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 ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4243-4243 ◽  
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.

scholarly journals The Poor Prognosis of High Cytogenetics Abnormalities in Elderly Patients Might be Overcome with an Optimized Total Therapy Approach Including Proteasome Inhibitors, Imid's Compounds and Alkylators

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5688-5688 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Norma C Gutierrez ◽  
María-Luisa Martín ◽  
Joaquín Martínez-López ◽  
Miguel-T Hernandez ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Board Of Directors ◽  
Research Funding ◽  
Poor Prognosis ◽  
Plasma Cells ◽  
Fish Analysis ◽  
Advisory Committees ◽  
The Poor ◽  
Standard Risk

Abstract Background:Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors.Cytogenetic abnormalities (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. In the relapse setting, the combinations including proteasome inhibitors and immunomodulatory drugs have shown to improve, and some of them to overcome, the outcome of patients with high-risk CA. 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 of 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/m2once 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). The rates of CA was similar in both treatment arms. 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 51 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 33 months, p=0.03) and this also translated into a significantly shorter OS (38.4m vs not reached, p=0.002). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (29.5 months vs 31.5 months, p=0.9) and OS (46m vs 63m, p=0.1). This beneficial effect observed in the sequential arm applied to both 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 (36 months vs 29 months) and 4-years OS (63% vs 68%) in the whole series and no differences were observed between 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: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Martínez-López:Novartis: Honoraria, Speakers Bureau. Oriol:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

Clinical Outcome According to Both Cytogenetic Abnormalities (CA) Detected by Fluorescence In Situ Hibridization (FISH) and Hyperdiploidy Assessed by Flow Cytometry (FCM) In Elderly Newly Diagnosed Myeloma Patients Treated with A Bortezomib-Based Combination

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 309-309 ◽  
Author(s):  
María-Victoria Mateos ◽  
Norma C. Gutierrez ◽  
Bruno Paiva ◽  
Albert Oriol ◽  
Joaquín Martínez-López ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Poor Prognosis ◽  
Dna Ploidy ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
High Risk Patients ◽  
Risk Patients ◽  
Standard Risk ◽  
Ploidy Status

