Use of bortezomib to overcome the poor prognosis of t(4;14), but not del(17p), in young patients with newly diagnosed multiple myeloma.

Abstract Abstract 957 Translocation t(4;14)(p16;q32) has been associated with a poor outcome in multiple myeloma. This poor prognosis has been identified both in patients treated with melphalan-prednisone (MP) and in those treated with high-dose melphalan after a VAD induction. For instance, in 100 patients with t(4;14) treated with VAD and MEL200, the median PFS and OS were 21 months and 41 months, respectively, as compared to 37 months and 65 months for patients lacking the t(4;14) (Moreau et al., Leukemia 2007). Some preliminary studies have suggested that bortezomib (Velcade®) was able to overcome the poor prognosis of the translocation in elderly patients treated with MP-Velcade® (San Miguel et al., NEJM 2008). In order to address this important question, we analyzed 436 patients treated in the IFM, according to the IFM-2005-01 trial, arm B: induction with 4 cycles of Velcade®/Dexamethasone (VD), followed by one or two courses of high-dose melphalan (MEL200). A translocation t(4;14) was observed in 67 of these 436 patients treated with VD (15%), whereas del(17p) was found in 51 patients (11%). Of note, 10 patients presented both the t(4;14) and the del(17p). The median PFS was 25 and 36 months, in patients with or without the t(4;14), respectively (p=0.006). At 3 years, 76% of the patients with t(4;14) were still alive, as compared to 88% of the patients lacking the translocation (p=.003). For comparison, the OS results were respectively 62% (patients with t(4;14)) and 73% (patients lacking the translocation) in patients treated with a VAD induction. Thus, it seems that VD is able to partially overcome the poor prognosis of t(4;14). We also looked at the prognostic value of del(17p) in this series of patients treated with VD. In contrast to the t(4;14) situation, VD was enable to rescue patients with del(17p) (same PFS and OS for patients treated with VD than for those treated with a VAD induction). Thus, this study (by far the largest so far reported) shows that VD as induction before intensification is able to improve the prognosis of patients with t(4;14), but not of those with del(17p). Disclosures: Avet Loiseau: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Attal:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Harousseau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees.

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RDD Versus VDD Followed by ASCT in Newly Diagnosed Young Patients With Multiple Myeloma

Case Medical Research ◽

10.31525/ct1-nct03908138 ◽

2019 ◽

Author(s):

Keyword(s):

Multiple Myeloma ◽

Young Patients ◽

Newly Diagnosed

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Low absolute CD4+ T cell counts in peripheral blood predict poor prognosis in patients with newly diagnosed multiple myeloma

Leukemia & Lymphoma ◽

10.1080/10428194.2020.1751840 ◽

2020 ◽

Vol 61 (8) ◽

pp. 1869-1876 ◽

Cited By ~ 2

Author(s):

Yan Gu ◽

Yuanyuan Jin ◽

Jie Ding ◽

Wu Yujie ◽

Qinglin Shi ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Peripheral Blood ◽

Poor Prognosis ◽

Cd4 T Cell ◽

Newly Diagnosed ◽

Cell Counts

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CD27 antigen negative expression indicates poor prognosis in newly diagnosed multiple myeloma

Clinical Immunology ◽

10.1016/j.clim.2020.108363 ◽

2020 ◽

Vol 213 ◽

pp. 108363

Author(s):

Bin Chu ◽

Li Bao ◽

Yutong Wang ◽

Minqiu Lu ◽

Lei Shi ◽

...

Keyword(s):

Multiple Myeloma ◽

Poor Prognosis ◽

Newly Diagnosed

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High Expression Levels of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 and Semaphorin 5A Indicate Poor Prognosis in Multiple Myeloma

Acta Haematologica ◽

10.1159/000502404 ◽

2019 ◽

Vol 143 (3) ◽

pp. 279-288 ◽

Cited By ~ 1

Author(s):

Ling-Juan Huang ◽

Ying Shen ◽

Ju Bai ◽

Fang-Xia Wang ◽

Yuan-Dong Feng ◽

...

