Subgroup Analysis of US Patients in Preamble, an Ongoing Multinational Observational Study in Multiple Myeloma

Abstract Introduction: PREAMBLE (Prospective REsearch Assessment in multiple Myeloma: an oBservationaL Evaluation) is an ongoing, prospective, multinational, non-interventional observational study to collect information from medical records regarding treatment and diagnostic procedures. By analyzing these data, a better understanding can be gained of the real-world effectiveness of novel agents used in treating relapsed/refractory multiple myeloma (RRMM) and their impact on patient-reported outcomes. This analysis was performed to evaluate comorbidities, treatment patterns, and survival in a PREAMBLE subpopulation that included US patients with MM. Methods: US patients aged ≥18 years with RRMM, ≥1 prior therapy, and initiating treatment with an immunomodulatory drug (IMiD), proteasome inhibitor (PI), or IMiD+PI within 90 days before or 30 days after study enrollment (index therapy) were identified from PREAMBLE. Data were collected at the index healthcare provider visit and every 3 (Year 1) and 6 (Years 2-3) months (mo) over 3 years or until the end of patient follow-up. Data were summarized using descriptive statistics and included age, sex, International Staging System (ISS) stage, type of visits and hospitalizations, disease status, line of therapy, and concomitant disorders. Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox regression and Kaplan-Meier techniques. MM-specific survival was calculated using Cumulative Incidence Function. Results: 239 patients (median age 66 years; 56% male) were enrolled. At the time of data cut-off (7 December 2015), 124 (52%) were still in the study and 115 (48%) had disenrolled, including 71 (62%) who had disenrolled due to death. Median follow-up was 12.0 mo (range, 0.5-37.7). At study entry, 178 (74%) patients had relapsed MM; 140 had ISS stage assigned, with 28% (n=39), 26% (n=36), and 46% (n=65) for Stage I, II, and III disease, respectively. Median time to index therapy since initial diagnosis was 39.6 mo (range, 4.8-174.2). Cardiovascular disease (CVD) was the most common comorbidity (62%) and other comorbidities were highly prevalent as well (Table). At enrollment, most patients were receiving a PI (n=136, 57%; carfilzomib n=68/136, 50%) or an IMiD (n=63, 26%; pomalidomide n=29/63, 46%); 40 patients (17%) were receiving an IMiD+PI (carfilzomib and/or pomalidomide n=11/40, 28%). Median number of prior therapies was 2 (range, 1-10). The overall median PFS was 7.9 mo, with a median PFS for second-line, third-line, and fourth- or greater line of 15.4, 9.0, and 6.9 mo, respectively. Median OS has not yet been reached. 18-mo all-cause mortality was 31.1% (95% CI 24.9-38.5), while 18-mo MM-related mortality was 22.3% (95% CI 16.2-28.4), meaning that at 18 mo, approximately 8.8% of patients died due to non-MM-associated causes (Figure). Death rates were independent of comorbidities and number of lines of prior therapy. A strong association was found between disease status and rate of death: refractory disease was associated with higher death rates (hazard ratio 1.92; 95% CI 1.16-3.16), while sex and ISS stage showed weak association with death rates. Conclusions: The progressively shorter PFS with each successive treatment regimen reflects ongoing development of drug resistance. In this preliminary survival analysis of US patients, the majority of deaths resulted from MM. This finding demonstrates the need for additional treatment options for treating RRMM. CVD was highly prevalent as a comorbidity across all lines of treatment. Figure Figure. Disclosures Vij: Jazz: Consultancy; Karyopharma: Consultancy; Shire: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Novartis: Consultancy. Popov:PAREXEL: Employment. Chen:Bristol-Myers Squibb: Employment.

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An Ongoing, Observational Cohort Study in Multiple Myeloma (PREAMBLE): Preliminary Efficacy Analyses in Patients with 1 Line of Prior Therapy

Blood ◽

10.1182/blood.v128.22.2403.2403 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2403-2403

Author(s):

Brian Durie ◽

David J Kuter ◽

Catherine Davis ◽

Teresa Zyczynski ◽

Hartmut Goldschmidt ◽

...