Abstract Abstract 309 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. DNA ploidy is another important prognostic factor with non-hyperdiploid cases being associated with a poor outcome. There are some controversies about whether or not bortezomib-based combinations are able to overcome the poor prognosis of CA. In the VISTA trial, bortezomib plus melphalan and prednisone (VMP) appeared to overcome the poor prognosis of CA in terms of response rate (RR) and survival; however, the number of patients with CA was rather small. Here we report a subanalysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM05MAS65 trial, in order to evaluate the influence of CA by FISH as well as DNA ploidy status on RR and survival. Patients and methods: Patients included in this study were randomized to receive 6 cycles of VMP vs bortezomib, thalidomide and prednisone (VTP) as induction therapy consisting on one 6-week cycle of bortezomib using a bi-weekly schedule (1·3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29 and 32) plus either melphalan 9 mg/ m2 on days 1 to 4 or oral daily thalidomide 100 mg, and prednisone 60 mg/ m2 on days 1 to 4; this first cycle was followed by five 5-week cycles of once-weekly bortezomib (1·3 mg/ m2 on days 1, 8, 15 and 22) plus the same doses of MP and TP. After induction therapy, patients were subsequently randomised to maintenance therapy with VP or VT, consisting of one convencional 3-week cycle of bortezomib (1·3 mg/ m2 on days 1, 4, 8 and 11) every 3 months, plus either prednisone 50 mg every other day or thalidomide 50 mg/day, for up to 3 years. FISH analysis for del(13q), t(11;14), t(4;14), t(14;16) and del(17p) was performed at diagnosis according to standard procedures using purified plasma cells, and DNA ploidy status was analysed following induction therapy by multiparametric FCM using propidium Iodide and specific markers for discrimination between myelomatous and normal cells. Result: In 231 out of the 260 patients included in the trial, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 44 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=187 patients without CA, and/or del(13q) and/or t(11;14)). There weren't differences in the rates of CA according to the treatment arm. RR was the same in the high-risk vs standard-risk groups, both after induction (21% vs 27% CR) and maintenance (39% vs 45% CR). However, high-risk patients showed shorter PFS as compared to standard risk both from first (24 versus 33 months, p=0·04, HR 0·6, 95% IC 0·4-0·9) and second randomization (17 versus 27 months, p=0·01, HR 0·5, 95% IC 0·2-0·8). This also translated into shorter OS for high risk patients (3-year OS rate: 55% versus 77% from first randomization, p=0·001, HR 0·4, 95% IC 0·2-0·7) and 60% versus 85% from second randomization, p<0·001, HR 0·2, 95% IC 0·1-0·5). This adverse prognosis applied to either t(4;14) or del(17p), without differences in terms of PFS from the first (24 months for del(17p) patients and 20 months for t(4;14)) and second randomization (16 months for both CA); in addition, the outcome was not modified by the treatment scheme used. When we analyzed the influence on survival of the DNA ploidy status (224 patients) by comparing patients with hyperdiploid (132 patients) versus non-hyperdiploid DNA content (92 patients) assessed by FCM, it was found that the former group showed longer OS (77% versus 63% at 3 years, p=0·04), and this difference was more evident in patients treated with VTP (77% versus 53% at 3 years, p=0·02), while no significant differences were observed in the VMP arm. Conclusion: The present schema, particularly after month sixth (using maintenance with bortezomib every 3 months) doesn't overcome the negative prognosis of high-risk cytogenetics in terms of PFS and OS in elderly myeloma patients, and this applied to either patients with t(4;14) or del(17p), and it was independent of the induction treatment arm. Our data also show that non-hyperdiploid cases displayed worse outcome than hyperdiploid patients, particularly under VTP induction treatment. These results suggest that continuous efforts are still required in order to overcome the dismal prognosis of high-risk patients. Disclosures: Mateos: Janssen Cilag: Honoraria; Celgene: Honoraria. Off Label Use: VTP is not approved for the treatment of elderly newly diagnosed myeloma patients. VT and VP are not approved for maintenance therapy. Gutierrez:Janssen Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen Cilag: Honoraria; Celgene: Honoraria. Martínez-López:Janssen Cilag: Honoraria; Celgene: Honoraria. Garcia-Laraña:Janssen Cilag: Honoraria; Celgene: Honoraria. Palomera:Janssen Cilag: Honoraria. Hernández:Janssen Cilag: Honoraria. García-Sanz:Janssen Cilag: Honoraria; Celgene: Honoraria. Cibeira:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen Cilag: Honoraria; Celgene: Honoraria. Blade:Janssen cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen Cilag: Honoraria; Celgene: Honoraria.

The Frequency of Genetic Anomalies According to Clonal Plasma Cells' Phenotype in Patients with Newly Diagnosed (ND) Multiple Myeloma (MM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5316-5316
Author(s):  
Andrei Garifullin ◽  
Irina Martynkevich ◽  
Sergei Voloshin ◽  
Alexei Kuvshinov ◽  
Ludmila Martynenko ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Risk Groups ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Definition Of ◽  
Standard Risk