Keyword(s):

Multiple Myeloma ◽

Noncoding Rna ◽

Poor Prognosis ◽

Clinical Characteristics ◽

Staging System ◽

High Expression ◽

Newly Diagnosed ◽

High Expression Group ◽

International Staging System ◽

Nucleolar Rna

Background: The aim of this study was to detect the expression of long noncoding RNA small nucleolar RNA host gene 18 (SNHG18) andsemaphorin 5A (SEMA5A) genes in multiple myeloma (MM) patients and to explore the correlation of the expression of these genes with the clinical characteristics and prognosis of MM patients. Methods: Forty-seven newly diagnosed MM, 18 complete remission MM, 13 refractory/relapse MM, and 22 iron deficiency anemia (serving as control) samples were extracted at the Department of Hematology, Second Aﬃliated Hospital of Xian Jiaotong University between January 2015 and December 2016. The clinical features of the MM patients are summarized. Real-time quantitative PCR was performed to analyze the relative expression levels of the SNHG18 and SEMA5Agenes. The clinical characteristics and overall survival (OS) of the MM patients were statistically analyzed while measuring different levels of SNHG18 and SEMA5Agene expression. At the same time, the correlation between the expression of SNHG18 and SEMA5A was also analyzed. Results: The analysis confirmed that SNHG18 and its possible target gene SEMA5A were both highly expressed in newly diagnosed MM patients. After analyzing the clinical signiﬁcance of SNHG18 and SEMA5A in MM patients, we found that the expression of SNHG18 and SEMA5A was related to the Durie-Salmon (DS), International Staging System (ISS), and Revised International Staging System (R-ISS) classification systems, and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART; p < 0.05). Moreover, we observed a significant difference in OS between the SNHG18/SEMA5A high expression group and the low expression group. We found a positive correlation between SNHG18 and SEMA5A expression (r = 0.709, p < 0.01). Surprisingly, the expected median OS times of both the SNHG18 and SEMA5Ahigh expression groups were significantly decreased, which was in contrast to those of both the SNHG18 and SEMA5Alow expression groups and the single-gene high expression group (p < 0.05). Conclusion: High expression of both SNHG18 and SEMA5A is associated with poor prognosis in patients with MM.

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A Better Mobilization Regimen for Newly Diagnosed Multiple Myeloma Patients,

Blood ◽

10.1182/blood.v118.21.4051.4051 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4051-4051

Author(s):

Ahmed Y Abuabdou ◽

Eric R Rosenbaum ◽

Saad Usmani ◽

Bart Barlogie ◽

Michele Cottler-Fox

Keyword(s):

