Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside

2018 ◽  
pp. 675-680 ◽  
Author(s):  
Aurore Perrot ◽  
Jill Corre ◽  
Hervé Avet-Loiseau
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Plasma Cells ◽  
Mechanisms Of Action ◽  
The Past ◽  
Novel Drugs ◽  
Genetic Abnormalities ◽  
Frequent Mutations ◽  
Risk Patients ◽  
First Relapse

In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains. Assessing these markers is mandatory at diagnosis and at least at first relapse, since it has been clearly shown that the lenalidomide-dexamethasone combination is not efficient in these high-risk patients. In contrast, a triplet combination adding a proteasome inhibitor or a monoclonal antibody to the lenalidomide-dexamethasone backbone clearly improves the survival. Another way to improve the outcome would be to specifically target genetic abnormalities with specific inhibitors. The sequencing of more than 1,000 MM exomes revealed again a huge heterogeneity. The most frequent mutations involve the KRAS and NRAS genes (20%–25% each). However, to date, no good RAS-inhibitors are clinically available, preventing targeted therapy. The only drugable target is the V600E BRAF mutation. Unfortunately, this specific mutation is present in only 3% of the patients. Finally, it has been recently reported a specific efficiency of the BCL2-inhibitor venetoclax in patients with the t(11;14) translocation, which is found in 20% of the patients.

scholarly journals Aberrations Detected By FISH in Brazilian Multiple Myeloma Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5509-5509
Author(s):  
Maria de Lourdes Chauffaille ◽  
Aline Dos Santos Borgo Perazzio
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
High Risk Patients ◽  
Total Percentage ◽  
Genetic Abnormalities ◽  
Interphase Cells ◽  
Risk Patients ◽  
Standard Risk

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy with genetic abnormalities that comprise the most important prognostic factors. Chromosomal aberrations also influence the evolution and treatment refractoriness. Abnormalities progress in a stepwise way, from the pre-malignant stage of monoclonal gammopathy of undetermined significance, through smoldering until symptomatic MM. While marrow karyotype reveals only <30% of aberrations, FISH may show in up 90% of cases. FISH has become an essential tool in diagnosis, risk-classification and personalized therapy. There are two main groups of abnormalities: primary (trisomies and 14q or IGH gene translocations) which occur in plasma cells evolving into clonal stage, and secondary (-13/13q-, del(17p), +1q21/del1p), occurring during disease progression. As there are few reports of genetic aberrations in Brazilian MM patients, the objective of this study was to enlarge the casuistic and compare results. Objective: To dissect FISH aberrations detected in a larger set of Brazilian MM patients. Material and Methods: From Jan 2012 to Nov 2017, 417 MM patients were selected for the study. FISH was performed on isolated CD138 immunomagnetic beads plasma cells, using probes for 6q23.3 (MYB), 11q12.1 (D11S3347), 11q22.3 (ATM), 13q14.3 (D13S319-D13S25-RB1), 13q34 (D13S1825-LAMP1), 14q32 (IGH, break-a-part), 17p13.1 (TP53) IGH/FGFR3, IGH/CCND1 and IGH/MAF, according to the manufacturer´s instructions. At least 100 interphase cells were counted, and results described according to ISCN 2016. The cut off level was in-house established by mean +2 standard deviation from normal bone marrow controls. Results: Patients mean and median ages were 63.9 and 64y, respectively. M:F rate was 1.5:1. FISH showed abnormalities in 80% (333) of cases. Considering primary abnormalities: IGH-FGFR3 rearrangements were detected in 22.5% (30 patients), IGH-CCND1 in 57.2% (76), IGH-MAF in 3.7% (5 patiens), and 16.6% (22) IGH-unidentified gene. The most frequent trisomies were: 6 (62 patients), 11 (93 patients) and 17 (33 patients), some co-occurring and others isolated. 89 (31.6%) cases presented >3 aberrations, from which 25% had del(17p) (TP53) as well; 65 cases had three aberrations and 127 less than three abnormalities. Referring to secondary aberrations, 67(20.1%) cases presented del(13q) (RB1 and LAMP) and 32 (9.6%) del(17p) (TP53). Stratifying to prognosis (mSmart 2.0) 37 (10%) patients were considered as high-risk; 92 (27.6%) intermediate; 160 (48%) standard and 44 were not classified. Discussion: Comparing these results to literature reports, at diagnosis, Brazilian MM patients have mean and medium ages younger than European and North American populations. This type of difference has been detected in other hematopoietic neoplasias as well. FISH results were thoroughly similar referring to the total percentage and type of aberrations, but some variations in the frequency of aberrations were observed. Most patients were classified in the standard-risk group, presenting hyperdiploidy (30%) and t(11;14)(19%). The percentage of high-risk patients was reasonable (10%). Most of those with more than three aberrations also presented del(17p), a marker of adverse cytogenetics, as expected. The frequency of del(17p) was not unexpected, most being heterozigous deletion. Cases described as IGH-unidentified gene rearrangements may have been due to the unavailability of probes for chromosomes 6 and 20, at the time of the study. The same happened to 1q gain and del(1p). In summary, the spectrum of aberrations detected allowed identifying high-risk patients, choosing adapted therapy and improving outcomes. Disclosures No relevant conflicts of interest to declare.

