Substratification of patients with newly diagnosed standard‐risk multiple myeloma

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.

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

Blood ◽

10.1182/blood-2019-130092 ◽

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.

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Early Infection Risk in Newly Diagnosed Multiple Myeloma Patients in the Modern Era

Blood ◽

10.1182/blood-2021-146035 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3794-3794

Author(s):

Ryan Stevenson ◽

Diane M. Carpenter ◽

Adnan Khan ◽

Raleigh Fatoki ◽

Sumanth Rajagopal ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

High Risk ◽

Race And Ethnicity ◽

The United States ◽

Newly Diagnosed ◽

Infection Rates ◽

Community Based ◽

The Past ◽

Standard Risk

Abstract Background: Multiple myeloma (MM) is the second most common hematologic malignancy, with an estimated 30,000 new cases in the United States annually. Advances in management of MM over the past 20 years have significantly improved outcomes, but MM continues to be an incurable disease. Infections continue to be a major cause of morbidity and mortality, with a high proportion of MM patient developing infections within the first 3 months of diagnosis. There have been limited data on infection rates in MM patients in community-based oncology setting over the past two decades. This study looked to define infection rates and associated risk factors in newly diagnosed MM patients within 90 days of initial diagnosis. Methods: A retrospective, observational study was conducted on MM patients ages 18-89 newly diagnosed January 1, 2010-December 31, 2018 within Kaiser Permanente Northern California. Patients were required to have a minimum of one year of membership prior to MM diagnosis. SEER data was used to identify MM patients, and clinical data were extracted from the electronic health record. Bacterial, viral, and fungal infections were identified using ICD9/ICD10 codes. Baseline demographic and clinical characteristics from visit notes, laboratory and pathology results, and transplant data from utilization and claims data were analyzed to assess infection risks. High-risk cytogenetics was defined as notation of the following in pathology reports or oncology notes: add 1q, t(4:14), t(14:16), t(14:20), deletion of 17p. Bivariate analyses were conducted to assess differences across groups using the chi-squared test and the Wilcoxon-Mann-Whitney nonparametric test. Results: A total of 2030 newly diagnosed MM patients identified for this study. Median age at diagnosis was and n=828 (40.8%) of patients were female. Among this cohort, 522 (25.7%) had an infection within 90 days of MM diagnosis. The median age of patients having infections was 71 years (IQR 63-80), and the median age of those not having infections was 68 years (IQR 60-76, p<0.001). The median Charlson Comorbidity Index (CCI) of patients having infections was 3 (IQR 1-5) and the median CCI of those not having infections was 2 (IQR 1-4, p<0.001). Patients having hemoglobin <10.0 g/dl were more likely to have infection than those having hemoglobin >10.0 g/dl (30.4% vs. 23.6% respectively, p=0.011). Similarly, patients presenting with hypercalcemia (calcium >11.0 mg/dL) were more likely to have infection (37.4% vs. 24.6% in patients having calcium <11.0 mg/dL, p<0.001) as were patients with creatinine clearance <60.0 mL/min of those having <60.0 mL/min vs. 20.7% of those having >60.0 mL/min, p<0.001). Patients having indicators of high-risk cytogenetics were less likely to have infections within 90 days of diagnosis compared to those with standard risk cytogenetics (21.1% vs 26.2% respectively, p=0.031). We did not detect significant differences across transplant eligible status within the first year after diagnosis (22.1% infection among transplant eligible vs. 26.6% among those who were not transplant eligible, p=0.059) nor across sex (27.3% among females vs. 24.6% among males, p=0.176). Additionally, no significant differences in infection were detected across race and ethnicity (24.0% infection among Asian patients, 26.4% among Black patients, 27.7% among Hispanic patients, 25.5% among White patients, and 14.3% among patients having unknown or other race and ethnicity, p=0.741). Conclusions: In this community-based oncology study, infection within 90 days of diagnosis continues to be a significant complication of multiple myeloma and these results are comparable to previous studies. Risk factors for infection include age, CCI, standard risk cytogenetics, anemia, hypercalcemia, and renal failure. Stem cell transplant, sex and ethnicity were not associated with increased risk for infection. Future analysis will include assessments of hospitalization and mortality associated with infection. This study illustrates the importance of further research looking at decreasing infection rates in multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.

