scholarly journals Impact of Newer Agents on Progression Free Survival of Multiple Myeloma in the 2nd 3rd and 4th Line Setting- a Systematic Review

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5645-5645
Author(s):  
Muhammad Sardar ◽  
Jemin Aby Jose ◽  
Zunairah Shah ◽  
Chaudhry Saad Sohail ◽  
Insija Ilyas Selene ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Conflicts Of Interest ◽  
Case Series ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Control Group ◽  
Combination Regimen ◽  
Free Survival ◽  
Line Setting

Abstract Background: Multiple Myeloma (MM) remains incurable. Majority of the patients ultimately relapse with a lower median event free survival after each successive line of therapy. For newly diagnosed MM patients, the median progression free survival (PFS) has improved drastically with the advent of novel agents. Aim of our review is to discuss median PFSnwith novel agents in the 2nd 3rd and 4th line of treatment in MM. Methods: A comprehensive literature search was done in accordance with the PRISMA guidelines from Jan 1st 2010 to May 30th 2018 using the following 4 databases: PubMed/ Medline, Elsevier/Embase, Wiley/Cochrane and clinicaltrials.gov. Inclusion criteria consisted of all prospective clinical trials that a) included patients with 1-3 prior lines of therapies b) received novel therapeutic agents as an intervention c) outcome was reported as median PFS. We excluded case series, retrospective/observational studies, systematic reviews/meta-analysis. We identified 4777 records through initial database search. After removing duplicates and further screening, 59 full-text articles were assessed for eligibility. 50 articles were subsequently excluded with reason and 9 articles constituting 4937 patients were selected for data extraction and final analysis. Result In a randomized clinical trial (RCT) by Dimopolous et al (2017), 396 patients (median age: 64) in the carfilzomib, lenalidomide and dexamethasone (KRD) arm had median PFS of 26.3 m. In comparison, 396 patients in the control group (median age: 65) that received RD regimen had a median PFS of 17.6 m. Percentage of patients with prior bone marrow transplant (BMT) and high-risk (HR) cytogenetics was 54.8% and 12.1% respectively in the KRD regimen and 57.8% and 13.1% respectively in the RD regimen. The median prior number of therapies was 2 in each group. In the trial by Avet-Loiseau et al 2017, patients in the Ixazomib-RD arm (n=360; HR cytogenetics=21%) had a median PFS of 20.6m as compared to 14.7 m in the control group (RD) arm (n=362; HR cytogenetics=17%). Median prior number of therapies was 2 in each group and 59% and 57% of the patients had prior BMT respectively. Lonial et al (2015) showed that the group (n=321; median age 67) that received elotuzumab-RD regimen had median PFS of 19.4m compared to 14.5m in the control group (n=325; median age 66) that received RD regimen. Prior median therapies were 2 in each arm and BMT was done in 52% and 57% of the patients respectively. A RCT of two drug regimen by Chang et al (2017) showed that patients (n= 464) who received KD had a higher median PFS (18.7m) as compared to patients (n= 465) who received bortezomib(V)-D (9.4 m). KD arm had 37.2% patients with prior BMT as compared to 49.6% in the VD arm whereas the median prior number of therapies was 2 in each arm. HR cytogenetics were present in 21% and 24% respectively. In the trial by Orlowski et al (2015), there was no improvement in the median PFS with the addition of Siltuximab to V as compared to V alone. Similarly, no significant improvement in median PFS was noted by Dimopolus et al (2017) in the combination regimen of Vorinostat-V as compared to placebo-V. In the trial by white et al (2017), the median PFS was 6.2 with bevacizumab-V as compared to 5.1m with placebo-V. In a trial by Richardson et al (2016), Panobinostat-VD had a median PFS of 11.99 which was higher than 8.08 with placebo-VD. Conclusion: Regimen consisting of KRD has the highest median PFS in MM patients with multiple prior lines of therapy followed by IRD based regimen. Limitations of our analysis include a heterogeneous patient population and exclusion of data with daratumumab based regimen because of unavailability of median PFS specifically in the 2nd 3rd and 4th line setting in the published clinical trials. Disclosures No relevant conflicts of interest to declare.

