Daratumumab-based therapies in transplant-ineligible patients with untreated multiple myeloma and hepatic dysfunction: A systematic review of subgroup analyses

2021 ◽  
pp. 107815522110621
Author(s):  
Manuel David Gil-Sierra ◽  
Maria del Pilar Briceño-Casado ◽  
Silvia Fénix-Caballero ◽  
Emilio Jesús Alegre-Del Rey ◽  
Catalina Alarcón de la Lastra-Romero ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Subgroup Analysis ◽  
Randomized Clinical Trials ◽  
Progression Free Survival ◽  
Hepatic Function ◽  
Free Survival ◽  
Statistical Interaction ◽  
Subset Analysis ◽  
Normal Hepatic Function

Introduction There is subgroup analysis suggesting a lack of benefit of daratumumab use in multiple myeloma (MM) and hepatic disease (HD). The objectives of this study were to conduct a systematic review and interpretation of daratumumab-based regimen efficacy in transplant-ineligible patients with untreated MM and HD. Methods A systematic search in Pubmed® database about randomized clinical trials (RCTs) with subgroup analysis regarding hepatic function for overall survival (OS) or progression-free survival (PFS) were developed. Two methodologies were applied. One of them considered statistical interaction, prespecification, biological support and consistency of subgroup results. Second methodology was two-part validated tool: preliminary questions to reject subset analysis without minimal relevance, and a checklist relating a recommendation for applicability in clinical practice. Results It was included three records. About first methodology, statistical interaction among subgroups was found for PFS in one RCT. Subsets were prespecified in all RCTs. Biological support of efficacy differences could be reasonable. Inconsistent results were found. Second methology directly rejected applicability of subset analysis in two records. Checklist recommended “null” application of results in the remaining RCT. Conclusions No consistent heterogeneity for daratumumab-based regimen efficacy was observed among subgroups regarding hepatic function in transplant-ineligible patients with untreated MM. Patients with normal hepatic function and HD could benefit from these treatments.

Efficacy of Single-Agent Bortezomib Versus Thalidomide in Patients with Relapsed or Refractory Multiple Myeloma: A Systematic Review.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5160-5160
Author(s):  
Miles Prince ◽  
Michael Adena ◽  
Dell Kingsford Smith ◽  
Judy Hertel
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Response Rate ◽  
English Literature ◽  
Progression Free Survival ◽  
Cochrane Library ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
One Year ◽  
Intent To Treat

Abstract Aim: To perform a systematic review of the efficacy of monotherapy with bortezomib versus thalidomide in patients with relapsed or refractory multiple myeloma. Methods: Published English literature from 1966 to June 2005 (MEDLINE, EMBASE, Cochrane library), publication reference lists, Janssen-Cilag Pty Ltd data-on-file, and abstracts from recent multiple myeloma conferences were reviewed. Prospective studies containing at least a single arm of any treatment group with n ≥ 30 and using continuing or variable thalidomide dosing were included. Studies adding dexamethasone for non-responders were excluded. Outcomes were analysed on an intent-to-treat basis. Statistical pooling was performed where possible for the following outcome measures: primary outcome of response rate, defined by a serum M-protein reduction ≥50% (A) and strict (e.g. EBMT) criteria (B), and for the secondary outcomes of overall survival and progression-free survival. Results: One bortezomib (n=333, APEX, NEJM2005, 352; 2487–98) and 15 thalidomide (n=1007) studies were included. Patient baseline characteristics including age, gender, IgG:IgA, disease duration and β2M were well matched, except that 48% of bortezomib patients had received prior thalidomide. On an intent-to-treat basis, the overall estimate for response rate (A) was 53% for patients receiving bortezomib versus 32% for thalidomide (p<0.001, n=10 studies). For response rate (B) the estimate was 36% for patients receiving bortezomib versus 22% for thalidomide (p<0.001, n=4 studies). One-year survival was 81% for patients receiving bortezomib versus 67% for thalidomide (p<0.001, n=6 studies). Due to differences in disease monitoring and definitions of progression, it was not possible to compare results for progression-free survival. Conclusion: In patients with relapsed or refractory multiple myeloma, bortezomib achieved significantly higher response rates and longer one-year survival than thalidomide, despite 48% of bortezomib-treated patients having received prior thalidomide.

scholarly journals Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX

2020 ◽  
Vol 10 (11) ◽  
Author(s):  
Jonathan L. Kaufman ◽  
Meletios A. Dimopoulos ◽  
Darrell White ◽  
Lotfi Benboubker ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Subgroup Analysis ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Free Survival ◽  
Poor Outcomes ◽  
Line Of Therapy