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Response Adapted Therapy Using Single Agent Lenalidomide in Older Adults with Newly Diagnosed Standard Risk Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4060.4060 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4060-4060

Author(s):

Rachid Baz ◽

Melissa Alsina ◽

Kenneth H. Shain ◽

Jennifer Paleveda ◽

Nancy Hillgruber ◽

...

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

Stable Disease ◽

Research Funding ◽

Progressive Disease ◽

Single Agent ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Standard Risk

Abstract Abstract 4060 Introduction: Rajkumar et al. reported improved survival with lenalidomide and low dose dexamethasome as compared with lenalidomide and high dose dexamethasone (Rajkumar V, Lancet Oncol 2010). In addition, we reported promising outcomes of a retrospective cohort of newly diagnosed multiple myeloma patients treated with single agent lenalidomide(Baz R Leuk Lymphoma. 2010). Accordingly, we conducted this prospective single center open label study to evaluate the efficacy of a response adapted approach using single agent lenalidomide in older adults with newly diagnosed standard risk multiple myeloma. Patients/Methods: Eligible patients had symptomatic multiple myeloma without high risk features (b2microglobulin (b2m) ≤5.5, absence of t(4;14), t(14;16), 17p deletion, aneuploidy or 13q by metaphase cytogenetics) and were not eligible or not willing to receive high-dose therapy and stem cell transplant. Patients received lenalidomide 25 mg PO D1–21 every 28 days for 2 cycles. If patients had a minimal response or better (MR, 25% reduction in serum M spike) after 2 cycles, they continued on single agent lenalidomide until progressive disease. If patients had stable disease after 2 cycles, prednisone 100 mg PO D1–5 was added to their lenalidomide. In the event of progressive disease on single agent lenalidomide or on lenalidomide/prednisone, therapy was changed to lenalidomide (at the tolerated dose) and dexamethasone 40 mg PO weekly. Thromboprophylaxis was with aspirin, warfarin or low molecular weight heparin. Responses were per IMWG response criteria. The study was approved by the institutional review board. Results: Between February 2010 and May 2012, 22 patients were screened and 19 were eligible. The median age was 75 years (range 65–83) and 12 were males. Per protocol, no patient had ISS stage 3 disease but 8 patients had ISS stage 2 and 11 stage 1 (median b2m was 3.2 mg/L (range 2.2–5.5)). 5 patients had 13q deletion by FISH alone, 4 had t(11;14), another 3 had trisomy 11, and 2 had trisomy or tetrasomy 1q. The median baseline creatinine clearance was 66.5 ml/min (range 43–109). After 2 cycles of single agent lenalidomide, 9 patients (47%) had a PR (partial response), 6 (32%) MR, 3 (16%) stable disease (SD), and 1 (5%) progressive disease. The best response to single agent lenalidomide was as follows: 3 had a stringent complete response sCR (16%), 1 (5%) a very good partial remission (VGPR), 8 PR (42%), 4 MR (21%), 2 SD (11%) and 1 PD (5%). The estimated 1 year PFS to single agent lenalidomide is 80%. Five patients required the addition of dexamethasone with the following responses: 1 VGPR, 1 PR, 1 MR, 1 SD and 1 PD; Three patients required the addition of prednisone and the response to lenalidomide prednisone was 1PR, 1 MR, 1 SD. Five patients went off study, 2 for PD and 3 withdrew consent (2 were in PR at the time and 1 in SD). The estimated 1 year PFS for the protocol therapy is estimated at 94%. Eleven patients had dose reduction in lenalidomide; 5 patients to 15mg and 6 patients to 10 mg. Grade 3/4 neutropenia, thrombocytopenia, anemia, febrile neutropenia and fatigue occurred in 58%, 5%, 10%, 5% and 5% of patients respectively. Conclusion: In this patient population, single agent lenalidomide results in an ORR (PR and better) of 63% and clinical benefit rate (MR and better) of 84% with only a quarter of patients requiring the addition of dexamethasone. A response adapted therapy using single agent lenalidomide is safe and effective in older adults with standard risk myeloma sparing dexamethasone toxicities from the majority of patients. Updated results for ongoing accrual of up to 30 evaluable patients will be presented at the meeting. Disclosures: Baz: Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Off Label Use: lenalidomide for newly diagnosed multiple myeloma. Alsina:Millenium: Consultancy, Research Funding. Finley-Oliver:celgene: Speakers Bureau.