Efficacy of Daratumumab Based Regimens Compared to Standard of Care for Transplant Ineligible Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Zahoor Ahmed ◽  
Karun Neupane ◽  
Rabia Ashraf ◽  
Amna Khan ◽  
Moazzam Shahzad ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Standard Care ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Control Group ◽  
Two Phase ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Phase Iii Clinical Trials

Introduction: Daratumumab (Dara) is a human anti-CD38 monoclonal antibody approved for multiple myeloma (MM) treatment. Dara has a promising efficacy and a favorable safety profile in newly diagnosed MM (NDMM) patients. This study is focused on the efficacy and safety of Dara when added to the standard care regimen in transplant ineligible NDMM in phase III clinical trials. Methods: We performed a comprehensive database search on four major databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and key words for multiple myeloma and Dara including trade names and generic names from date of inception to May 2020. Initial search revealed 587 articles. After excluding review articles, duplicates, and non-relevant articles, two phase III clinical trials were included which reported overall response rate (ORR), and progression free survival (PFS) of transplant ineligible NDMM patients with Dara addition to standard care regimen. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using a fixed effect model in RevMan v.5.4. Results: A total of 1453 transplant ineligible NDMM patients were enrolled and evaluated in two phase III randomized clinical trials. Seven hundred and eighteen patients were in Dara group and 735 patients were in control group. Bahlis et al. (2019) studied Dara + lenolidamide (R) and dexamethasone (d) vs Rd in NDMM pts (n=737) in MAIA phase III trial. Similarly, Mateos et al. (2018) reported the role of Dara + bortezomib (V) + melphalan (M), and prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). A pooled analysis of these phase III trials showed ORR (OR: 3.26, 95% CI 2.36-4.49; p < 0.00001, I2 = 0%), and progression free survival (PFS) (HR: 0.53, 95% CI 0.43-0.65; p < 0.00001, I2 = 0%). Achievement of minimal residual disease (MRD) negative status was significant in Dara based regimen as compared to control group (OR: 4.49, 95% CI 3.31-6.37; p < 0.00001, I2 = 0%). Dara addition to standard care regimen (Rd and VMP) decreased the risk of progression/death to 42% (HR: 0.58, 95% CI 0.48-0.70; p < 0.00001, I2 = 0%). The addition of Dara increased the risk of neutropenia (OR: 1.41, 95% CI 1.07-1.85; p < 0.02, I2 = 44%), and pneumonia (OR: 2.25, 95% CI 1.54-3.29; p < 0.0001, I2 = 37%) vs control group. However, decreased risk of anemia (OR: 0.64, 95% CI 0.49-0.85: p < 0.002, I2=30%) was observed in Dara group vs control group (Figure 1). Conclusion: Addition of Dara to the standard care regimen for transplant ineligible NDMM achieved the surrogate end points with improved efficacy and MRD negative status with manageable toxicity. However, data from more randomized controlled trials is needed. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Efficacy of Upfront Daratumumab Combination Regimen in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3158-3158 ◽  
Author(s):  
Kyaw Zin Thein ◽  
Thura Win Htut ◽  
Myint Aung Win ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Novel Agents ◽  
Combination Regimen ◽  
Newly Diagnosed ◽  
Standard Risk