Keyword(s):

Multiple Myeloma ◽

Treatment Outcomes ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hematologic Malignancy ◽

Research Assessment ◽

Advisory Committees ◽

Prior Therapy

Abstract Introduction: Multiple myeloma (MM) is an incurable hematologic malignancy associated with high disease burden and relapse rates. In recent years, several treatment options for MM have become available that have improved patient outcomes. However, robust data on real-world treatment outcomes associated with these MM treatments are sparse. PREAMBLE (Prospective REsearch Assessment in Multiple myeloma: an oBservationaL Evaluation; NCT01838512) is an ongoing multinational observational study that aims to increase understanding of real-world clinical effectiveness of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and combination therapy for relapsed/refractory MM (RRMM). Here, we present preliminary efficacy analyses on data from patients with 1 line of prior MM therapy both with and without prior transplantation experience. Methods: Eligible patients had a confirmed diagnosis of RRMM with 1 prior treatment and started treatment with an IMiD, PI, or IMiD+PI 90 days prior/30 days following study enrollment. Patient data were collected at each healthcare provider visit for a follow-up period of 3 years. Vital status was recorded every 6 months for all patients. Response rates (defined as minimal response or better) were assessed using cumulative incidence function, with progression as competing risk. Time in response, progression-free survival (PFS), and overall survival (OS) were assessed using the Kaplan-Meier method. Results: Of 855 treated patients, 367 (43%) had 1 prior line of therapy (median age 70 years, 56% male). In this group, 71 (19%) had refractory disease, with even distribution among International Staging System stages I, II, and III. Index therapy was IMiD (n=193, 53%), PI (n=148, 40%), or IMiD+PI (n=26, 7%). At data cut-off (April 2016), median (Q1-Q3) follow-up was 16.7 (9-27) months, and 225 (61%) patients were still on study; the most common reasons for discontinuation were death or entering into a randomized clinical trial. Discontinuation was attributed to death for 92 (25%) patients; 69 (75%) of these deaths were due to disease progression. Approximately one-third of patients (128/367; 35%) had prior transplantation experience: 5% of patients had 2 prior transplantations, 99% of transplantations were autologous, and 83% were received after frontline (first) therapy. In patients without transplantation experience (n=238), the response rate (95% CI) was 46% (39-53) at 6 months, 58% (50-65) at 12 months, and 60% (53-67) at 18 months, versus 43% (34-53), 60% (50-70), and 60% (50-70), respectively, in those with prior transplantation. Median time in response was 14.6 months in patients without prior transplantation versus 20.3 months in those with prior transplantation. In patients with and without prior transplantation, time in response was longer in patients who had received an IMiD as index therapy (Table). Median PFS was 11.5 months in patients without transplantation and 14.1 months in those with transplantation; PFS rates (with/without prior transplantation) was: 6 months, 71%/67%; 12 months, 56%/49%; 18 months, 41%/32%. OS rate at 12 months was 81% in patients without prior transplantation and 82% in those with prior transplantation. In patients (≥6 months on study) who responded within 6 months, OS rate (IMiD/PI cohorts) was: 6 months, 100%/100%; 12 months, 93%/91%; 18 months, 85%/78%. In patients (≥6 months on study) who progressed within 6 months, OS rate (IMiD/PI cohorts) was: 6 months, 100%/100%; 12 months, 84%/69%; 18 months, 56%/64%. Conclusions: In patients with MM and 1 line of prior therapy either with or without prior transplantation experience, approximately 45% achieved a response, with approximately 40% of these patients maintaining their response at 18 months. Regardless of index therapy type or prior transplantation experience, loss of response was observed over time, highlighting the continuing unmet medical need in RRMM. Collectively, these data exemplify the importance of novel therapies that have potential to provide durable responses and improve treatment outcomes for patients with RRMM. Further analyses exploring any impact of prior transplantation and type of frontline therapy on treatment outcomes with subsequent lines of therapy are ongoing, and will be included in the final presentation. Study support: Bristol-Myers Squibb (BMS). Medical writing assistance was provided by K Rees, of Caudex, funded by BMS. Disclosures Durie: Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Kuter:Amgen: Consultancy; Eisai: Consultancy; Genzyme: Consultancy; GlaxoSmithKline: Consultancy; ONO: Consultancy; Pfizer: Consultancy; Shionogi: Consultancy; Shire: Consultancy; 3SBios: Consultancy; Bristol-Myers Squibb: Research Funding; Protalix: Research Funding; Rigel: Research Funding. Davis:Bristol-Myers Squibb: Employment. Zyczynski:Bristol-Myers Squibb: Employment. Goldschmidt:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Honoraria, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Vij:Amgen: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Karyopharm: Honoraria. Popov:Bristol-Myers Squibb: Consultancy. Cella:Abbvie, Inc.: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Bayer Pharmaceuticals, Inc.: Consultancy, Research Funding; Alexion, Inc., Astellas, Biogen Idec, Celgene, Clovis Oncology, Inc., Daiichi Sankyo, Eli Lilly, Evidera, Inc., Exelixis, Fiborgen, Genetech, Helsinn Therapeutics, Inc., Immunogen, Ipsen Pharma, Janssen, Lexicon Pharmaceuticals, Inc., Merck, Novartis, Onc: Consultancy, Research Funding; Facit.org: Other: President; Bristol-Meyers Squibb: Consultancy, Research Funding. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Extended follow-up of outcome measures and analysis of prognostic factors in multiple myeloma patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7617 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7617-7617 ◽