Abstract High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.

scholarly journals Carfilzomib vs bortezomib in patients with multiple myeloma and renal failure: a subgroup analysis of ENDEAVOR

Blood ◽  
2019 ◽  
Vol 133 (2) ◽  
pp. 147-155 ◽  
Author(s):  
Meletios Dimopoulos ◽  
David Siegel ◽  
Darrell J. White ◽  
Ralph Boccia ◽  
Karim S. Iskander ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Subgroup Analysis ◽  
Progression Free Survival ◽  
Free Survival ◽  
Grade 3 ◽  
Intent To Treat ◽  
Post Hoc ◽  
Event Rates ◽  
Baseline Renal Function

Abstract In ENDEAVOR, carfilzomib (56 mg/m2) and dexamethasone (Kd56) demonstrated longer progression-free survival (PFS) over bortezomib and dexamethasone (Vd) in patients with relapsed/refractory multiple myeloma (RRMM). Here we evaluated Kd56 vs Vd by baseline renal function in a post hoc exploratory subgroup analysis. The intent-to-treat population included 929 patients (creatinine clearance [CrCL] ≥15 to &lt;50 mL/min, n = 85 and n = 99; CrCL 50 to &lt;80 mL/min, n = 186 and n = 177; and CrCL ≥80 mL/min, n = 193 and n = 189 for Kd56 and Vd arms, respectively). In these respective subgroups, median PFS was 14.9 vs 6.5 months (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.320-0.757), 18.6 vs 9.4 months (HR, 0.48; 95% CI, 0.351-0.652), and not reached (NR) vs 12.2 months (HR, 0.60; 95% CI, 0.434-0.827) for those receiving Kd56 vs Vd, respectively; median overall survival (OS) was 42.1 vs 23.7 months (HR, 0.66; 95% CI, 0.443-0.989), 42.5 vs 32.8 months (HR, 0.83; 95% CI, 0.626-1.104), and NR vs 42.3 months (HR, 0.75; 95% CI, 0.554-1.009). Complete renal response (ie, CrCL improvement to ≥60 mL/min in any 2 consecutive visits if baseline CrCL &lt;50 mL/min) rates were 15.3% (95% CI, 8.4-24.7) and 14.1% (95% CI, 8.0-22.6) for those receiving Kd56 vs Vd, respectively. In a combined Kd56 and Vd analysis, complete renal responders had longer median PFS (14.1 vs 9.4 months; HR, 0.805; 95% CI, 0.438-1.481) and OS (35.3 vs 29.7 months; HR, 0.91; 95% CI, 0.524-1.577) vs nonresponders. Grade ≥3 adverse event rates in the respective subgroups were 87.1% vs 79.4%, 84.4% vs 71.8%, and 77.1% vs 65.9% for those receiving Kd56 vs Vd, respectively. Thus, Kd56 demonstrated PFS and OS improvements over Vd in RRMM patients regardless of their baseline renal function. The ENDEAVOR trial was registered at www.clinicaltrials.gov as #NCT01568866.

scholarly journals A Systematic Review and Network Meta-Analysis of Randomized Data on Efficacy of Novel Therapy Combinations in Patients with Lenalidomide Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-12
Author(s):  
Ghulam Rehman Mohyuddin ◽  
Jill Hampton ◽  
Muhammad Aziz ◽  
Sadik Khuder ◽  
Saad Ullah Malik ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Controlled Trials ◽  
Significant Heterogeneity ◽  
Free Survival ◽  
Treatment Regimens ◽  
Randomized Controlled