Introduction: Management of newly diagnosed multiple myeloma (NDMM), which accounts for 1% of all cancers, is an area in dire need of therapeutic innovation. In recent years, the introduction of novel agents is one of the major advances in the management of patients with NDMM, in both transplant- eligible and transplant- ineligible candidates. Studies have combined daratumumab, a human IgGκ monoclonal antibody that targets CD38 which is highly expressed on myeloma cells, with proteasome inhibitors and immunomodulatory agents-based regimens in the first-line treatment of NDMM. The purpose of our study is to explore and consolidate the efficacy of upfront daratumumab combination regimen in patients with NDMM. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with newly diagnosed/ untreated multiple myeloma were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) for overall response rate (ORR), including stringent complete response (sCR), CR and very good partial response (VGPR). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Three phase III RCTs with a total of 2,528 patients with NDMMwere included.Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. The I2statistic for heterogeneity was 0, suggesting homogeneity among RCT. The pooled HR for PFS was statistically significant at 0.52 (95% CI: 0.44-0.61; P < 0.0001). The PFS benefit was observed in all ISS categories, types of immunoglobulin (Ig) and standard risk cytogenetic; ISS I cohort (HR, 0.55; 95% CI: 0.37- 0.82; P = 0.003), ISS II cohort (HR, 0.43; 95% CI: 0.33- 0.55; P < 0.0001), ISS III cohort (HR, 0.63; 95% CI: 0.48- 0.82; P = 0.0006), IgG cohort (HR, 0.56; 95% CI: 0.40- 0.77; P = 0.0003), non-IgG cohort (HR, 0.52; 95% CI: 0.28- 0.97; P = 0.04), and standard risk cytogenetic cohort (HR, 0.43; 95% CI: 0.35- 0.53; P < 0.0001). The pooled HR for PFS in high risk cytogenetic cohort was not statistically significant at 0.76 (95% CI: 0.53- 1.10; P = 0.15). The pooled RR for ORR was 1.13 (95% CI: 1.01-1.26; P = 0.03), sCR was 2.02 (95% CI: 1.33-3.08; P = 0.001), CR was 1.46 (95% CI: 1.20-1.79; P = 0.0002),and VGPR was 1.01 (95% CI: 0.82-1.25; P = 0.93). The pooled RR for negative minimal residual disease (MRD) was 2.54 (95% CI: 1.24-5.20; P = 0.01). Conclusions: Upfront combination regimen with daratumumab significantly improved PFS, ORR, sCR and CR along with negative MRD, compared to control arm in patients with NDMM. The improvement in PFS was noted across all subgroups except in high-risk cytogenetic group. More randomized studies are required to explore further novel agents and to formulate optimal combination regimen to improve survival in this high-risk cytogenetic subset. Disclosures No relevant conflicts of interest to declare.

Autologous Stem Cell Transplant Has a Role In Consolidating Chemotherapy Given At First Disease Progression In Multiple Myeloma Treated Exclusively With Novel Agents

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5514-5514
Author(s):  
Bhuvan Kishore ◽  
Shankaranarayana Paneesha ◽  
Syed W Bokhari ◽  
Shrinivas Pillai ◽  
Jason Sangha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Cell Transplant ◽  
Patient Age ◽  
Free Survival ◽  
Patient Âgé

Abstract Introduction Up-front autologous stem cell transplantation (ASCT-1) post front line therapy with novel agents is standard of care in newly diagnosed multiple myeloma. The role for salvage transplantation (ASCT-2) in relapsed patients after retreatment remains unclear in the era of the novel agents. Majority of published studies include patients treated in pre-thalidomide era. Our retrospective study investigates the safety and efficacy of ASCT-2 in patients exclusively treated with novel drugs both at upfront and at relapse. Primary end point was non relapse mortality (NRM) at day 100. Secondary end points were progression free survival from ASCT-2 (PFS-2) and overall survival (OS) Patients and Methods Thirty-nine patients (21 female and 18 male) underwent ASCT-2 at 4 centres between 2008 and 2013. At initial presentation all received thalidomide based treatments pre ASCT-1. Therapy at progression was bortezomib based in 92% and thalidomide in 8%. Melphalan 200 mg/m2 was used as conditioning for 90% of patients, 140 mg/m2 in 10%. OS and PFS-2 were calculated from ASCT-2. Statistical analysis was carried out using IBM SPSS 19 for Windows. Results Median progression free survival (PFS-1) post ASCT-1 was 35 (10-90) months with 4 patients receiving thalidomide maintenance. Median age at ASCT-2 was 60 (37-68) years with a median stem cell dose of 2.7×106 (2-7) CD34 cells /kg body weight. All patients engrafted with median times to neutrophil (>0.5) and platelet (>20) engraftment of 12 days each with a day+100 and 1 year NRM of 0%. With a median follow up from ASCT-2 of 18 (3-52) months, the median PFS-2 was 18 (12-24) months and OS was 42 (33-50) months. PFS-1 of greater than 18 months was associated with prolonged PFS-2 (19 vs. 6 months, p=0.001, log rank), however there was no statistical difference observed for PFS-1 beyond 24 months. Similarly PFS-1 >18 months predicted for improved OS (39 vs. 14 months, p=0.007, log rank). Age at ASCT-2(>or <60yrs) had no impact on PFS-2 or OS. Patient age>60 and with PFS-1 of >24 months had a median PFS-2 of 25months as compared to 14 months in patient age <60 with a PFS-1 of >24 months. Conclusion In the era of novel agents ASCT-2 can be safely delivered with 0% 1 year NRM. PFS-1 greater than 18 months gives better PFS-2 and OS suggesting a definite role of this therapy in a selected population Age greater than 60 years does not have adverse impact on either PFS or OS. Thus ASCT-2 should be considered in treatment strategies at disease progression and warrants further prospective studies Disclosures: No relevant conflicts of interest to declare.