Multiple Myeloma ◽

Conflicts Of Interest ◽

Optimal Number ◽

P Value ◽

Newly Diagnosed ◽

The Poor ◽

Cd34 Cells ◽

Significant Difference ◽

Minimum Number ◽

Poor Mobilizer

Abstract Abstract 4051 Introduction: What constitutes an acceptable mobilization regimen for collecting CD34+ cells depends on whether the goal of collection is to obtain a minimum number versus optimal number of cells. When treating patients with high-risk myeloma it may be important to obtain an optimal number. Here we compare retrospectively our earlier mobilization regimen, VTD-PACE, with MVTD-PACE in newly diagnosed, previously untreated multiple myeloma patients. Materials and Methods : We reviewed data for all patients who collected hematopoietic progenitor cells on Total Therapy protocols TT3a/TT3b with VTD-PACE (n=394) from February 2004 to September 2008 (138 females and 256 males, median age 59y; range 31–75), and on TT4/TT5 with MVTD-PACE (n=188) from August 2008 to May 2011 (78 females and 110 males, median age 61y, range 30–76). Based on their predicted first day collection with a large volume leukapheresis (30L processed), using our center's predictive formula (Blood 2010; 116(21):1182a), patients were stratified into 4 mobilizer types: poor (<2×106 CD34+ cells/kg), intermediate (≥2 to 10×106), good (>10 to 20×106) and excellent (>20×106). Variables examined included number of CD34+ cells/μl blood on day 1 and day 2 of collection (we have a minimum 2 day collection requirement), number of collection days to reach our minimum goal of 20×106 CD34+ cells/kg, and total CD34+ cells/kg collected for both chemotherapy groups. Variables for both groups stratified by mobilizer type were compared using two-tailed student's t-tests, except for the poor mobilizer group, where population size was too small for formal statistical analyses (VTD-PACE n=7, MVTD-PACE n=4), although averages were calculated. Results : There was no significant difference between VTD-PACE and MVTD-PACE for CD34+ cells/μl blood on day 1 of collection among the excellent [mean 368.9 (n=184) vs. 434.6 x106 (n=92); p-value 0.07], good [mean 138.6 (n=102) vs. 128.6 x106 (n=40); p-value 0.19], and intermediate [mean 60.1 (n=100) vs. 55.9 x106 (n=52); p-value 0.39] groups. A statistically significant difference between VTD-PACE and MVTD-PACE was found for CD34+ cells/μl blood on day 2 of collection for excellent mobilizers [mean 333.8 (n=184) vs. 460 ×106 (n=92); p-value <0.001], but not for the good [mean 165.7 (n=102) vs. 189.5×106 (n=40); p-value 0.21] and intermediate [mean 80.1 (n=101) vs. 102.3 ×106 (n=52); p-value 0.07] groups. When CD34+ cell/kg collection totals with VTD-PACE and MVTD-PACE were compared, a significant difference was seen for the intermediate mobilizer group only [mean 23.6 (n=101) vs. 26.3 ×106 (n=52); p-value 0.03]. For the poor mobilizer group, VTD-PACE had an average CD34+ cells/μl blood of 13.5×106 for day 1 of collection and 17.0 ×106 for day 2, with a total of 14.5×106 CD34+cells/kg collected; while MVTD-PACE had an average of 13.2×106 CD34+ cells/μl blood for day 1 of collection, 24.9×106 for day 2, with a total of 24.2×106CD34+ cells/kg collected. The number of collection days was similar between VTD-PACE and MVTD-PACE in the excellent mobilization group (2 days), but was slightly more for VTD-PACE compared to MVTD-PACE for the good (2.1 vs. 2 days), intermediate (3.2 vs. 2.9 days), and poor (6.1 vs. 5.8 days) groups. Conclusion : Both regimens allow more than minimum collections, but MVTD-PACE provides a higher peak number of CD34+ cells/μl blood, resulting in a slightly lower mean number of days of collection than VTD-PACE to reach an optimal collection. Disclosures: No relevant conflicts of interest to declare.

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High Trip13 and Low P31 Comet Cause Drug Resistance and Poor Prognosis In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.3820.3820 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3820-3820

Author(s):

Yi Tao ◽

Zhimin Gu ◽

Ye Yang ◽

Hongwei Xu ◽

Xiaojing Hu ◽

...

Keyword(s):