Introduction: Advancements in the treatment of multiple myeloma (MM) with proteasome inhibitors [bortezomib (bort), carfilzomib (carf)], monoclonal antibodies [daratumumab (dara), isatuximab (isa) and elotozumab (elo)], and immunomodulatory drugs [IMiD) [lenalidomide and pomalidomide (pom)] have improved outcomes. However, using lenalidomide as frontline treatment and maintenance therapy exposes greater numbers of patients to lenalidomide prior to relapse. Consequently, the treatment of lenalidomide-refractory (LR) disease is an increasing area of concern. Given the lack of direct comparisons of different treatment regimens for LR MM, we used a systematic review to identify randomized controlled trials (RCTs) that included subgroup analysis of LR patients. The objective of our study was to compare the efficacy of novel treatment regimens in randomized trials for patients with LR MM using a network meta-analysis. Methods: Three databases were searched: MEDLINE/PubMed, Embase, and Cochrane Registry of Controlled Trials. All studies published between January 1, 2005 and December 30, 2019 were queried using keywords "multiple myeloma" and "randomized controlled trial". Only RCT's were included. Primary outcome was progression free survival (PFS) of patients enrolled in myeloma RCT's. Two independent investigators reviewed all the studies and resolved any conflict through mutual discussion. WNetwork meta-analysis using random-effects model was performed to generate direct and indirect comparisons between various treatment groups. Frequentist method was used to rank the interventions and P-score was generated. A higher P score (close to 1.00) corresponded to superior progression free survival. A P-value of &lt;0.05 was considered statistically significant. Hazard ratios (HR) with 95% confidence interval (CI) were calculated. I2statistic was used to assess heterogeneity between the studies as defined by the Cochrane Handbook for Systematic Reviews with a value &gt;50% considered as significant heterogeneity. We used 'R' (Bell Labs, Murray Hill, NJ, USA) for generating our statistical analysis and plots. Results: Our initial search strategy yielded 1171 results. After excluding duplicates, trials in progress, subset analysis and non-randomized studies, 123 RCTs were identified. Only 8 studies clearly reported outcomes of patients with LR myeloma and 7 studies (1698 patients) were included in final analysis of two discrete networks. Pom/bort/dex (HR: 0.65,95% CI: 0.50-0.84), dara/bort/dex (HR: 0.36, 95% CI: 0.21-0.63), and dara/carf/dex (HR: 0.38, 95% CI: 0.21-0.69) were all found to have improved PFS compared to bort/dex (Figure 2). These interventions were ranked as follows: Dara-bort-dex was the most efficacious with a P-score of 0.8758, followed by Dara/carf/Dex (P of 0.8514), Pom/bort/dex (P of 0.4791), Carf/dex (P of 0.2707) and Bort/dex (P of 0.0231). Within Network 2 (Figure 3), pom/dex (HR :0.50, 95% CI= 0.40-0.62), isa/pom/dex (HR: 0.30, 95% CI= 0.20-0.44) and elo/pom/dex (HR: 0.27, 95% CI=0.16-0.45), were all found to have improved PFS compared to dexamethasone (Figure 4). In Network 2, the ranking of interventions was as follows with Elo-pom-dex (P of 0.8716) the most efficacious, followed by Isa-pom-Dex (P of 0.7932) and Pom-dex (P of 0.3352). Conclusion: The results of our network meta-analysis of 1698 patients with lenalidomide refractory myeloma enrolled in seven randomized myeloma trials demonstrate that for lenalidomide refractory myeloma, triplet therapy is superior to doublet therapy. Regimens with the highest efficacy in this subset of patients were triplets containing monoclonal antibodies (such as dara/elo/isa). There is a need for further randomized data to better ascertain the best standard of care for these patients. Disclosures No relevant conflicts of interest to declare.

Efficacy Of Bortezomib-Based Regimens With Or Without An Immunomodulatory Agent In Older Adults With Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5580-5580
Author(s):  
Jordan Atkins ◽  
Susan A Fowler ◽  
Methodius Tuuli ◽  
Aimee S James ◽  
Tanya M Wildes
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Overall Survival ◽  
Partial Response ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Complete Response ◽  
Inclusion Criteria ◽  
Free Survival ◽  
Good Partial Response