Therapeutic efficacy of specific immunotherapy for glioma: a systematic review and meta-analysis

2018 ◽  
Vol 29 (4) ◽  
pp. 443-461 ◽  
Author(s):  
Sara Hanaei ◽  
Khashayar Afshari ◽  
Armin Hirbod-Mobarakeh ◽  
Bahram Mohajer ◽  
Delara Amir Dastmalchi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Clinical Trials ◽  
Specific Immunotherapy ◽  
Data Extraction ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Control Group ◽  
Free Survival ◽  
Median Difference

Abstract Although different immunotherapeutic approaches have been developed for the treatment of glioma, there is a discrepancy between clinical trials limiting their approval as common treatment. So, the current systematic review and meta-analysis were conducted to assess survival and clinical response of specific immunotherapy in patients with glioma. Generally, seven databases were searched to find eligible studies. Controlled clinical trials investigating the efficacy of specific immunotherapy in glioma were found eligible. After data extraction and risk of bias assessment, the data were analyzed based on the level of heterogeneity. Overall, 25 articles with 2964 patients were included. Generally, mean overall survival did not statistically improve in immunotherapy [median difference=1.51; 95% confidence interval (CI)=−0.16–3.17; p=0.08]; however, it was 11.16 months higher in passive immunotherapy (95% CI=5.69–16.64; p<0.0001). One-year overall survival was significantly higher in immunotherapy groups [hazard ratio (HR)=0.69; 95% CI=0.52–0.92; p=0.01]. As the hazard rate in the immunotherapy approach was 0.83 of the control group, 2-year overall survival was significantly higher in immunotherapy (HR=0.83; 95% CI=0.69–0.99; p=0.04). Three-year overall survival was significantly higher in immunotherapy as well (HR=0.67; 95% CI=0.48–0.92; p=0.01). Overall, median progression-free survival was significantly higher in immunotherapy (standard median difference=0.323; 95% CI=0.110–0.536; p=0.003). However, 1-year progression-free survival was not remarkably different between immunotherapy and control groups (HR=0.94; 95% CI=0.74–1.18; p=0.59). Specific immunotherapy demonstrated remarkable improvement in survival of patients with glioma and could be a considerable choice of treatment in the future. Despite the current promising results, further high-quality randomized controlled trials are required to approve immunotherapeutic approaches as the standard of care and the front-line treatment for glioma.

scholarly journals Treatment Burden in Patients with Multiple Myeloma According to Comorbidity

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4775-4775
Author(s):  
Ernesto Pérez Persona ◽  
Ariane Unamunzaga Cilaurren ◽  
Ana Vega Gonzalez de Viñaspre ◽  
Itziar Oiartzabal Ormategui ◽  
Ana Santamaría Lopez ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Conflicts Of Interest ◽  
Real Life ◽  
Progression Free Survival ◽  
P Value ◽  
Treatment Burden ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Time To Death