Multiple Myeloma ◽

Drug Resistance ◽

Cell Lines ◽

Poor Prognosis ◽

Caspase 3 ◽

Plasma Cells ◽

Myeloma Cell ◽

Newly Diagnosed ◽

Caspase 9 ◽

Over Expression

Abstract Background We have recently established that increased chromosomal instability (CIN) signature is linked to drug resistance and poor outcome in multiple myeloma (MM) and other cancers. Thyroid Hormone Receptor Interactor 13 (Trip13), one of the 56 drug-resistant genes, plays a key role in chromosomal recombination and structure development during meiosis and has been reported to be increased in some malignancies including lung cancer, prostate cancer and breast cancer. In this study, we investigated how important Trip13 is in myelomagenesis and progression. Materials and Methods Gene expression profiling (GEP) was analyzed on plasma cells from 22 healthy donors, 44 patients with monoclonal gammopathy of undetermined significance (MGUS), 351 patients with newly diagnosed multiple myeloma, and 9 human myeloma cell lines, as well as on 36 sequential samples at diagnosis, pre-1st, pre-2nd and post-2nd autologous stem cell transplantation (ASCT). Over-expression and knock-down experiments of Trip13 were performed on myeloma cell lines by lentivirus transfection. Cell viability was assessed by trypan exclusion assay. Western blots were used to detect the expression of Trip13, P31 comet, caspase-8, caspase-9, caspase-3 and PARP, and checkpoint related proteins MAD2 and CDC20 in Trip13 overexpressed or Trip13 shRNA-transfected myeloma cells. Results Sequential GEP samples showed that Trip13 expression increased in 8 of 9 patients after chemotherapy and ASCT compared to the samples at diagnosis strongly suggesting that increased Trip13 is associated with drug resistance. Trip13 was already significantly increased in MGUS patients, newly diagnosed MM patients and MM cell lines compared with normal plasma cells. Furthermore, Trip13 was significantly higher in high-risk MMs than in low-risk MMs and increased Trip13 was linked to an inferior event-free survival (EFS) (p<0.01) and overall survival (OS) (p<0.01) in 351 newly diagnosed MMs. In contrast, the Trip13-interacting gene P31 comet was down-regulated in high-risk MMs and high expression of P31 was associated with good outcome. Interestingly, patients with high Trip13 and low P31 comet have the worst outcome compared to patients with only one of these, suggesting the interaction of Trip 13 and p31 has a synergistic effect on MM progression. Transfection of Trip13 into ARP1 and OCI-My5 cells significantly increased cell proliferation, while knock-down Trip13 in OCI-My5, H929, RPMI8226 cells inhibited cell growth and induced MM cell apoptosis with increases of cleaved caspase-8, caspase-9, caspase-3 and PARP. Mechanistic studies showed that Trip13 over-expression decreased P31comet and MAD2 expression by western blotting, but increased CDC20. Conclusions The association of increased Trip13 and decreased p31 is a good biomarker for MM drug resistance and poor prognosis. Our results also show Trip13 and P31 comet could be potential targets to overcome drug resistance in MM. Disclosures: No relevant conflicts of interest to declare.

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Bortezomib Plus Melphalan and Prednisone (VMP) Followed By Lenalidomide and Dexamethasone (Rd) in Newly Diagnosed Elderly Myeloma Patients Overcome the Poor Prognosis of High-Risk Cytogenetic Abnormalities (CA) Detected By Fluorescence in Situ Hibridization (FISH)

Blood ◽

10.1182/blood.v126.23.4243.4243 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4243-4243 ◽

Cited By ~ 1

Author(s):

Maria-Victoria Mateos ◽

Norma C Gutierrez ◽

María-Luisa Martín ◽

Joaquín Martínez-López ◽

Miguel T Hernandez ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Poor Prognosis ◽

Plasma Cells ◽

Risk Group ◽

Fish Analysis ◽

Newly Diagnosed ◽

The Poor ◽

Risk Patients ◽

Standard Risk

Abstract Background: Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors. CA has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. Bortezomib-based combinations have shown to improve the outcome of patients with high-risk CA but they do not completely overcome their adverse prognosis. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). There weren't differences in the rates of CA according to the treatment arm. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 37 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 36 months, p=0.01, HR 2.2, 95% IC 1.1-4.2) and this also translated into a significantly shorter 4-years OS (27% vs 72%, p=0.006, HR 3.3, 95% IC 1.4-7.7). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (32 months vs 30 months) and 4-years OS (64% vs 60%). This effect was observed only in the sequential arm applied to either t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (33 months vs 30 months) and 4-years OS (58% vs 65%) in the whole series and no differences were observed in the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Celgene: Consultancy, Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy. Gironella:Celgene Corporation: Consultancy, Honoraria. Paiva:BD Bioscience: Consultancy; Binding Site: Consultancy; Sanofi: Consultancy; EngMab AG: Research Funding; Onyx: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Puig:Janssen: Consultancy; The Binding Site: Consultancy. San Miguel:Millennium: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria; Sanofi-Aventis: Honoraria.