Abstract Introduction Multiple myeloma (MM) is an incurable disease within older adults, caused by the malignant proliferation of plasma cells and destruction of skeletal structure, with subsequent end-organ dysfunction. In the elderly and transplant ineligible population, chemotherapeutic regimens that include novel and conventional drugs are currently being employed to attain optimal response and survival outcomes. We performed a systematic review and meta-analysis to investigate the efficacy of the proteasome inhibitor bortezomib, in combination with an immunomodulatory drug (IMiD) versus bortezomib-containing regimens alone in improving overall survival, progression-free survival, and response in patients aged 65 and older ineligible for stem cell transplant. Methods We searched Pubmed/Medline, Embase, Scopus, CENTRAL, DARE, and clinicaltrials.gov databases for randomized controlled trials (RCTs) published from January 1946 until March 2013 using search terms such as: “bortezomib” “thalidomide/analogs and derivatives” and “lenalidomide.” Primary outcomes such as overall survival “OS” and progression-free survival “PFS” were harvested from standard indexes and on-topic articles. We abstracted data from relevant studies for analysis. Heterogeneity was assessed using Cochrane's Q and Higgin's I2 with p<0.1 considered significant. Pooled risk ratios (RR) and hazard ratios (HR) were estimated using DerSimonain and Laird random effect models. Results We identified 762 studies, 201 of which were duplicates that were excluded. Of these studies, 561 met initial inclusion criteria. After screening and systematic review, we found a majority of the articles originated from sub-analyses or reviews of 2 major studies which fully met inclusion criteria: 1) bortezomib-melphalan-prednisone-thalidomide (VMPT) versus bortezomib-melphalan-prednisone (VMP) [Palumbo JCO 2010] and 2) bortezomib-thalidomide-prednisone (VTP) versus VMP [Mateos Lancet Onc 2010). Of the two studies included, 384 patients received thalidomide and bortezomib-containing regimens (VMPT or VTP), and 387 patients received VMP. Thalidomide-containing combinations were associated with improvement in complete response (pooled RR 1.55 [95% Confidence intervals 1.23-1.95]) and very good partial response (pooled RR 1.19 [95% Confidence intervals 1.04-1.38]). There was no evidence of significant heterogeneity associated with either of these outcomes across the studies (I2=0; p=0.559 and I2=0; p=0.600). There were no significant differences in partial response (pooled RR 1.08; 95% CI 0.98-1.19), overall survival (pooled HR 1.04; 95% CI 0.65-1.44), or progression-free survival (pooled HR 0.91; 95% CI 0.29-1.42). There were also no significant differences in toxic side effects (Table). Conclusion Based on the limited data included in this meta-analysis, we found that the addition of thalidomide to a bortezomib-based regimen was associated with improved complete response and very good partial response, but no improvement in overall or progression-free survival. Larger studies of thalidomide and other immunomodulatory agents are required to further clarify the role of adding IMiDs to bortezomib-based regimens in the treatment of MM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacy and Safety of Isatuximab in Relapsed Refractory Multiple Myeloma: A Systematic Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Mydah Sajid Hashmi ◽  
Ali Jaan ◽  
Muhammad Ans Sharif ◽  
Summera Aziz ◽  
Zahoor Ahmed ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trial ◽  
Multiple Myeloma ◽  
High Risk ◽  
Adverse Effects ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Phase 1B ◽  
High Risk Cohort

Introduction: Multiple myeloma (MM) plasma cells express CD38, which is the target of isatuximab (ISA), a monoclonal antibody (mAb), approved for treatment. This systematic review aims to explore the efficacy and safety of ISA based regimens for the treatment of relapsed refractory MM (RRMM). Methods: A systematic search of the literature was performed by searching PubMed, Cochrane Library, Embase, and Clinicaltrials.gov. Our search strategy included MeSH (Medical Subject Headings) terms and keywords for multiple myeloma, and isatuximmab including trade name and generic name from the date of inception to June 5, 2020. Initial databases search yielded 371 articles. After excluding review articles, duplicates, and non-relevant articles, we included five clinical trials reporting the efficacy and safety of ISA for RRMM. Results: Among a total of 526 enrolled patients, 517 patients were evaluated, ISA was given as a monotherapy in 84 patients and given as a part of the combination regimen in 433 patients. In these studies, patients were refractory to multiple lines of therapy. In phase III trial, Attal et al. (2019) studied ISA + Pomalidomide (P) and dexamethasone (d) (n=307) compared with Pd (n=153) with an overall response rate (ORR) of 63% (n=97) in ISA-PD group compared to 32% (n=49) in PD group. At a median follow-up of 11·6 months, median progression-free survival (PFS) was 11·5 months (95% CI: 0·9-13·9) in the ISA-PD group versus 6·5 months (95% CI: 4·5-8·3) in the PD group; hazard ratio (HR) 0·596, (95% CI: 0·44-0·81; p=0·001). Martin et al. (2019) studied ISA as monotherapy in RRMM patients with a median of five prior therapy and observed an ORR of 20 % (n=17) and clinical benefit rate (CBR) of 16.7 % (n=14). For the high-risk cohort, the ORR was 16.7% (3/18), and CBR 27.8% and progression-free survival (PFS) was 2.9 months (95% confidence interval (CI) 1.87 to 5.49). In another phase 1b clinical trial by Mikhael et al. (2019) using ISA-Pd. It showed an ORR of 62.2% (n=28), and partial response (PR) of 35.6% (n=16) with median PFS of 17.6 months (95 % CI: 6.8-20.5 months). Richter et al. (2018) reported a phase 1b clinical trial of ISA in combination with carfilzomib with ORR of 69% (n=20), and PR of 41.4% (n=12). Martin et al. (2017) (phase 1b) studied ISA + lenalidomide + d. The ORR was 56% (n=29) and median PFS was 8.5 months (95 % CI: 4.73-16.59). The ORR of 31% was observed in the high-risk cohort. The majority of adverse effects were hematological: pancytopenia. The main non-hematological adverse effects encountered were infusion-related reactions, fatigue, upper and lower respiratory tract infections (table 02). Conclusion: Isatuximab showed promising responses for the treatment of RRMM, maximal responses were observed with combination regimens. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

scholarly journals The Prognostic Impact of Abnormal Protein Bands in Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4738-4738
Author(s):  
Soon Khai Low ◽  
Matthew Ho ◽  
Saad Jamshed
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Complete Response ◽  
Oligoclonal Bands ◽  
Prognostic Impact ◽  
Free Survival ◽  
Abnormal Protein ◽  
Statistical Heterogeneity