Abstract Background. Genetic anomalies (GA) are primary link of pathogenesis in MM. GA lead to formation of clonal plasma cells, which has different phenotype. Aim. To estimate the incidence of GA and their correlation with clonal plasma cells' phenotype in patients with ND MM. Methods. We analysed 22 patients with ND MM (median age 57 years, range 38-80; male/female - 1:1.75). Cytogenetic analysis was performed on bone marrow samples using standard GTG-method. Metaphase FISH analysis was performed according to the manufacturer's protocol using DNA probes: LSI 13(RB1)13q14, IGH/CCND1, IGH/FGFR3, LSI TP53 (17q13.1). 8-color immunophenotypic by flow cytometry using antibody to CD45, CD38, CD138, CD56, CD19, CD20, CD27 and CD117 antigenes. Results. Translocation t(11;14) was detected in 3/14 (21.4%) patients, del(13q) - 2/14 (14.3%), t(11;14) - 3/14 (21.4%), hypodyploidy - 1/20 (5%), del(17р) - 0% patients. Clonal plasma cells' phenotype CD38+CD138+CD45- was detected in 100%. Expression CD56+ was revealed in 11/22 (50%) patients, CD19+ in 9/22 (40.9%), CD117+ in 5/22 (22.7%), CD20+ in 1/22 (4.5%), CD27+ in 1/22 (4.5%). The frequency of GA didn't depend on clonal plasma cells' phenotype and was 27.3%(3/11) in CD56+ phenotype, 23.8%(5/21) - CD20-, 23.8%(5/21) - CD27-, 23.5%(4/17) - CD117-, 23%(3/13) - CD19-, 22.2%(2/9) - CD19+, 20%(1/5) - CD117+, 18.2%(2/11) - CD56-, 0%(0/1) - CD20+, 0%(0/1) - in CD27+ phenotype. Patients of standard risk group according to mSMART 2.0 with GA had CD19-negative plasma cells' phenotype vs. CD19-positive phenotype in patients of intermediate and high-risk groups (p<0.05). 3-years overall survival in standard risk group with CD19- phenotype was 92,3%, CD19+ - 77,7% (p>0.05). Conclusion . Identification of GA, which has adverse forecast, correlates with CD19+ plasma cells phenotype. The combined definition of plasma cells phenotype and GA can improve the system of risk stratification in MM. Disclosures No relevant conflicts of interest to declare.

scholarly journals Multiple myeloma immunoglobulin λ translocations portend poor prognosis

2018 ◽  
Author(s):  
Benjamin G. Barwick ◽  
Paola Neri ◽  
Nizar J. Bahlis ◽  
Ajay K. Nooka ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factor ◽  
High Risk ◽  
Poor Prognosis ◽  
Plasma Cells ◽  
Whole Genome ◽  
Newly Diagnosed ◽  
Myeloma Cells ◽  
Current Therapies ◽  
Standard Risk

AbstractMultiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed ‘high-risk’. To better understand and identify high-risk myeloma, we analyzed the translocation landscape of 826 newly-diagnosed patients by whole genome sequencing as part of the CoMMpass study. Translocations at the IgL locus were present in 10% of myeloma patients, and corresponded with poor prognosis. Importantly, 70% of IgL translocations co-occurred with hyperdiploid disease, a marker of standard risk, which is routinely diagnosed clinically whereas IgL-translocations are not. Thus, it is likely that the majority of IgL-translocated myeloma is being misclassified. The IgL enhancer is among the strongest in myeloma cells, indicating it can robustly drive oncogene expression when translocated. Consistent with this, IgL-translocated patients failed to benefit from immunomodulatory imide drugs (IMiDs), which target the lymphocyte-specific transcription factor Ikaros. These data implicate the IgL enhancer as resistant to IMiD-inhibition, and when translocated, as a driver of poor prognosis.

Updated Results of Phase II Study of Cyclophosphamide(Cy), Bortezomib(Bz), Pegylated Doxorubicin(DOX), and Dexamethasone(dex), (CVDD), in Patients with Newly Diagnosed Myeloma:an Effective Induction Regimen for High Risk Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4071-4071 ◽  
Author(s):  
Melissa Alsina ◽  
Rachid Baz ◽  
Kenneth H. Shain ◽  
Leonel Ochoa ◽  
Taiga Nishihori ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Risk Group ◽  
Newly Diagnosed ◽  
Risk Patients ◽  
Cell Mobilization ◽  
Standard Risk