Abstract Introduction: Over the last few years, novel agents-based combinations have been incorporated into the treatment of MM patients, particularly in relapse setting. However, these novel combinations have been evaluated in clinical trials and patients included represent a selected population. Patients in real life are usually older with comorbidities and disabilities and not allowed to be included in the trials, so, in real setting, is expected worse outcomes and shorter survival. The information about treatment burden in real life is scarce. The aim of our study was to analyze the outcome of MM patients in the real life outside clinical trials, in terms of treatment lines in a single institution setting, and to analyze the influence of comorbidities on the treatment burden. Material and methods: Medical records of MM patients treated at Txagorritxu hospital (Spain) between 2009 and January 2017 were retrospectively evaluated with the aim of mapping the course of patients as well as to investigate the factors that influence treatment-decisions at different stages of the disease. Results: 176 patients with MM were diagnosed from jan-2009 to jan-2017. Baseline patient's characteristics are presented in Table 1. The median age at diagnosis was 71 years (range 33.2-93), main of the patients where non-transplant eligible newly diagnosed MM (NTENDMM): 114 (65%). With a median follow-up of 25 months, 90.6% of newly diagnosed MM patients transplant-eligible (TENDMM) remain alive versus 65% NTENDMM patients (p value: 0.000)(figure 1). Overall, patients received a median of 2 lines of treatment, it should be noted that 86% of patients had received 3 or less lines of treatment and only 14% of the patients could receive more than 3 lines of therapy. To better evaluate treatment burden, we focused on deceased patients. At the time of analysis, 19% of TENDMM (12 patients) and 51.4% of in NTENDMM (57 patients) has died with a median time to death of 29.6 months and 18 months to death, respectively. Median lines of therapy for death patients TENDMM was 3.5 (range 1-8), with a 75 percentile of 5 lines of therapy, by contrast, death NTENDMM patients received a median of 2 lines of therapy (range: 1-6), with an 80 percentile of 3 lines of therapy (figure 2). In order to evaluate the influence of comorbidities in treatment burden for NTENDMM patients, CIRS score was estimated retrospectively. Median CIRS score was 5.5 (1-19). CIRS scale did not predict progression free survival (PFS) among the different groups: CIRS <4: 23.4 months; CIRS4-8: 25.1 months and CIRS> 8: 30.6 months (p: 0.819), however, interestingly CIRS scale predicted overall survival (OS): CIRS <4: 48 moths; CIRS4-8: 50.8 months and CIRS> 8: 12.3 months, (p: 0.012) (figure 2). Analyzing treatment burden for each CIRS score group 63% of patients with CIRS> 8 received only one line of treatment before death, compared to 39.5% and 37.5% of patients with CIRS4-8 and CIRS <4, respectively. Conclusion: Although the impressive progress in the management of relapse/refractory MM patients in recent years, half of the patients, particularly those not suitable to received an autologous transplant, will be able to received only 2 lines of treatment before dying. In fact, an adequate comorbidity assessment could select patients that will only need only one line of treatment. To the best of our known, this is the first study that correlate treatment burden according to comorbidities at diagnostic. This study could guide strategies adapted according to the comorbidity of the patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Case series: MRD negativity assessment using 11C-Acetate PET with 3-weekly daratumumab-based quadruplet induction in newly diagnosed multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110303
Author(s):  
Cheong Ngai ◽  
Shaji Kumar ◽  
Garrett Chi-lai Ho ◽  
Sirong Chen ◽  
Chor-sang Chim
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Case Series ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Positron Emission ◽  
Pet Ct ◽  
Subsequent Relapse

Complete response (CR) is an important favorable factor for survival in multiple myeloma (MM). However, CR patients continue to relapse, especially in the presence of minimal residual disease (MRD). Bone marrow (BM) MRD is predictive of progression-free survival (PFS) in MM. However, myeloma outside the BM aspiration site may result in subsequent relapse despite MRD-negativity. Therefore, positron emission tomography-computed tomography (PET-CT) based on F-fluorodeoxyglucose (FDG) is a complementary tool to monitor residual disease in MM. However, FDG may miss myeloma lesions that are not FDG-avid. On the other hand, 11C-Acetate (ACT) has been found to be a more sensitive and specific tracer than FDG in MM. Recently, the addition of daratumumab to bortezomib, thalidomide, dexamethasone (VTd) or bortezomib, lenalidomide, dexamethasone (VRd) backbone has been proven to improve outcomes. Herein, we report three newly-diagnosed MM patients achieving deep responses with imaging CR using ACT PET in addition to conventional immunofixation CR and MRD-negative CR after a 3-weekly daratumumab-based quadruplet induction regimen.

scholarly journals Cereblon (CRBN) Gene Polymorphisms Predict Clinical Response and Progression-Free Survival in Multiple Myeloma Patients Treated with Lenalidomide: A Pharmacogenetic Study of Immense Consortium