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Gene Expression and Genomic Markers Identify a Subpopulation of Poor Prognosis t(4;14) Patients in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-128907 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 366-366

Author(s):

Maria Ortiz ◽

Fadi Towfic ◽

Erin Flynt ◽

Nicholas Stong ◽

Sneh Lata ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

High Risk ◽

Poor Prognosis ◽

Newly Diagnosed ◽

Employment Equity ◽

Gene Set ◽

Combining Data ◽

Genomic Markers ◽

Equity Ownership

Cytogenetics is an important prognostic marker in multiple myeloma (MM). Patients with t(4;14) (~15% of newly diagnosed MM patients) are known to have short progression free survival (PFS) and overall survival (OS). This feature, measured by FISH, is used in combination with ISS=3 as a selection marker for patients with high risk (HR) of progression. Only a subset of patients grouped by t(4;14) and ISS=3 display genuinely poor survival, however, with ~25% dying within 24 months after diagnosis (similar to the Double Hit subgroup defined by Walker et al1). To elucidate this observation, we created the largest dataset of MM t(4;14) patients to date by combining data from the Myeloma Genome Project (MGP, n=73) and data from TOUL (n=100, patients analyzed in routine practice) to identify transcriptomic and/or genomic markers associated with HR t(4;14). Gene expression (GE), copy number aberration (CNA), single nucleotide variant (SNV) and translocations were derived from RNAseq and WGS/WES profiling of biopsies from patients aged less than 75 years who received transplant, and integrated with clinical information (including Age, PFS and OS). Demographics: MGP median age=61; 30% female; median PFS (mPFS)=26.2months (m) and median OS (mOS) not reached. TOUL median age=60; 35% female, mPFS=23.7m and mOS = 86.1m. Our previous work (Ortiz ASH 2018, Ortiz EHA 2018) identified a molecularly-defined HR MM patient subgroup (MDMS8, mPFS<20m, m0S<35m) defined by GE patterns related to cell cycle dysregulation. In that analysis, 24% of t(4;14) patients were identified as MDMS8 (mPFS<13m, mOS<30m), the rest (76%) were grouped in other lower risk molecular segments (mPFS<30m, mOS NR). A GE classifier for t(4;14) in MDMS8 vs the rest of t(4;14) patients was created on the MGP dataset and applied to identify similar patients in the TOUL data, obtaining a significant difference between MDMS8-like t(4;14) patients (20% prevalence, mPFS<15m, mOS<26m) in the TOUL dataset and non-HR t(4;14) (mPFS<26m, mOS<103m) in both PFS (p.value<1e-3) and OS (p.value<1e-5). Although there are some conventional t(4;14) gene expression surrogates, they do not identify the HR t(4:14) subgroup. Comparison of known t(4;14) gene expression markers MMSET and FGFR3 in HR t(4;14) (OS < 24ms & not_alive, N=34) versus non-HR t(4;14) patients (N=94) across both datasets combined did not yield significant differential expression of either gene (p.value>0.10). MMSET was over-expressed in all t(4;14) patients, while FGFR3 displayed a binomial distribution (two groups of patients with high (N=37, median value=10 log2CPM) and low (N=91, median value=2 log2CPM) FGFR3 expression) within t(4;14) patients (p.value<0.05) without association with outcome (p.value>0.10). GE analysis of HR t(4;14) vs non-HR t(4;14) patients aligned with MDMS8 biology, but identified new pathways also including DNA repair, MYC targets and Oxidative Phosphorylation being up-regulated in the HR t(4;14) group. A gene-set variation analysis based on the MSigDb C1 gene-set, wherein genes are grouped based on their genomic location, was performed to identify GE changes of potentially epigenomic origin. Results highlighted chr9q22, chr9q33, and chr13q13 as down-regulated in the HR t(4;14) group, while genes in 16q24 were significantly up-regulated. CNA analysis identified amplifications in chromosomes 3 and 19 and deletions in chr12p as significantly associated with the HR t(4;14) population (p.value < 0.05); while deletions in chr14q (preceding the translocated region) occurred more frequently in the non-HR t(4;14) group. Our results provide new insights into identification of these patients and underlying biology that could drive poor prognosis in t(4;14) patients. Molecular identification of HR t(4;14) patients would enable proper risk classification for this MM patient group and understanding differences in HR t(4;14) biology could provide the basis for identification of a specific therapeutic target for this HR subpopulation. An ongoing aim of this work is development of a clinically applicable classifier that accurately identifies this subpopulation of MM patients and the biological drivers of their high-risk disease. Disclosures Ortiz: Celgene Corporation: Employment, Equity Ownership. Towfic:Celgene Corporation: Employment, Equity Ownership. Flynt:Celgene Corporation: Employment, Equity Ownership. Stong:Celgene Corporation: Employment, Equity Ownership. Lata:Celgene Corporation: Employment, Equity Ownership. Sampath:Celgene Corporation: Employment, Equity Ownership. Rozelle:Celgene Corporation: Other: Contractor for Celgene. Trotter:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership.