Abstract Abstract 4071 Background: The VDD treatment regimen has been shown to be effective as initial therapy for multiple myeloma, as demonstrated by a Phase II trial with overall response rates of 89% and VGPR + CR rates of 53%. Given the established synergy between bortezomib and alkylating agents, incorporating an alkylator to VDD may increase the depth of response and may improve long term outcome. We previously reported the results of a Phase I study of VDD with escalating doses of cyclophosphamide and reached the maximum planned dose (MPD) of the regimen without dose limiting toxicities. We now report updated results from the Phase II trial of CVDD in patients with newly diagnosed myeloma. Methods: Patients were treated at the MPD defined by the phase I study, and received Cy 750 mg/m2 IV on day 1, Bz 1.3 mg/m2 IV on days 1, 4, 8, 11, DOX 30mg/m2 on day 4, a Dex 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 for up to eight 21-day cycles. Patients with Gr ≥ 2 peripheral neuropathy (PNY) were excluded. Responses were assessed by International Working Group criteria. Patients were stratified in 2 cohorts by risk. Patients with high risk cytogenetics defined as the presence of one of the following at diagnosis; deletion of chromosome 13 by cytogenetics, hypodiploidy, or t(4;14, t(14;16) or deletion of 17 p by FISH, were included in the high risk cohort (HR) and all others in the standard risk cohort (SR). Patients with at least partial response (≥PR) and standard risk cytogenetics could proceed to autologous stem cell transplant (ASCT) after ≥6 cycles. Responsive patients with high risk cytogenetics completed 8 cycles of therapy. Results: Forty nine pts were treated in study and forty eight patients are evaluable for response. Median age was 57 yrs, 59% male. Twenty five % of forty nine patients had high risk myeloma. The median number of cycles completed by patients is 6 in the SR cohort and 8 in the HR cohort. The overall response rate (ORR; ≥PR) is 89% for the SR cohort and 100 % for the HR cohort. The rate of ≥VGPR was 69% and similar in both cohorts. However the rate of CR/sCR was higher in the HR cohort compared to the SR cohort at 50% and 25%, respectively. 62% patients proceeded to transplant and all had successful stem cell mobilization with G-CSF alone. At a median follow up of 24 months the median PFS or OS has not been reached, and the 2 year OS is 89.19 % for the standard risk group and 100% for the high risk group. Most common ≥ grade 3 toxicities events related to protocol treatment were myelosupression (48%), dizziness (7.7%), fatigue (6.5%), and PNY (6.5%). Conclusions: CVDD produces high quality responses and is well tolerated in newly diagnosed MM patients, regardless of their cytogenetic status. Stem cell mobilization has been successful in all patients, with transplant course in patients otherwise unremarkable. The high rate of CR rates and OS in high risk patients warrants further evaluation of this regimen in that patient population. Disclosures: Alsina: Millenium: Consultancy, Research Funding; Ortho Biotech: Research Funding. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding.

Cohort Analysis of FISH Testing of CD138+ Cells in Relapsed Multiple Myeloma: Implications for Prognosis and Choice of Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3399-3399
Author(s):  
Dean Smith ◽  
Clemency Stephenson ◽  
Anna Lach ◽  
Steve Chatters ◽  
Helena Kempski ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Cohort Analysis ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Interphase Fish ◽  
Line Of Therapy ◽  
Standard Risk