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3628-3628 ◽  
Author(s):  
Elzbieta Iskierka-Jazdzewska ◽  
Anna Stepien ◽  
Federico Canzian ◽  
Alessandro Martino ◽  
Daniele Campa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Alternative Splicing ◽  
Clinical Response ◽  
Proportional Hazards ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Lower Probability ◽  
Pharmacogenetic Study ◽  
Free Survival ◽  
Gene And Protein Expression

Abstract Background: Cereblon (CRBN), a subunit of cullin 4-based E3 ubiquitine ligase complex, has been characterized as the main immunomodulatory drugs (IMiDs), thalidomide, lenalidomide and pomalidomide, binding protein that is crucial for their antiproliferative and immunomodulatory properties. Several recent reports have suggested that CRBN gene and protein expression or alternative splicing affect sensitivity to IMiDs in multiple myeloma (MM). It can be speculated that CRBN expression level, alternative splicing or CRBN-E3 ubiquitine ligase substrate specificity in MM and microenvironment cells may be partially determined by inherited genetic background including functional single nucleotide polymorphisms (SNPs). Aim: The objective of this study was to verify whether naturally occurring SNPs in CRBN encoding CRBNgene (locus chromosome 3p26.2) may influence outcome of lenalidomide-based therapy in patients with MM. Methods: We genotyped 14 tagging SNPs in CRBN gene in 169 Polish Caucasian patients with refractory/relapsed MM treated with lenalidomide-based therapy. Among these patients 151 (89%) received lenalidomide/dexamethasone (Len-Dex) regimen while the remaining patients were treated with lenalidomide-based three drug combinations. Genomic DNA samples were collected and genotyped in the context of the IMMEnSE consortium. The influence of CRBNallelic variants on probability to achieve clinical response (at least partial response, PR) to lenalidomide-based therapy, achievement of complete response (CR), duration of progression-free survival (PFS) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. For all genotyped SNPs co-dominant, dominant and recessive inheritance modes were tested. Results: We found that carriers of minor alleles of two studied SNPs, namely CRBN rs1714327G>C and CRBN rs1705814T>C significantly associated with lower probability of achievement of clinical response (≥PR) to lenalidomide-based therapy using dominant inheritance model (OR=0.25, 95%CI 0.10-0.63; p=0.0033, Bonferroni corrected p=0.019 and OR=0.21, 95%CI 0.07-0.61; p=0.0041, Bonferroni corrected p=0.024, respectively). Moreover, in concordance with these findings one of these two SNPs, namely CRBN rs1705814T>C, was also significantly associated with shorter PFS in the analyzed group of lenalidomide treated MM patients (OR=2.49; 95%CI 1.31-4.74; P=0.0054, Bonferroni corrected p=0.032). In contrast, none of the tested allelic variants of CRBN showed significant influence on OS. Conclusions: Taken together, our observations suggest that selected germline CRBN SNPs (rs1714327G>C and rs1705814T>C) affect lenalidomide efficacy in relapsed/refractory MM. Further studies are needed to explain functional mechanisms underlying these associations as well as to establish whether CRBN genetic variants may be useful as potential biomarkers for IMiDs-based therapy. Acknowledgments: This work was supported by the grants of Polish Young Heamatologists Club and Polish Myeloma Consortium. The work of Pawe³ Gaj was supported by a grant from the European Commission 7th Framework Programme: FP7-REGPOT-2012-CT2012-316254-BASTION Disclosures No relevant conflicts of interest to declare.

Genetic Variations Associated with Overall and Progression-Free Survival in Multiple Myeloma Patients Treated with Thalidomide Combinations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 426-426 ◽  
Author(s):  
David C Johnson ◽  
Walter M Gregory ◽  
Nicholas J Dickens ◽  
Brian A Walker ◽  
Alex J Szubert ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Survival Analysis ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Strand Break ◽  
Individual Response ◽  
Nucleotide Polymorphisms ◽  
Free Survival ◽  
Disease Response