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Long Term Response To Lenalidomide With and Without Continuous Therapy Among Patients With Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.3209.3209 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3209-3209

Author(s):

Taxiarchis Kourelis ◽

Shaji K Kumar ◽

Geetika Srivastava ◽

Morie A Gertz ◽

Martha Q Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Control ◽

Median Time ◽

Research Funding ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Newly Diagnosed ◽

Best Response ◽

Standard Risk

Abstract Introduction Lenalidomide is an immunomodulatory drug that is active in newly diagnosed as well as relapsed multiple myeloma (MM). The goal of this study is to describe patients with newly diagnosed MM remaining on lenalidomide for more than 3 years (long term responders) as well as patients that after discontinuing lenalidomide were able to maintain disease control while only on observation (LenO group). Methods We retrospectively reviewed 283 patients with newly diagnosed MM that were treated with lenalidomide between January 2003 and January 2011. We excluded patients that underwent early autologous stem cell transplant (n=102) or had less than 3 years of follow-up (n=6), leaving 175 patients for the current analysis. Results Long term responders Thirty-three patients (19%) received lenalidomide for more than 3 years. When compared to patients receiving lenalidomide for less than 3 years, at baseline, long term responders were more likely to have standard risk disease (64% versus 44%, p=0.03) and less likely to have high risk disease (18% versus 4%, p=0.04). They were more likely to have achieved a deeper response (VGPR versus PR, p<0.001) and had a longer median time to best response (6 versus 4 months, p<0.001). When considering the 12 patients who received lenalidomide for more than 5 years, this group was more likely to have achieved a deeper response (CR versus PR, p<0.0001) and had a longer median time to achieving best response (9 versus 4 months, p<0.0001) than those 163 patients who remained on lenalidomide for fewer than 5 years. Observation group Thirty-three patients (19%) discontinued lenalidomide for reasons other than progression and were observed without receiving further treatment (LenO group). Prior to moving to observation, five patients had received lenalidomide for more than three years. Indications for stopping in the LenO group included: prolonged disease stability (n= 20); and toxicity (n=13). The only differences in baseline characteristics between the LenO group and patients that were not observed off any treatment was depth of response, with 61% (n=20) of LenO in VGPR or better versus 23% (n=23) in the remainder, p=0.0003. Median PFS from the time of discontinuing lenalidomide was significantly longer in those patients who took lenalidomide for more than 1 year (n=24) when compared to patients taking it for less than one year (n=9) (median PFS off therapy was 38.5 months versus, 14.9 months log rank 0.08; Wilcoxon p<0.05), figure 1a; PFS for those treated for 1-2 years (n=11) as compared to 2 years or greater (n= 13) were comparable to each other (data not shown). Among those taking lenalidomide for at least a year, PFS from time of discontinuing lenalidomide was superior in patients who had achieved a VGPR/CR (n=20) as compared to those who achieved only a PR (n=13) (Median 48.4 months versus 14.8 months, log-rank p<0.05; Wilcoxon p=0.01), figure 1b. Conclusion Approximately one out of five patients with newly diagnosed MM can achieve responses lasting more than three years while on treatment with lenalidomide. Patients with standard risk FISH and those achieving at least VGPR are more likely be long-term responders. Furthermore, long-term responders were more likely to be slow responders. We also demonstrate that suspension of lenalidomide therapy after 1 year among those patients achieving a VGPR or better can result in long-term disease control and can be considered as a therapeutic strategy. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Gertz:Celgene: Honoraria. Lacy:Celgene: Honoraria. Dispenzieri:Celgene: Research dollars Other.

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Phase 2 Study of Carfilzomib, Thalidomide, and Low-Dose Dexamethasone As Induction/Consolidation in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma, the Carthadex Trial

Blood ◽

10.1182/blood.v128.22.1141.1141 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1141-1141 ◽

Cited By ~ 6

Author(s):

Ruth Wester ◽

Bronno van der Holt ◽

Emelie Asselbergs ◽

Mark van Duin ◽

Sonja Zweegman ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Induction Therapy ◽