Abstract Introduction: Interphase FISH on CD138-selected bone marrow cells enables genetic risk stratification in newly diagnosed multiple myeloma (MM), however as MM remains incurable, most centres still treat newly diagnosed MM uniformly, utilising the most active regimens available. At relapse an increasing choice of regimens, coupled with co-morbidities and treatment-emergent toxicities, means no uniform approach is possible. Instead, therapy is tailored to disease and patient related risk factors. In this setting, FISH testing may be particularly useful if not done at diagnosis and to identify progression events that may alter prognosis. Aim: To evaluate the outcome of FISH analysis in consecutive patients with relapsed MM undertaken at our centre: success rate, frequency of abnormalities, incidence of progression events and correlation of FISH abnormalities with treatment outcomes. Methods: FISH analysis was performed on 192 samples from 154 relapsed patients (2012-13). Plasma cells were selected using magnetic CD138 MicroBeads and interphase FISH carried out using probes as recommended by the EMN (Ross et al, 2012). If patients had no prior results, a full FISH MM panel was performed, using probes for t(4;14), t(14;16), t(11;14), deletion 17p (17p-), Chr 1 abnormalities (1p-/1q+) and deletion 13q (13q-). If patients had been previously tested for an IgH translocation (Tx), a progression event panel was used: 1p-/1q+, 17p- and 13q-. Patients underwent FISH testing prior to starting the next line of therapy. Results: 79% of samples were successfully analysed, with analysis limited in 16% and failed in 5%. Common reasons for failure were poor quality/aged slides, insufficient material and poor hybridisation. 17% of patients had no cytogenetic abnormality. The most common abnormality was 13q- (43.1%), followed by 1q+ (41.4%), t(11;14) (18.3%), t(4;14) (12.4%), 17p- (12.0%) 1p- (8.9%), and t(14;16) (5.6%) Progression events were more common in t(14;16) and t(4;14) groups. All patients with t(14;16) and 82% with t(4;14) had an additional genetic lesion. Only 21% of patients with t(11;14) and 54% with no IgH Tx had an additional event. 80 patients (51.3%) had prior FISH results and 13 (16.3%) had developed a new abnormality on the later test. In 9 cases the progression event was 17p-, in 2 it was 1q+ and 2 cases developed 17p- and 1q+. The patients developing 1q+ were previously standard risk, so repeat testing altered risk group. Acquisition of 17p- indicates especially poor outcome, thus in all 13 cases repeat FISH analysis altered risk. Among patients with progression events none harboured t(11;14), 8 (64%) had no IgH Tx, 3 had t(14;16) and 2 had t(4;14). FISH results were correlated with clinical outcome. Patients were stratified as having high risk genetics [t(4;14), t(14,16), 17p- in ≥50% cells, 1p-/1q+] or standard risk [t(11;14), normal cytogenetics]. 63 (41%) patients were high risk, 83 (54%) standard risk, with no information available for 8 (5%). Both groups had received a median of 2 prior lines of therapy. Response rates (≥PR) to the next line of therapy were similar (60.4% standard risk vs 56.0% high risk). PFS from time of FISH was significantly longer in the standard risk group (9.8 months vs 5.9, p<0.01) as was OS (not reached vs 17.1 months, p<0.01, Fig. 1). In the high risk group, PFS was significantly longer in patients receiving a proteasome inhibitor (PI) as the next line of treatment versus those receiving other therapies (9.6 months vs 4.6, p=0.01) as was OS (not reached vs 9.7 months, p<0.01, Fig. 2). In the standard risk group, PFS was similar if patients received PI or not (9.5 months PI vs 9.8 other) as was OS (not reached both groups, Fig. 2). Conclusions: FISH analysis on MM patients at relapse was achievable. 74/154 patients had no prior results and a further 13 developed new poor prognostic markers, thus FISH at relapse provided new information in 56% of patients. Progression events were more common in patients harbouring t(4;14) or t(14;16). FISH at relapse was prognostic with high risk abnormalities associated with significantly shorter PFS and OS. The use of PI appeared to abrogate this poor prognosis, suggesting FISH at relapse could be a predictive and prognostic marker. Given the availability of second generation PI and the option of bortezomib re-treatment, results of FISH testing at relapse could directly influence clinical practice. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Survival in Patients with Newly Diagnosed Myeloma Undergoing Therapy with Lenalidomide and Dexamethasone: Impact of High-Risk Cytogenetic Risk Status on Outcome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 95-95 ◽  
Author(s):  
Prashant Kapoor ◽  
Shaji Kumar ◽  
Rafael Fonseca ◽  
Martha Q. Lacy ◽  
Thomas E Witzig ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Plasma Cell ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
High Risk Patients ◽  
Risk Patients ◽  
The Impact ◽  
Standard Risk