Abstract Introduction: The detection of abnormal protein bands (APB) different from the original monoclonal protein in patients with multiple myeloma (MM) who underwent stem cell transplantation and/or chemotherapy has been reported. These atypical serum immunofixation patterns may be monoclonal (also termed secondary monoclonal gammopathy of undetermined significance) or oligoclonal bands (OB). The prognostic significance of this phenomenon remains controversial. This systematic review and meta-analysis aimed to summarize and analyze the evidence for the association between APB with survival in MM patients. Methods: A systematic search of PubMed, Cochrane, Google Scholar, Medline-Ovid, CINAHL, and ERIC, was conducted using relevant search terms. All studies were screened using predefined selection criteria and critically appraised for quality assessment following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All studies that described the presence of APB, defined as monoclonal spike with heavy or light chain immunoglobulin distinct from the original paraprotein at initial diagnosis of MM, and its associations with survival were included. Studies that reported multivariate adjusted hazard ratios (HR) were further included for meta-analysis. Random-effects model was used to synthesize the pooled HR estimate for the association of APB with survival. Cochran's Q statistics and I2 tests were used to evaluate statistical heterogeneity. Results: A total of 24 out of 181 eligible studies were included for qualitative synthesis. Four studies (including 1115 patients) that reported HR estimates were included in the final meta-analysis. The random-effect summary HR for the progression-free survival among patients with APB was 0.44 (95% CI, 0.31-0.65) with no statistical heterogeneity (I2=0%, p=0.93). The pooled HR for the association with overall survival was 0.31 (95% CI, 0.14-0.66) with moderate statistical heterogeneity (I2=45%; p=0.16) for patients with APB. One study (Silva et al, 2017) only included patients with at least very good partial response while the other three studies reported similar findings of higher occurrence of APB with complete response (Tovar et al, 2013; Jo et al, 2014; Zou et al, 2014). These results are also consistent with the presumed association of APB with complete response as suggested in other studies included in qualitative review. Conclusions: This study indicated a potential prognostic value of APB for favorable outcomes in the context of both overall and progression-free survival in MM patients after treatment. Further research is needed to evaluate the prognostic impact of the sole emergence of APB irrespective of treatment response. Figure 1 Figure 1. Disclosures Jamshed: Takeda: Honoraria.

scholarly journals Genetic program activity delineates risk, relapse, and therapy responsiveness in multiple myeloma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Matthew A. Wall ◽  
Serdar Turkarslan ◽  
Wei-Ju Wu ◽  
Samuel A. Danziger ◽  
David J. Reiss ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosomal Abnormalities ◽  
Transcriptional Regulatory Network ◽  
Progression Free Survival ◽  
Cross Sectional ◽  
Free Survival ◽  
Extreme Risk ◽  
Transcriptional Regulatory ◽  
Transcription Regulators ◽  
Immunosuppressive Microenvironment

AbstractDespite recent advancements in the treatment of multiple myeloma (MM), nearly all patients ultimately relapse and many become refractory to multiple lines of therapies. Therefore, we not only need the ability to predict which patients are at high risk for disease progression but also a means to understand the mechanisms underlying their risk. Here, we report a transcriptional regulatory network (TRN) for MM inferred from cross-sectional multi-omics data from 881 patients that predicts how 124 chromosomal abnormalities and somatic mutations causally perturb 392 transcription regulators of 8549 genes to manifest in distinct clinical phenotypes and outcomes. We identified 141 genetic programs whose activity profiles stratify patients into 25 distinct transcriptional states and proved to be more predictive of outcomes than did mutations. The coherence of these programs and accuracy of our network-based risk prediction was validated in two independent datasets. We observed subtype-specific vulnerabilities to interventions with existing drugs and revealed plausible mechanisms for relapse, including the establishment of an immunosuppressive microenvironment. Investigation of the t(4;14) clinical subtype using the TRN revealed that 16% of these patients exhibit an extreme-risk combination of genetic programs (median progression-free survival of 5 months) that create a distinct phenotype with targetable genes and pathways.

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