scholarly journals Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics

Blood ◽  
2012 ◽  
Vol 119 (9) ◽  
pp. 2100-2105 ◽  
Author(s):  
Shaji Kumar ◽  
Rafael Fonseca ◽  
Rhett P. Ketterling ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
High Risk ◽  
Median Overall Survival ◽  
Diagnostic Testing ◽  
Prognostic Significance ◽  
Genetic Abnormalities ◽  
Impact On Survival ◽  
Risk Patients ◽  
Standard Risk

Abstract Routine incorporation of FISH into multiple myeloma (MM) diagnostic testing has led to a better appreciation of the heterogeneity of genetic abnormalities associated with this disease. We studied a group of 484 patients with newly diagnosed symptomatic MM to better understand the prevalence of the various abnormalities and the prognostic significance of the overlapping abnormalities. A translocation involving the IgH locus and 1 of the 5 recurrent partner chromosomes was seen in 161 (33%) patients, and 275 (57%) had trisomy of at least 1 odd-numbered chromosome. High-risk FISH, defined as the presence of t(4;14), t(14;16), t(14;20), or loss of P53, was seen in 115 (24%) patients; the median overall survival for this group was 3.9 years, compared with “not reached” for standard-risk patients (P < .001). Among the patients with high-risk FISH, 49 patients who also had at least 1 trisomy had a median overall survival that was not reached, compared with 3 years for high-risk patients without a concurrent trisomy (P = .01). Based on the current findings, we conclude that the presence of trisomies in patients with t(4;14), t(14;16), t(14;20), or p53 deletion abnormalities in MM ameliorates the usual adverse impact associated with these prognostic markers.

1610: High-Risk Patients Undergoing Radical Prostatectomy Today are Less High-Risk than in the Past

2005 ◽  
Vol 173 (4S) ◽  
pp. 436-436
Author(s):  
Christopher J. Kane ◽  
Martha K. Terris ◽  
William J. Aronson ◽  
Joseph C. Presti ◽  
Christopher L. Amling ◽  
...  
Keyword(s):  
High Risk ◽  
Radical Prostatectomy ◽  
High Risk Patients ◽  
The Past ◽  
Risk Patients

137 Genomics of multiple myeloma influences the expression of CAR T-cell targets

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A150-A150
Author(s):  
Christina Yu ◽  
Brian Walker ◽  
G David Roodman ◽  
Kun Huang ◽  
Michel Sadelain ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
High Risk ◽  
Cell Surface ◽  
T Cell Therapy ◽  
Genomic Features ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Risk Patients