Abstract Background: Multiple myeloma (MM) is a heterogeneous disease with very divergent outcomes that are dictated in a large part by specific cytogenetic abnormalities, as well as other prognostic factors such as the proliferative rate of marrow plasma cells. Prognostic systems incorporating these factors have shown clinical utility in identifying high-risk patients, and are increasingly being utilized for treatment decision-making. However, the prognostic relevance of these factors may change with the application of novel therapies. The objective of this study was to determine the impact of risk-stratification (incorporating plasma cell metaphase cytogenetics, interphase fluorescent in-situ hybridization (FISH) and the slide-based plasma cell labeling index (PCLI)) in a cohort of patients with newly diagnosed MM treated initially with lenalidomide + dexamethasone (Rev-Dex). Methods: From March 2004 to November 2007, 100 consecutive patients treated with Rev (25mg/day) on days 1 through 21 of a 4-week cycle in combination with dexamethasone as initial therapy for newly diagnosed myeloma, were identified. High-risk MM was defined as presence of any one or more of the following: hypodiploidy, monoallelic loss of chromosome 13 or its long arm (by metaphase cytogenetics only), deletion of p53 (locus 17p13) or PCLI ≥ 3% or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23) on FISH. PFS and OS survival estimates were created using the Kaplan Meier method, and compared by log-rank tests. Results: The median estimated follow-up of the entire cohort (N=100) was 36 months. The median PFS was 31 months; the median OS has not been reached. The 2- and 3-year OS estimates were 93% and 83%, respectively. 16% patients were deemed high-risk by at least one of the 3 tests (cytogenetics, FISH or PCLI). Response rates (PR or better) were 81% versus 89% in the high-risk and standard risk groups, respectively, P=NS; corresponding values for CR plus VGPR rates were 38% and 45% respectively. The median PFS was 18.5 months in high-risk patients compared to 37 months in the standard-risk patients (n=84), P<0.001(Figure). Corresponding values for TTP were 18.5 months and 36.5 months, respectively, P=<0.001. OS was not statistically significant between the two groups; 92% 2-year OS was noted in both the groups. Overall, 95 patients had at least one of the 3 tests to determine risk, while 55 patients could be adequately stratified based on the availability of all the 3 tests, or at least one test result that led to their inclusion in the high-risk category. The significant difference in PFS persisted even when the analysis was restricted to the 55 patients classified using this stringent criterion; 18.5 months vs. 36.5 months in the high-risk and standard- risk groups respectively; P<0.001. In a separate analysis, patients who underwent SCT before the disease progression were censored on the date of SCT to negate its effect, and PFS was still inferior in the high-risk group (p=0.002). Conclusion: The TTP and PFS of high-risk MM patients are inferior to that of the standard-risk patients treated with Rev-Dex, indicating that the current genetic and proliferation-based risk-stratification model remains prognostic with novel therapy. However, the TTP, PFS, and OS obtained in high-risk patients treated with Rev-Dex in this study is comparable to overall results in all myeloma patients reported in recent phase III trials. In addition, no significant impact of high-risk features on OS is apparent so far. Longer follow-up is needed to determine the impact of risk stratification on the OS of patients treated with Rev-Dex. Figure Figure

scholarly journals Children's Oncology Group (COG) AALL0434: Successful Disease Control without Cranial Radiation in Newly Diagnosed T Lymphoblastic Lymphoma (T-LL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1000-1000 ◽  
Author(s):  
Robert James Hayashi ◽  
Stuart S. Winter ◽  
Kimberly P. Dunsmore ◽  
Meenakshi Devidas ◽  
Brent Wood ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Partial Response ◽  
Board Of Directors ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Patients ◽  
To Receive ◽  
Standard Risk

