J Med, 2015). Disclosures Hulin: Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Dimopoulos:Celgene: Honoraria; Onyx: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Genesis: Honoraria. Reece:Lundbeck: Honoraria; Amgen: Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millennium Takeda: Research Funding; Otsuka: Research Funding. Catalano:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria. Pinto:Takeda: Honoraria, Research Funding; Celgene Corporation: Honoraria; Spectrum: Honoraria. Ludwig:Takeda: Research Funding; Celgene Corporation: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau. Bahlis:Celgene Corporation: Honoraria, Research Funding. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard; Celgene: Honoraria, Other: Adboard. Qiu:Johnson & Johnson: Speakers Bureau; Celgene Corporation: Speakers Bureau; Roche: Speakers Bureau. Schots:Celgene Corporation: Research Funding. Marek:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Yiu:Celgene Corporation: Employment, Equity Ownership. Ervin-Haynes:Celgene Corporation: Employment. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees.

Efficacy and Safety of Carfilzomib and Dexamethasone Vs Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma Based on Cytogenetic Risk Status: Subgroup Analysis from the Phase 3 Study Endeavor (NCT01568866)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 30-30 ◽  
Author(s):  
Wee-Joo Chng ◽  
Hartmut Goldschmidt ◽  
Meletios A. Dimopoulos ◽  
Philippe Moreau ◽  
Douglas Joshua ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Plasma Cells ◽  
Risk Group ◽  
High Risk Group ◽  
Advisory Committees ◽  
Risk Status ◽  
Grade 3 ◽  
Standard Risk ◽  
Support Research

Abstract Introduction: Single-agent carfilzomib has previously shown activity in patients with relapsed and refractory multiple myeloma (MM) who have high-risk cytogenetic abnormalities (Jakubowiak et al, Leukemia 2013;27:2351-56). In the randomized phase 3 study ENDEAVOR (NCT01568866; N=929), carfilzomib plus dexamethasone (Kd) demonstrated a clinically meaningful and statistically significant 2-fold improvement in median progression-free survival (PFS) compared with bortezomib plus dexamethasone (Vd; 18.7 vs 9.4 months; hazard ratio [HR]: 0.53; 95% confidence interval [CI]: 0.44-0.65; P<.0001) (Dimopoulos et al, J Clin Oncol 2015;33:abstr 8509; Dimopoulos et al, Haematologica 2015;100[s1]:abstr LB2071). Herein we present results of a preplanned subgroup analysis of the efficacy and safety of Kd vs Vd in the ENDEAVOR study based on baseline cytogenetic risk status. Methods: Adult patients with relapsed MM (RMM; 1-3 prior lines of therapy) were eligible. Patients in the Kd arm received carfilzomib (30-minute intravenous [IV] infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle. Patients in the Vd arm received bortezomib 1.3 mg/m2 (IV bolus or subcutaneous injection) on days 1, 4, 8, and 11 and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Cycles were repeated until disease progression, withdrawal of consent, or unacceptable toxicity. The primary end point was PFS. Secondary end points included overall survival, overall response rate (ORR), duration of response (DOR), rate of grade ≥2 peripheral neuropathy (PN), and safety. Fluorescence in situ hybridization was used to assess cytogenetic risk status. The high-risk group was defined as those patients with the genetic subtypes t(4;14) or t(14;16) in ≥10% of screened plasma cells, or deletion 17p in ≥20% of screened plasma cells based on central review of bone marrow samples obtained at study entry; the standard-risk group consisted of patients without these genetic subtypes. Results: A total of 929 patients were randomized (Kd: 464; Vd: 465). Baseline cytogenetic risk status was well-balanced between the treatment arms (high-risk: Kd, 20.9%; Vd, 24.3%; standard-risk: Kd, 61.2%; Vd, 62.6%; unknown: Kd, 17.9%; Vd, 13.1%). Efficacy end points by baseline cytogenetic risk status are presented in the Table; Kaplan-Meier PFS curves by baseline cytogenetic risk status are shown in the Figure. Median PFS in the high-risk group (n=210) was 8.8 months (95% CI: 6.9-11.3) for Kd vs 6.0 months (95% CI: 4.9-8.1) for Vd (HR: 0.646; 95% CI: 0.453-0.921). Median PFS in the standard-risk group (n=575) was not estimable for Kd (95% CI: 18.7-not estimable) vs 10.2 months (95% CI: 9.3-12.2) for Vd (HR: 0.439; 95% CI: 0.333-0.578). ORRs (≥partial response) were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ≥CR. Median DOR in the high-risk group was 10.2 months for Kd vs 8.3 months for Vd. Median DOR in the standard-risk group was not estimable for Kd vs 11.7 months for Vd. Grade ≥3 adverse events (AEs) were reported at higher rates with Kd vs Vd in the high- and standard-risk groups (70.1% vs 63.1% and 73.9% vs 68.3%). Rates of grade ≥3 AEs of interest by baseline cytogenetic risk status are shown in the Table. Grade ≥2 PN was reported at lower rates with Kd vs Vd in the high-risk group (3.1% vs 35.1%; odds ratio: 0.059; 95% CI: 0.018-0.198) and also in the standard-risk group (6.4% vs 33.4%; odds ratio: 0.135; 95% CI: 0.079-0.231). Conclusion: As expected, median PFS for patients with high-risk cytogenetics was lower compared with the overall population; however, patients treated with Kd had a clinically meaningful improvement in PFS compared with Vd in patients with high- or standard-risk cytogenetics. Higher response rates, a greater depth of response, and longer DOR were also observed with Kd vs Vd across cytogenetic subgroups. Kd had a favorable benefit-risk profile in patients with high-risk relapsed MM, and was superior to Vd, regardless of baseline cytogenetic risk status. Disclosures Goldschmidt: BMS: Consultancy, Research Funding; Amgen, Takeda: Consultancy; Onyx: Consultancy, Honoraria; Janssen, Celgene, Novartis: Consultancy, Honoraria, Research Funding; Chugai, Millennium: Honoraria, Research Funding. Dimopoulos:Onyx: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Moreau:Novartis, Janssen, Celgene, Millennium, Onyx Pharmaceuticals: Consultancy, Honoraria. Joshua:Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria. Facon:Onyx/Amgen: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene Corporation: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Takeda: Research Funding. Niesvizky:Celgene, Millennium, Onyx: Consultancy, Speakers Bureau. Oriol:Celgene, Janssen, Amgen: Consultancy, Speakers Bureau. Rosinol:Celgene, Janssen: Honoraria. Gaidano:Morphosys, Roche, Novartis, GlaxoSmith Kline, Amgen, Janssen, Karyopharm: Honoraria, Other: Advisory Boards; Celgene: Research Funding. Weisel:Takeda: Other: Travel Support; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support; Noxxon: Consultancy. Gillenwater:Onyx, Amgen: Employment, Other: Stock. Mohamed:Onyx/Amgen: Employment, Other: Stock. Feng:Amgen/Onyx: Employment, Equity Ownership. Hájek:Janssen-Cilag: Honoraria; Celgene, Amgen: Consultancy, Honoraria.

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