BackgroundMultiple Myeloma (MM) is an incurable disease, with a particularly poor prognosis for patients with refractory/relapsed MM or high-risk cytogenetics. Chimeric Antigen Receptor (CAR) T-cell therapy targeting BCMA can induce deep responses in highly pretreated RRMM; however, remissions are not sustained, and the majority of patients eventually relapse. We hypothesized that genomic determinants of MM play a role in dictating the expression of surface targets that can be of use for immune targeting.MethodsWe analyzed the gene expression of 24 immunotherapeutic targets in a combined dataset of 1900 MM patients from three independent expression datasets obtained from the Multiple Myeloma Research Foundation CoMMpass study and Gene Expression Omnibus. Given that CAR T-cell therapy may be especially important for patients with high-risk myeloma, we defined the expression of each target in high-risk MM patients by stratifying patients based on several genomic features impacting prognosis. Additionally, we conducted a gene co-expression network analysis and identified 30 gene modules highly correlated with 16 cell surface targets from our panel, further suggesting that genetic determinants of MM may shape a targetable cell surfaceome. In order to determine whether targeting any of these candidate antigens might cause major toxicity to normal cells, we utilized several repositories providing protein data1 to annotate their expression in several normal cell types.ResultsWe determined that a number of genomic factors could stratify the 24 targets into three general groups: 1) targets that show consistent overexpression in high-risk patients: IGF1R, ITGB7, GPRC5D and CD70, and are thus suitable for most high-risk patients; 2) targets that are down-regulated in patients with high-risk genomic features: CD200, CD19, CD40, CD1D and IGKC, perhaps playing a role in cancer immune escape; and 3) targets associated with one specific genetic abnormality, i.e. t(4;14): FUT3, SLAMF7, CD56, CD138 and BCMA, thus of use for precision CAR therapy in this high-risk patient subset.ConclusionsOur work provides a means of target selection for precision CAR therapy, by considering both patient genomic backgrounds and cancer cell surface profiles. Furthermore, our results provide a roadmap for immunotherapy of MM by unbiasedly comparing the expression of top MM cell surface targets in patient data and normal cells and suggest that the genetic landscape of MM may predict the expression of specific targets for precision immunotherapy. The quest for novel MM targets for immunotherapies remains open, and CAR target discovery driven by specific genetic events remains an active area of investigation.ReferencePerna F, Berman SH, Soni RK, et al. Integrating proteomics and transcriptomics for systematic combinatorial chimeric antigen receptor therapy of AML. Cancer Cell 2017;32(4):506–19.

scholarly journals The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110196
Author(s):  
Albert Oriol ◽  
Laura Abril ◽  
Anna Torrent ◽  
Gladys Ibarra ◽  
Josep-Maria Ribera
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Safety Profile ◽  
Proteasome Inhibitors ◽  
Clinical Development ◽  
Phase Iii ◽  
Acceptable Safety Profile ◽  
Refractory Multiple Myeloma ◽  
High Risk Patients ◽  
Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

Transjugular Intrahepatic Portosystemic Shunts in High-Risk Patients

2020 ◽  
Vol 04 (02) ◽  
pp. 148-156
Author(s):  
David S. Shin ◽  
Hong Vo ◽  
Guy Johnson ◽  
Raimund Pichler ◽  
Scott W. Biggins
Keyword(s):  
High Risk ◽  
Cardiac Disease ◽  
Poor Prognosis ◽  
Hepatic Malignancy ◽  
Safety And Efficacy ◽  
End Stage Liver Disease ◽  
The Past ◽  
Portosystemic Shunts ◽  
Risk Patients ◽  
End Stage

AbstractCirrhosis with complications of portal hypertension portends a poor prognosis. Transjugular intrahepatic portosystemic shunts (TIPS) can successfully treat some of these complications in select patients. While the safety and efficacy of TIPS have improved significantly over the past decade, certain patients are categorized as high-risk based on various demographic, laboratory, and comorbid factors. Herein, we provide an in-depth review of TIPS in these settings, including high model for end-stage liver disease score, hepatic malignancy, advanced age, cardiac disease, renal dysfunction, and pregnancy, and discuss their impact on patient selection and procedural considerations.

scholarly journals Peripheral blood monoclonal plasma cells as a predictor of survival in patients with multiple myeloma [see comments]

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1780-1787 ◽  
Author(s):  
TE Witzig ◽  
MA Gertz ◽  
JA Lust ◽  
RA Kyle ◽  
WM O'Fallon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
High Risk ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Cell Labelling ◽  
Newly Diagnosed ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Beta 2 Microglobulin

Abstract The purpose of this study was to quantitate the number and labeling index of monoclonal plasma cells in the blood of patients with newly diagnosed multiple myeloma (MM) to learn if these values were independent prognostic factors for survival. Patients were candidates for this study if they had untreated myeloma requiring therapy, were evaluated at our institution between 1984 and 1993, and had a sample of blood analyzed with a sensitive immunofluorescence technique for monoclonal plasma cells and the blood B-cell labelling index (BLI). The % blood monoclonal plasma cells (%BPC) and the BLI were analyzed along with stage, marrow plasma cell LI, % marrow plasma cells, calcium, creatinine, albumin, beta-2-microglobulin, and C-reactive protein as univariate and multivariate factors for survival. Eighty percent of the 254 patients accrued to this study had monoclonal BPC detected. The median % BPC was 6% and 57% (144 of 254) of patients had a high number (> or = 4%). Patients with > or = 4% BPC had a median survival of 2.4 years vs 4.4 years for those with < 4% BPC (P < .001). The BLI was also prognostic (P = .008). In a multivariate analysis, the % BPC, age, albumin, stage, marrow plasma cell LI, and the BLI were independent factors for survival. The %BPC and the marrow plasma cell LI best separated the group into low, intermediate, and high risk myeloma with median survivals of 52, 35, and 26 months, respectively. Patients with high %BPC were less likely to have lytic bone disease from their MM (P = .002). The %BPC and the BLI are independent prognostic factors for survival and are useful in identifying patients as low, intermediate, and high risk. Clonal cells in the blood should be quantified in future clinical trials for myeloma.