Abstract Background: COG AALL0434 evaluated the safety and efficacy of a multi agent chemotherapy backbone containing Capizzi based methotrexate/pegaspargase in newly diagnosed T-LL patients. High-risk patients were randomized to receive the COG augmented BFM (ABFM) regimen with or without Nelarabine. This was part of a larger trial including T-Lymphoblastic Leukemia (T-ALL) patients featuring a 2 x 2 pseudo-factorial randomization at the end of induction using the COG ABFM regimen with a randomization of Capizzi MTX/pegaspargase (C-MTX) verses high dose MTX and a randomization with or without Nelarabine (Nel). Methods: AALL0434 enrolled 277 patients with T-LL (2010-2014). Patients were assigned to two risk categories based upon the degree of bone marrow involvement at diagnosis: (≥1%, High Risk, <1% Standard Risk), and the ability to achieve at least a partial response at the end of induction. Patients with prior steroid treatment were assigned to the high risk group. Both groups were treated using the ABFM C-MTX regimen. High-risk patients were randomized to receive or not receive six, 5-day courses of Nel 650 mg/m2/day. No patients received prophylactic cranial radiation and CNS3 patients were ineligible. Response criteria included, Complete Response (CR): disappearance, Complete Response unconfirmed (CRu): >75% reduction, Partial Response (PR): >50% reduction, of all measurable disease, all without new lesions. Results: At the end of induction, 98.9% of the evaluable patients achieved at least a partial response (30.7% CR, 34.7% CRu, 33.5% PR). For all T-LL patients, the 4-year event free survival (EFS) and overall survival (OS) were 87.0 +/- 2.1% and 90.0+/-1.8%. The 4-year Disease Free Survival (DFS) from end of induction was 90.0+/- 2.1%. There was no difference in DFS observed between the high risk and standard risk groups, (p=0.25) or by treatment regimen (p=0.31). Nel did not show an advantage for high-risk T-LL patients, with 4-year DFS 85.0 +/- 5.6% with Nel (N=60) vs 89.0 +/- 4.7% without Nel (N=58) (p=0.28). Neither stage nor tumor response at the end of four weeks of induction therapy resulted in differences in EFS (p= 0.34 and p= 0.22, respectively). Minimal detectable disease (MDD) of the bone marrow at diagnosis (<0.1%, 0.1-0.99%, >1.0%), used to establish the risk assignment for this trial, failed to demonstrate thresholds at diagnosis that resulted in differences in EFS (p=0.27). Relapse involving the CNS only occurred in 4 patients (1.4%). Overall toxicity and neurotoxicity was acceptable and not significantly different than that experienced from the ALL cohort. There was one observed second malignancy and 5 deaths not from progressive disease. Conclusion: COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provides excellent disease control regardless of stage, or the degree of disease involvement of the bone marrow at diagnosis. Nelarabine did not show an improvement in the outcome, although the trial was underpowered to address this specific question. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Bollard:Torque: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neximmune: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Significance of Modified Risk Stratification Msmart 3.0 and Autologous Stem Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5593-5593
Author(s):  
Andrey Garifullin ◽  
Sergei Voloshin ◽  
Vasily Shuvaev ◽  
Irina Martynkevich ◽  
Elizaveta Kleina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Risk Stratification ◽  
Risk Group ◽  
High Risk Group ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Genetic Abnormalities ◽  
Standard Risk

Background The risk-stratification systems are repeatedly updated in accordance with the emergence of new information about the prognostic impact of anomalies and other factors. The most extensive and modern system in this time is mSMART risk stratification involving many parameters such as genetic anomalies, albumin, beta-2-microglobulin, LDH, Plasma Cell S-phase and GEP levels. It is possible to use risk-adapted treatment programs with or without ASCT. Nevertheless, the role of complex karyotype, combination of genetic abnormalities and ASCT remains unclear. Aims To estimate the genetic abnormalities in patients with newly diagnosed multiple myeloma and define the role of risk-stratification and ASCT in prognosis of disease. Methods The study included 159 patients (median age 63 years, range 28 - 83; male: female ratio - 1:1.37) with NDMM. Metaphase cytogenetics on bone marrow samples was done by standard GTG-method. FISH analyses were performed according to the manufacturer's protocol for detection primary IgH translocations, 13q (13q14/13q34) deletion, 1p32/1q21 amplification/deletion, P53/cen 17 deletion (MetaSystems DNA probes). We additional searched the t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20) in patients with IgH translocation. All patient was treated by bortezomib-based programs (VD, CVD, VMP, PAD). ASCT was performed at 42% patients. Results The frequency of genetic abnormalities in NDMM patients was 49% (78/159). IgH translocation was detected in 26.4% (42/159) patients: t(11;14) - 16.3% (26/159), t(4;14) - 5.0% (8/159); TP53/del17p - 5.6% (9/159); 1p32/1q21 amp/del - 12% (19/159); hypodiploidy - 3.1% (5/159); hyperdiploidy - 1.25% (2/159); del5q - 0,6% (1/159); other - not found. Combination two aberrations was discovered in 11.9% (19/159) patients, complex abnormalities (>3 aberrations) - in 4.4% (7/159) patients. The median OS in "two aberration" and "complex abnormalities" groups were lower than in standard-risk mSMART 3.0 (normal, t(11;14), hypodiploidy, hyperdiploidy and other): 49 months, 26 months and was not reached, respectively (p=.00015). The median PFS for these groups was 12 months, 11 months and 30 months, respectively (p=.011). Differences between "two aberration" and "complex abnormalities" groups were not find (p> .05). We modified high-risk (gain 1q, p53 mutation, del 17p deletion, t(4;14), t(14;16), t(14;20), R-ISS stage III, double and triple hit myeloma) mSMART 3.0 by adding "two aberration" and "complex abnormalities" groups on based the OS and PFS results. The final analysis was based on the results of the complex examination of 87 patients: 53 patients in standard-risk group and 34 patients in high-risk group. The median OS in standard-risk mSMART 3.0 was not reached, in high-risk mSMART 3.0mod - 48 months; 5-years OS was 62% and 38%, respectively (p=0.0073). The median PFS was 43 and 29 months, respectively (p=.09). The best results of OS and PFS were reach in both groups of patient who performed ASCT. The median OS in standard-risk mSMART 3.0 with ASCT (n=37) was not reached, in high-risk mSMART 3.0mod with ASCT - 48 months (n=20); standard-risk mSMART 3.0 without ASCT - 40 months (n=16); in high-risk mSMART 3.0mod without ASCT - 22 months (n=14); 5-years OS was 81%, 60%, 33% and 28%, respectively (p=0.0015). The median PFS was not reached, 46, 22 and 19 months, respectively (p=.017). Conclusions The combination of two aberrations and complex abnormalities is unfavorable prognostic markers. The median OS and PFS was higher in standard-risk than high-risk group according mSMART 3.0mod. The ASCT can improve treatment's outcomes and life expectancy especially in patients with high-risk. It can be useful for update risk stratification in a future. Disclosures Shuvaev: Novartis: Consultancy; Pfize: Honoraria; Fusion Pharma: Consultancy; BMS: Consultancy.