Research Funding ◽

Fixed Dose ◽

Phase 2 ◽

Newly Diagnosed ◽

Significant Difference ◽

Standard Risk

Abstract Introduction A phase 2 dose escalation trial of Carfilzomib in combination with Thalidomide and Dexamethasone (KTd) for induction and consolidation in newly diagnosed, transplant-eligible patients with multiple myeloma (MM). We report the results of 4 dose levels. Methods In this multicenter, open-label, phase 2 trial, transplant-eligible patients aged between 18 and 65 years with previously untreated symptomatic MM were included. Patients were treated with 4 cycles of escalating dose of Carfilzomib + fixed-dose thalidomide and dexamethasone (KTd) for induction therapy. The dose of Carfilzomib was 20 mg/m2 i.v. on days 1, 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 and 16 of cycles 2 to 4. Thalidomide dose was 200 mg orally on days 1 through 28 and Dexamethasone 40 mg orally on days 1, 8, 15 and 22. Carfilzomib was escalated to 20/36 mg/m2 in cohort 2, to 20/45 mg/m2 in cohort 3 and to 20/56 mg/m2 in cohort 4. Induction was followed by stem cell harvest after Cyclophosphamide priming (2 to 4 mg/m2) and G-CSF. Hereafter patients received high-dose Melphalan (HDM, 200mg/m2) and autologous stem cell transplantation followed by consolidation treatment with 4 cycles of KTd in the same schedule except a lower dose of Thalidomide (50mg). The primary endpoint was response after induction therapy and overall, specifically complete response (CR) and very good partial response (VGPR). Secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results All 111 patients with a median follow-up of 55, 42, 35 and 28 months, in cohorts 1 to 4, respectively were included in the analysis. Median age was 58 years. ISS stages I/II/III were 41%/34%/23%, respectively, R-ISS stages I/II/III/unknown were 23%/59%/9%/9%, respectively. Of 111 patients, 9 patients stopped treatment during/after induction, 8 patients after cyclophosphamide priming or HDM and 9 patients during consolidation because of toxicity (n=9), non-eligibility for further treatment (n=6), progression (n=5), refusal (n=2) or other reasons (n=4). Overall response rate for all cohorts was 95%. Response after induction was CR/sCR in 18% of patients, ≥ VGPR in 66% of patients, ≥ PR in 94% of patients. After HDM the CR/sCR rate increased to 31% and after consolidation to 64%. Responses between cohorts were in general comparable. See Table 1. Response based on risk status by ISS/FISH in either cohort and accumulated did not show a difference in CR/sCR rate after consolidation between standard-risk (67%) and high risk defined as t(4;14) and/or del17p and/or add1q and/or ISS3 (60%). OS at 30 months was comparable between standard risk and high risk, 91% versus 90%. PFS at 30 months for standard risk and high risk was 79% and 62%, logrank p=0.02 (HR=2.3, 95% CI=1.1-4.5). PFS at 30 months per cohort was 70% (95% CI, 55% to 81%), 70% (95% CI, 45% to 85%), 80% (95% CI, 56% to 92%) and 62% (95% CI, 32% to 82%) in cohorts 1,2, 3 and 4, respectively, and 71% (95% CI, 61% to 79%) in all patients. OS at 30 months per cohort was 90% (95% CI, 77% to 96%), 90% (95% CI, 66% to 97%), 95% (95% CI, 71% to 99%) and 88% (95% CI, 58% to 97%) respectively, and 91% (95% CI, 83% to 95%) in all patients. Gene expression profiling using the Affymetrix U133 Plus 2.0 GeneChips was performed on purified tumor cells for 49 patients. Using the prognostic classifier EMC92 a high-risk group of patients (16%) was identified versus standard risk (in terms of OS: logrank p=0.06 (HR=3.7, 95% CI=0.8-16.8), and in terms of PFS: logrank p=0.14 (HR=2.1, 95% CI=0.8-6.0)). Safety analysis for all 111 patients showed non-hematological grade 3 and 4 toxicity, mainly respiratory disorders (in 15%), GI disorders (13%) and skin lesions (10%). Toxicity between cohorts did not show a significant difference. Cardiac adverse events were limited and included heart failure (n=2 at 27 mg/m2), hypertension (n=2) and chest pain (n=1 at 45mg/m2). Conclusion Carfilzomib, thalidomide, dexamethasone (KTd) is an effective regimen, with increasing CR percentages following KTd consolidation. With escalated doses of Carfilzomib responses and toxicity were comparable to standard dose of 27 mg/m2. Disclosures Zweegman: Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kersten:Celgene: Research Funding; Amgen: Honoraria. Minnema:Celgene: Consultancy; BMS: Consultancy; Amgen: Consultancy; Jansen Cilag: Consultancy. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broijl:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

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Clinical Outcomes of Newly Diagnosed Multiple Myeloma Patients with Elevated Lactate Dehydrogenase Who Underwent Autologous Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-120077 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4623-4623

Author(s):