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Retrospective Analysis of the Efficacy of Triplet Therapy, Including Lenalidomide, in Newly Diagnosed Multiple Myeloma Patients Who Obtained Responses Less Than VGPR after Rd Therapy

Blood ◽

10.1182/blood-2019-131617 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5595-5595

Author(s):

Naoki Takezako ◽

Naoya Kaneko ◽

Airi Hamano ◽

Kenichi Ito ◽

Naohiro Sekiguchi ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Elderly Patients ◽

Poor Prognosis ◽

Staging System ◽

Initial Therapy ◽

Novel Agents ◽

Newly Diagnosed ◽

International Staging System ◽

Novel Agent

Background Although multiple myeloma remains an incurable disease, the triplet therapy with novel agents has significantly improved the prognosis. However, the utility of the novel agents is often not obtained in transplant-ineligible patients, particularly in unfit or frail patients because of the low tolerance. So, in real world, it is common to use a combination of lenalidomide and low dose dexamethasone (Rd), which are generally dose-adjusted. Certainly, in the elderly patients, triplet therapy including novel agents may be excessive treatment in terms of adverse events. However, patients with only partial response are known to have a poor prognosis, and it is important how to improve their prognosis. At our medical center, we select Rd therapy for elderly patients, except for fit patients, but we have switched to triplet therapy for patients who have not had a response above VGPR. Here, we retrospectively reviewed this treatment outcome. Method We retrospectively reviewed 71 transplant ineligible newly diagnosed multiple myeloma (NDMM) patients who received Rd therapy as initial therapy between November 2015 and March 2019. The median age was 73 years old (range 66~89). Patients received normal Rd therapy (lenalidomide 25 mg/day, day 1-21 (if they have normal renal function) and dexamethasone 20mg on days 1, 8, 15, 22) for every 4 weeks as initial therapy. If the response after 6 cycles was less than VGPR, another novel agent was added and treatment was continued as triplet therapy including lenalidomide. The International Staging System (ISS) were I in 15 (21.1%), II in 45 (63.3%) and III in 11 (15.5%). High-risk cytogenetics, defined as the presence of deletion 17, t(4;14) and t(14;16) by FISH analysis, were identified in 11 (15.4%) patients. The Revised International Staging System (R-ISS) were I in 14 (19.7%), II in 49 (69.0%) and III in 8 (11.2%). Results The overall response rate (ORR) after 6 cycles of Rd therapy was obtained in 69 (97.1%). including sCR in 5 (7.0%), CR in 3 (4.2%), VGPR in 23 (32.3%), and PR in 38 (53.5%). SD were observed in 2 patients (2.8%), respectively and they relapsed within six cycles. Twenty-nine out of 38 patients who had a response less than VGPR had changed to a triplet therapy with the addition of some novel agent (13 patients with elotuzumab, 5 patients with carfilzomib, 8 patients with ixazomib, and 3 patients with daratumumab). Forty-nine out of 71 cases (69.0%) achieved a response of at least VGPR, finally. The disease-free survival time was significantly longer in cases which obtained in excess of VGPR (figure). Grade 3 or greater toxicities occurring in 5% within 6 cycles, however, in triplet therapy, 6 patients (20.6%) were suffered from severe adverse events (most were infectious diseases such as pneumonia). Conclusion This retrospective analysis revealed that Rd therapy might be able to improve prognosis if patients obtain more than VGPR and even if treatment response is less than PR in the 6th cycle, triplet therapy might be effective to change the patients' prognosis. However, patients who do not reach VGPR even with triplet therapy have a poor prognosis and need further treatment. This results may be indicate that, in elderly NDMM patients, Rd therapy is sufficiently successful, and it is not always necessary to select triplet therapy as initial from the viewpoint of adverse events. Further study is warranted. Figure Disclosures Teshima: Novartis: Honoraria, Research Funding.

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