Cited By ~ 1

Author(s):

S. E. Biehn ◽

D. T. Moore ◽

P. M. Voorhees ◽

R. A. Garcia ◽

M. J. Lehman ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Liposomal Doxorubicin ◽

Cox Regression ◽

Single Agent ◽

Pegylated Liposomal Doxorubicin ◽

Rank Test ◽

Significant Activity ◽

Prior Therapy

7617 Background: Preclinical studies of bortezomib (bort) with pegylated liposomal doxorubicin (PLD) showed enhanced anti-tumor efficacy compared with either single agent. This led to a phase I trial in patients (pts) with advanced hematologic malignancies who received bort on days 1, 4, 8 and 11 at 0.9–1.5 mg/m2, and PLD on day 4 at 30 mg/m2, every three weeks (Blood 105:3058, 2005). Significant activity was seen, with 36% of relapsed/refractory multiple myeloma (MM) pts achieving a complete or near-complete response, while 73% attained at least a partial response. It was therefore of interest to define time to progression (TTP) and overall survival (OS) with this regimen. Methods: Additional follow-up was obtained on all 22 evaluable MM pts. TTP and OS were determined from day 1 of bort/PLD, and the Kaplan-Meier method was used to calculate time-to-event estimators. The log-rank test was used to compare TTP and time to retreatment (TTR) on bort/PLD vs. the prior therapy. Cox regression was used to evaluate covariates for association with TTP and OS. Results: Median TTP with bort/PLD was 9.3 months (mos)(95% confidence interval (CI) 8.3–22.4) versus 3.8 mos (95% CI 2.3–10.0) on the pt’s prior therapy (p=0.04). Similarly, the median TTR after bort/PLD was prolonged (p=0.04) compared with TTR after the prior regimen, with 3 pts having not yet received their next therapy. With a median follow-up of 36 mos, 13 of these patients (59%) remain alive, and the median OS has not yet been reached. Karnofsky performance status was significantly associated with TTP (p=0.02), while the hematocrit (hct; p=0.06) and IgA subtype (p=0.08) had borderline significance. Hct was significantly associated with OS (p=0.03), while the number of prior regimens (p=0.07) and the platelet count (p=0.06) had borderline significance. Conclusions: Bort alone induced a median TTP of 6.6 mos and OS of 16 mos in MM (N Engl J Med 348: 2609, 2003). The current results support the possibility that the bort/PLD regimen may improve upon TTP, and especially OS, compared with bort alone. This hypothesis is being studied in a randomized, international phase 3 trial ( NCT00103506 ) comparing bort and bort/PLD. No significant financial relationships to disclose.

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A Phase III Randomized Intergroup Trial (SWOG S0016) of CHOP Chemotherapy Plus Rituximab Vs. CHOP Chemotherapy Plus Iodine-131-Tositumomab for the Treatment of Newly Diagnosed Follicular Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v118.21.98.98 ◽

2011 ◽

Vol 118 (21) ◽

pp. 98-98 ◽

Cited By ~ 6

Author(s):

Oliver W. Press ◽

Joseph M Unger ◽

Lisa M. Rimsza ◽

Jonathan Friedberg ◽

Michael LeBlanc ◽

...

Keyword(s):