Abstract Abstract 426 It is anticipated that inherited single nucleotide polymorphisms (SNPs) in genes involved in drug absorption, distribution, metabolism and excretion influence individual response to thalidomide therapies in Multiple Myeloma. We extracted peripheral blood DNA from 631 myeloma patients of European descent enrolled in the MRC Myeloma IX trial who had received induction thalidomide (50-200mg). We genotyped 3404 SNPs selected in 983 candidate genes that may influence myeloma disease response, toxicity, and/or survival, on a “Bank on a Cure” (BOAC) Affymetrix® true-tag array. The BOAC array is a custom genotyping chip focused on coding and predicted regulatory SNPs. Quality control (QC) measures were applied on the resulting genotype data such that individual samples failing a chip call rate (> 95%), and SNP assays with missing data (< 0.05%) or with extreme departures from Hardy-Weinberg equilibrium (p > 10-5) were excluded from the statistical analysis. We then performed 2-way log rank tests under recessive, dominant and trend genetic models for each SNP which passed QC for both overall survival and PFS on the training and validation sets. Our training set consisted of 379 myeloma patients from the intensive pathway of the Myeloma IX trial who received CTD (cyclophosphamide, thalidomide, dexamethasone), with a validation set of 252 myeloma patients from the non-intensive pathway who received an attenuated CTD regime. Although the overall and progression-free survival is shorter for individuals in the non-intensive arm in comparison to the younger and fitter patients in the intensive arm, we expected variants influencing overall survival and PFS related to thalidomide to associate with outcome, if both pathways were analysed separately. We looked for significant associations (log-rank chi-squares > 6.5, p > 10-3) across both the training and validation sets, and discounted associations where the number of cases in any one genotype group <10. We detected significant cross validating associations in the survival analysis with genes involved in double-strand break repair: BLM, LIG1, MRE11A, SHFM1 and RAD51L3, and also saw associations with genes important in response to DNA damage stimulus: CYP19A1, GSTA4 and MGST1, along with other notably associations in genes NFKBIE, NFKB1 and SELL. We saw cross validating SNP associations in the progression-free survival analysis in genes including the cytokines: IL10, IL13, as well as NFATC1. In this large study we have seen results indicating that genetic variation plays a role in both overall and progression free survival following thalidomide treatment in multiple myeloma patients, and in doing so we have highlighted SNPs and pathways that may be important and informative in predictive classification of patients for overall survival and PFS following treatment with thalidomide containing regimes. Disclosures: No relevant conflicts of interest to declare.

Analysis of 179 Patients with Newly Diagnosed Multiple Myeloma (MM) Treated with Novel Agents Followed by Autologous Stem Cell Transplantation (ASCT): a Retrospective Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1343-1343
Author(s):  
Joyce Habib ◽  
Neil Dunavin ◽  
Gary Phillips ◽  
Patrick Elder ◽  
Meaghan Tranovich ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Research Funding ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Genetic Profile ◽  
Newly Diagnosed ◽  
Free Survival

Abstract Abstract 1343 Background: Multiple myeloma (MM) is the second most common hematological malignancy in the United States with an estimated 20,580 new cases in 2009. Over the past decade, the introduction of novel agents (thalidomide, lenalidomide and bortezomib) have played a pivotal role in improving response rates, duration of response, overall survival (OS) and quality of life. In this study we describe a single center experience with novel agents used for induction followed by high dose chemotherapy (HDT) and first autologous stem cell transplant (ASCT) in patients with MM. Method: A retrospective review of the medical records of 179 newly diagnosed patients with MM seen between October 2006 and December 2009 at The Ohio State University was performed. All patients received novel therapy containing thalidomide, bortezomib or lenalidomide as part of an induction regimen followed by ASCT. All patients received melphalan 140mg/m2 or 200mg/m2 as preparative regimen. Kaplan-Meier estimates were used to plot progression free survival and overall survival. Results: Of the 181 patients seen, 2 were excluded because they did not receive a novel agent as part of induction treatment. Of the 179 patients analyzed, median age was 56.8 years (29-80) with 30% of patients older than 60 years. African American represented 19%. Fifty-nine percent were male, 80% had Durie-Salmon (DS) stage III while 25%, 28%, 18% represented International prognostic score (IPS) stage I, II, and III respectively with 27% unknown. Median comorbidity index score was 2 (2-7) and median Karnofsky performance score (KPS) was 90% (70-100). Thirty percent had high risk genetic profile, and 73% received one line of treatment before ASCT. The median time from diagnosis to ASCT was 8.33 months (4-58). The overall response rate (ORR) prior to transplant was 84% (9% complete (CR), 29% very good partial (VGPR), and 46% partial (PR)). The ORR post ASCT was 89% (CR 45%, VGPR 22%, PR 21%). Non relapse mortality was 1% and 3% at 100 days and 1 year respectively. At a median follow up of 31 months (7-90), 69 patients (38%) had relapsed. Median progression free survival (PFS) was 29 months with 1 and 3 years PFS of 79.3% and 61.5% respectively (Fig. 1). The OS was not reached. One and 3 years OS were 93% and 88% respectively (Fig. 1). Univariate analysis showed that time to transplant > 12 months was associated with poor outcome and decreased overall survival (HR 3.30, p = 0.008). High risk genetic profile was also found to be associated with decreased overall survival although this was not statistically significant (HR 2.31, p = 0.070). Multivariate analysis found that only time to transplant > 12 months was an independent predictor of decreased OS. Significant predictors for disease progression were high risk genetic profile and time to transplant > 12 months in patients receiving 2 or more treatments before ASCT. Conclusion: Induction with novel agents followed by HDT and ASCT improves CR rate, in our case from 9% to 45%. Median PFS (29 months) was comparable to other published data. OS was not been reached after a median follow up of 31 months. Predictors of progression include high risk genetic profile and time to transplant > 12 months. The only significant predictor for survival was time to transplant. Our study suggests that an early transplant may improve OS and PFS. An extended analysis will be presented at the meeting. Disclosures: Phillips: NCI/NIH: Research Funding; NCCM Grant: Research Funding; ARRA RC2 Grant: Research Funding. Byrd:Genzyme Corporation: Research Funding.