Outcome of Adult AML at First Relapse Following a Risk-Oriented Strategy: An Update of the Northern Italy Leukemia Group (NILG) Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4385-4385 ◽  
Author(s):  
Irene Cavattoni ◽  
Enrico Morello ◽  
Elena Oldani ◽  
Tamara Intermesoli ◽  
Ernesta Audisio ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Risk Category ◽  
High Dose ◽  
High Risk Patients ◽  
Risk Patients ◽  
First Relapse ◽  
Group 2 ◽  
Standard Risk ◽  
Group 1

Abstract INTRODUCTION The impact on post-relapse survival of selected prognostic factors and salvage therapy (finalized to perform an allo-SCT) was retrospectively analyzed in 172 patients (patients) with relapsed non-APL AML, who had been initially treated with standard induction and risk-adapatiented consolidation. The aim was to identify factors associated with a better outcome at first relapse. METHODS All 172 patients were at first recurrence following consolidation of CR1 with high-dose Ara-C (HiDAC) multicycle therapy supported by blood stem cells (standard risk, as defined by mixed clinical-cytogenetic criteria) or allo-SCT in case of high-risk prognostic profile. Median age at relapse was 55 y (range 21–70). CR1 duration was &lt;6 months in 50 patients (29%), ranging from 0.6 to 52,7 mo (median 9,1). High risk patients were 128/172 (74%) and 43/172 patients (25%) had an unfavourable cytogenetics (CG). One hundred-eleven patients (64%) received HiDAC and 24 (14%) an allo-SCT according to study design. RESULTS 140 patients (81%) received salvage treatment. The remaining 32 patients (19%) received palliation and all of them died. The median OS was 17.1 mo, with a 2yOS of 34%. Favorable prognostic factors identified by univariate analisys were: favourable or intermediate CG (p=0,007), standard risk category according to first line protocol (p=0.004), availibility of a HLA matched donor (p= 0.048), achievement of an early CR1(p=0,000), HiDAC as first line therapy(p=0,000), alloHSCT perfomed at relapse (p=0,000) and a DFS from CR1&gt;12 mo (p=0,000). In multivariate analysis favourable or intermediate CG and DFS &gt;12 mo were confirmed as independent prognostic factors (p=0,036 and p=0,001 respectively). Among the 140 patients, 50 received an allo-SCT following relapse (36%, group 1), and the remaining 90 (64%, group 2) received high dose chemotherapy alone (85), autologous SCT (2), or DLI (3, in case of previous alloSCT). Both groups were comparable regarding age &gt;55 y, prior allo-SCT and risk class at diagnosis. After salvage therapy, 44 patients(88%) in the group 1 achieved CR2, compared to 26 patients (29%) in the group 2. The median duration of CR2 was 9 mo (range 2–64) and 3 mo (range 1–34) in group 1 and 2 respectively. NRM was 17/140: 12 patients (24%) in the allo-SCT group and 5 (6%) in group 2. The 2yOS was 57% and 23% respectively (p=0,000). Moreover, among 50 alloSCT patients, survival was affected by risk category at diagnosis: 2yOS of 19 (38%) standard risk patients was 83% compared to 42% in 31 high risk patients (62%) (p=0.01). This risk stratification has no impact on OS in the group 2. CONCLUSIONS DFS &gt; 12 mo and standard risk category at diagnosis, according to NILG protocol, are the most important independent positive prognostic factors impacting OS of AML relapsed patients. The availibility of a HLA matched donor and a subsequent intensification with alloSCT may offer substantial salvage rates and its outcome is affected by the risk stratification at diagnosis. Nevertheless, high risk patients could benefit from alloSCT, reaching an 2yOS of 42%.

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