Susan Bal ◽

Kwangmin Choi ◽

Heather J. Landau ◽

Daniel T. Starczynowski ◽

Saulius K. Girnius

Keyword(s):

Multiple Myeloma ◽

Induction Therapy ◽

Performance Status ◽

Newly Diagnosed ◽

Ecog Performance Status ◽

Significant Difference ◽

Cytogenetic Changes ◽

Baseline Characteristics ◽

Standard Risk ◽

Elevated Lactate

Abstract Background Multiple Myeloma (MM) is a clinically heterogeneous disorder of clonal plasma cells. Elevated Lactate Dehydrogenase (LDH) has been shown to be an independent prognostic marker associated with drug resistance and shorter survival. Methods Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA12) which includes over 1000 newly-diagnosed MM (NDMM) patients with enriched tumor and matched constitutional samples analyzed using whole genome/exome and RNA sequencing, we identified patients with baseline LDH values. High LDH was defined as LDH greater than the upper limit of normal, (>4.68 microkatals/liter). We compared baseline characteristics and outcomes with autologous stem cell transplant (ASCT), based on LDH as categorical variable. We sought to determine if there is enrichment of high and standard risk cytogenetic changes when stratified by LDH. Results We identified 871 patients with NDMM who had baseline LDH values. 143 patients had high LDH and 728 patients had a normal baseline LDH. Consistent with prior reports, high LDH was associated with shortened survival, 660 days vs 795 days (p=0.02852) in patients with normal LDH. 385 patients underwent ASCT (High LDH N=44; Normal LDH N=341). Those with high LDH had an inferior OS when compared with those with normal LDH (median OS 800.5 vs 878.8 days, p=0.019). In order to understand this difference, we examined baseline characteristics. Of the 44 patients with high LDH who underwent ASCT, median age was 60 years and ECOG performance status was 1. 61.36% were females, 77% were Caucasian, 11% were African American. Induction therapy consisted of 4 drugs or more in 16%, 3 drugs in 61%, and 2 drugs in 23%. Bortezomib and immune modulating agents (IMIDS) were combined in 72%. In those who did not receive an IMID, a bortezomib-based induction was used in 16% and carfilzomib-based induction was used in 11%. 93.18% underwent transplant in the consolidative setting with a median time to transplant was 178 days. 21 of the 44 patients (47.72%) received post-transplant maintenance. 10/21(48%) patients received triplet therapy (5/10 - lenalidomide, bortezomib, dexamethasone), 8/21 (38%) patients received lenalidomide alone. The median duration of maintenance was 217 days. Of the 341 patients with normal LDH who underwent ASCT, the median age was age 61 years, ECOG performance status was 1. 41.34% were females, 79% were Caucasian, 13% African American. Induction therapy consisted of 4 drugs in 8%, 3 drugs in 64%, 2 drugs in 24%. Combined Bortezomib-IMID in 76.24%, carfilzomib-IMID based therapy in 6%, and bortezomib-non-IMID based in 9.67%. 94.7% underwent an upfront consolidative with median time to transplant 164 days. Post-transplant maintenance was given in 213/341 (62.4%) of patients, in whom triplet therapy was given to 41/213 (19.2%), doublet therapy to 34/213 (16%), 130/213 (61%) received single agent. 107/213 (50%) received lenalidomide alone and 19/213 (6%) received bortezomib alone. Median duration of maintenance 266 days. There was no statistically significant difference in race, performance status, drug class and number of drugs used in induction therapy, time to transplant, whether or not patients received maintenance as well as maintenance duration between the groups when stratified by LDH. Female gender was enriched in the high LDH group (hypergeometric test, p=0.009). We used hypergeometric tests to assess for enrichment of high and standard risk cytogenetic changes. Del(17p13) was significantly enriched (p=0.011) in the high LDH subset where there were no statistically significant difference in the presence of t(4;14) (p=0.16) and t(14;16) (p=0.21). There was no difference in good risk hyperdiploid structural changes between the 2 groups. Conclusion Elevated LDH was confirmed as a poor prognostic factor in MMRF CoMMpass cohort. Among patients who underwent ASCT, those with high LDH have inferior survival, possibly driven by the presence of del(17p13). Since clinical outcomes remain poor despite the use of novel effective therapies and early consolidation with AHCT in patients with high baseline LDH, this group represents an unmet need for alternative therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM)

Leukemia ◽

10.1038/leu.2016.384 ◽

2016 ◽

Vol 31 (6) ◽

pp. 1363-1367 ◽

Cited By ~ 22

Author(s):