Relapsed Multiple Myeloma: Who Benefits From Salvage Autografts?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3059-3059 ◽  
Author(s):  
Annie W.S. Chow ◽  
Cindy H.S. Lee ◽  
Devendra K Hiwase ◽  
Luen Bik To ◽  
Noemi Horvath
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Selection Criterion ◽  
South Australia ◽  
Progression Free Survival ◽  
Novel Agents ◽  
High Dose ◽  
Cell Transplant ◽  
Free Interval

Abstract Abstract 3059 Aim Despite novel agents, multiple myeloma (MM) remains incurable. The majority of patients with MM will relapse at some stage after induction therapy and high dose chemotherapy with autologous stem cell transplant (ASCT). Published studies have recommended salvage ASCT as an effective option in patients with relapsed MM. However, the patient cohort who will derive maximum benefit from salvage ASCT is still undefined and is likely to evolve with increasing therapeutic options. We aimed to evaluate the role of salvage ASCT in relapsed MM patients. Methods We performed a retrospective analysis of patients who underwent salvage ASCT for relapsed MM in South Australia between 1992 and 2011. Results During this period, autologous stem cell transplants were performed for 457 patients with newly diagnosed MM. Thirty-nine patients subsequently underwent salvage ASCT for relapsed MM. The median age of patients at salvage ASCT was 59 (34–73) years, and 85% were ISS I and II at diagnosis. The majority of patients (90%, n=35) had a progression free interval (PFI) of at least 12 months after initial ASCT, consistent with recommendations by current literature. Salvage ASCT was performed for four patients with PFI shorter than 12 months, due either to suboptimal response to novel agents (thalidomide, lenalidomide, bortezomib), or the lack of novel agent availability in the earlier years. The median progression-free survival (PFS) and median overall survival (OS) following salvage ASCT were 22 months (95% CI: 11–32) and 52 months (95% CI: 30–74) respectively. Non-relapsed mortality at 2 years was 7%. Following salvage ASCT, the median PFS (28 vs. 12 months, p = 0.006) and OS (83 vs. 26 months, p = 0.02) were significantly longer in patients whose progression free interval after the initial ASCT was > 24 months (Figures 1 and 2). Use of novel agents in salvage induction and maintenance therapy post salvage ASCT did not appear to influence outcome. Conclusion Our results suggest that there remains a role for salvage ASCT, even in the era of novel therapies. Salvage ASCT may result in durable responses, particularly in patients with longer progression free interval (> 24 months) following initial ASCT. This interval could be included as a selection criterion for patients with relapsed myeloma who remain transplant eligible. Disclosures: No relevant conflicts of interest to declare.

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