scholarly journals Long-Term Follow-Up Results of Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy and Risk-Adapted Maintenance Approach in Newly Diagnosed Multiple Myeloma

2020 ◽  
Vol 38 (17) ◽  
pp. 1928-1937 ◽  
Author(s):  
Nisha S. Joseph ◽  
Jonathan L. Kaufman ◽  
Madhav V. Dhodapkar ◽  
Craig C. Hofmeister ◽  
Dhwani K. Almaula ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Entire Cohort ◽  
Induction Regimen ◽  
Risk Patients ◽  
Standard Risk

PURPOSE The combination of lenalidomide, bortezomib, and dexamethasone (RVD) is a highly effective and convenient induction regimen for both transplantation-eligible and -ineligible patients with myeloma. Here, we present the largest cohort of patients consecutively treated with RVD induction therapy followed by risk-adapted maintenance therapy with the longest follow-up and important information on long-term outcomes. PATIENTS AND METHODS We describe 1,000 consecutive patients with newly diagnosed myeloma treated with RVD induction therapy from January 2007 until August 2016. Demographic and clinical characteristics and outcomes data were obtained from our institutional review board–approved myeloma database. Responses and progression were evaluated per International Myeloma Working Group Uniform Response Criteria. RESULTS The overall response rate was 97.1% after induction therapy and 98.5% after transplantation, with 89.9% of patients achieving a very good partial response (VGPR) or better and 33.3% achieving stringent complete response after transplantation at a median follow-up time of 67 months. The estimated median progression-free survival time was 65 months (95% CI, 58.7 to 71.3 months) for the entire cohort, 40.3 months (95% CI, 33.5 to 47 months) for high-risk patients, and 76.5 months (95% CI, 66.9 to 86.2 months) for standard-risk patients. The median overall survival (OS) time for the entire cohort was 126.6 months (95% CI, 113.3 to 139.8 months). The median OS for high-risk patients was 78.2 months (95% CI, 62.2 to 94.2 months), whereas it has not been reached for standard-risk patients. Five-year OS rates for high-risk and standard-risk patients were 57% and 81%, respectively, and the 10-year OS rates were 29% and 58%, respectively. CONCLUSION RVD is an induction regimen that delivers high response rates (VGPR or better) in close to 90% of patients after transplantation, and risk-adapted maintenance can deliver unprecedented long-term outcomes. This study includes the largest cohort of patients treated with RVD reported to date with long follow-up and demonstrates the ability of 3-drug induction regimens in patients with newly diagnosed multiple myeloma to result in a substantial survival benefit.

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