J Krönke ◽

F Kuchenbauer ◽

M Kull ◽

V Teleanu ◽

L Bullinger ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Marker ◽

Study Group ◽

Intensive Chemotherapy ◽

Newly Diagnosed ◽

Standard Risk

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Lower Plasma Mir-92a Levels Predict Shorter Progression-Free Survival In Newly Diagnosed Symptomatic Multiple Myeloma Patients

Blood ◽

10.1182/blood.v122.21.1879.1879 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1879-1879

Author(s):

Seiichiro Yoshizawa ◽

Tomohiro Umezu ◽

Junko H Ohyashiki ◽

Shinsuke Iida ◽

Kazuma Ohyashiki

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Chromosomal Aberrations ◽

Progression Free Survival ◽

Risk Groups ◽

Newly Diagnosed ◽

Lower Plasma ◽

Free Survival ◽

Cut Points ◽

Standard Risk

Abstract Background Current prognostic model for multiple myeloma (MM) is based on International Staging System (ISS) and presence of specific chromosomal abnormalities (CAs), especially by fluorescence in situ hybridization (FISH) analysis. MicroRNAs (miRNAs) play important roles in the development and progression in multiple myeloma (MM). Previously, we have described that plasma miRNA profiling has showed considerably lower plasma miR-92a levels in newly diagnosed MM patients (Yoshizawa et al. Blood Cancer Journal 2(1):e53, 2012). The aim of this study was to investigate the impact of plasma miR-92a levels to CAs and to prognosis in patients with newly diagnosed MM. Patients and methods From April 2004 to December 2012, 60 patients with newly diagnosed symptomatic MM (median age, 66 years; range, 34-93 years) were included in this study. We measured plasma miR-92a values (miR-92a/miR-638) by qRT-PCR. They were divided into high-risk and standard-risk by using FISH and conventional cytogenetic studies: high-risk cytogenetics was defined as translocations t(4;14), t(14;16), or del (17p13) detected by FISH, or del (13q) by Q-banding according to IMWG guidelines. All others, including t(11;14), were defined as standard-risk cytogenetics. We analyzed the clinical relevance of plasma miR-92a levels with respects to CAs. Furthermore we identified miR-92a expression cut points with the most impact on outcome to investigate which of the some disease characteristics and its cut-off value had prognostic influence in MM patients. Results Chromosomal aberrations were noted in 26 (43%) MM patients after diagnosis, including 12 patients with t(4;14), 5 with t(11;14), 3 with t(14;16), 2 with del (17p13), 2 with del (13q), and 1 with t(4;14) and del (17p13), 1 with t(11;14) and del (17p13). Between MM patients with and without high-risk cytogenetics, there were no significant differences in β2-microglobulin and albumin levels (P = 0.994 and 0.85, respectively), ISS staging (P = 0.583), age (P = 0.651), sex (P = 0.585), frequency of CRAB symptoms (hypercalcemia, P = 0.755; renal insufficiency, P = 0.75; anemia, P = 0.375; bone lesion, P= 0.65, respectively). The plasma miR-92a level was significantly lower in the newly diagnosed MM with high-risk groups than in those with standard-risk groups (P = 0.015). Patients with plasma miR-92a levels < 0.04 had a significantly shorter progression-free survival (PFS) than patients with plasma miR-92a levels ≥ 0.04 (median PFS: 48 vs 15.8 months, P = 0.011). In addition, some clinical parameters were associated with adverse PFS: high-risk cytogenetics (P = 0.001), high proportions of bone marrow plasma cells (P = 0.043), high levels of serum β2-microglobulin (P = 0.022) and not attaining ≥ very good partial response (VGPR) (P = 0.007). On multivariate analysis, lower miR-92a level was an independent prognostic factor for PFS. Using the same miR-92a cut points, there was a tendency towards significant difference among standard-risk myeloma patients (P = 0.077). Moreover, the combinations of chromosomal aberrations and plasma miR-92a were able to classify newly diagnosed MM patients with three risk groups with different probabilities. Conclusion The plasma miR-92a values vary across high- and standard-risk cytogenetics in newly diagnosed MM patients. We conclude that measurement of plasma miR-92a levels may not only function as novel biomarkers for diagnosis, but may also be helpful for prognostic stratification. Disclosures: Ohyashiki: Janssen Pharmaceutical co.: Research Funding.

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