Research Funding ◽

Cox Regression ◽

Hazard Ratio ◽

Phase Iii ◽

Advanced Stage ◽

Chop Chemotherapy ◽

Prior Therapy ◽

Beta 2 ◽

Beta 2 Microglobulin

Abstract Abstract 98 Background: Advanced follicular lymphomas (FL) are incurable with conventional chemotherapy and there is no consensus on the best treatment approach. The SWOG cancer research cooperative group and Cancer and Leukemia Group B (CALGB) compared the safety and efficacy of two immunochemotherapy regimens for FL in a Phase III randomized intergroup protocol (S0016) that enrolled 554 patients with previously untreated, advanced stage FL between 3/1/2001 and 9/15/2008. Methods: Pts were eligible if they had advanced stage (bulky stage II, III or IV) evaluable FL of any grade (1, 2, or 3) and had not received any prior therapy. In one arm (CHOP-R), patients received 6 cycles of CHOP chemotherapy (750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine, and 100 mg prednisone daily for 5 days) at 3 week intervals with 6 doses of rituximab anti-CD20 antibody (375 mg/m2 on days 1, 6, 48, 90, 134 and 141 according to the schedule described by Czuczman et al.[J.Clin.Oncol 17:268, 1999]). In the second arm of the protocol, patients received 6 cycles of CHOP, followed by a dosimetric infusion of tositumomab/iodine I-131 tositumomab and then 1–2 weeks later a therapeutic infusion of I-131-tositumomab labeled with sufficient I-131 (median 85 mCi) to deliver a total body dose of 75 cGy (CHOP-RIT). The study was designed to have 86% power to detect a hazard ratio (HR) of CHOP-RIT to CHOP-R of 0.67 for 2 yr PFS based on a one-sided.021 level test (accounting for 3 interim analyses). Results: Of the 554 enrolled pts, 532 were eligible and 526 were evaluable for toxicity (263 on each arm of the protocol). Pt characteristics (age, sex, race, stage, beta 2 microglobulin level, tumor bulk, B symptoms) were well-balanced in the two arms of the protocol. In general, both regimens were well-tolerated (Table I). Median follow-up time among patients still alive is 4.9 years. One hundred and six of 267 eligible pts on the CHOP-R arm have progressed or died compared to 86 of 265 eligible pts on the CHOP-RIT arm. The 2 year estimate of PFS was 76% on the CHOP-R arm and 80% on the CHOP-RIT arm (Figure 1). In multivariate Cox regression adjusting for the stratification factor (serum beta-2 microglobulin level), the hazard ratio for CHOP-RIT vs. CHOP-R was 0.79 (95% CI: 0.60–1.05, p=.11 [2-sided] or p=.06 [1-sided]). Twenty-six of 267 pts on the CHOP-R arm have died compared to 40 of 265 eligible pts on the CHOP-RIT arm. The 2-year estimate of overall survival was 97% on the CHOP-R arm and 93% on the CHOP-RIT arm. In multivariate Cox regression adjusting for the stratification factor serum beta-2 microglobulin, the hazard ratio for CHOP-RIT vs. CHOP-R was 1.55 (95% CI: 0.95–2.54, p=.08 [2-sided]). Conclusion: No statistically significant differences in PFS, OS, or serious toxicities are yet demonstrable with either regimen administered in this trial. However, PFS and OS are outstanding with either of the two regimens with median times to progression not yet reached for either treatment. Future studies will be needed to assess whether combining CHOP-R with RIT consolidation and with maintenance rituximab will confer additive benefit, as being evaluated in a follow-up trial (SWOG protocol S0801) that has recently completed accrual. Disclosures: Press: Spectrum: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Off Label Use: Front-line use of I-131-tositumomab for consolidation therapy in 1st remission of follicular lymphoma. Friedberg:Genentech: Consultancy, Honoraria. Czuczman:Glaxo Smith Kline: Consultancy, Research Funding; Genentech: Consultancy, Honoraria. Kaminski:Glaxo Smith Kline: Patents & Royalties. Maloney:Genentech/Roche: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau. Cheson:Glaxo Smith Kline: Research Funding. Fisher:Roche: Consultancy, Honoraria.

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Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma.

Blood ◽

10.1182/blood.v116.21.4569.4569 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4569-4569

Author(s):

Qaiser Bashir ◽

Wei Wei ◽

Alexandre Chiattone ◽

Gabriela Rondon ◽

Simrit Parmar ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Disease Status ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Year 2000

Abstract Abstract 4569 Background: Allogeneic hematopoietic cell transplantation (allo HCT) is a potentially curative therapy for multiple myeloma (MM), but has high treatment-mortality (TRM). In addition, disease relapse occurs in a significant number of patients. We sought to evaluate if the recent advances in the field of HCT and MM have impacted the results of allo HCT for MM. We present the results of allo HCT performed at a single center over last 25 years. Methods: 149 patients with MM who underwent allo HCT between 11/1985 and 6/2010 using myeloablative (MA) N= 52, or reduced intensity conditioning (RIC) N=97 at our institution were retrospectively analyzed. Results: Patient characteristics and pertinent outcomes are summarized in the Table. 62 (42%) were female. Median age was 50 (28-70) years. Median follow up is 2.4 years [11.3 years for the patients who received allo HCT prior to year 2000(<2000); 2 years for the patients who received allo HCT in the year 2000 and onwards (≥2000)]. TRM at 2 year was 37%. TRM was significantly lower for year ≥2000, recipients of RIC regimens, recipients of peripheral blood stem cells (HPC-A), and disease status at transplant PR or better. There was no difference between TRM for patients above or below age 50 years (p 0.08). Grade II-IV acute and limited or extensive chronic graft-versus host disease was seen in 31%, and 37% patients, respectively. Progression free survival (PFS) at 2 year and 5 year was 23% (95% CI: 16–30) and 15% (95% CI: 9–21), respectively. Overall survival (OS) at 2 year and 5 year was 40% (95% CI: 32–48) and 21% (95% CI: 13–29), respectively. At the time of last follow up 40 patients are still alive and 28 are in remissionn, longest for 166 months. On univariate analysis the OS was significantly better for year ≥2000 versus year <2000; recipients of HPC-A versus HPC-M; primary responsive disease versus relapse or primary refractory disease at HCT; disease status at HCT PR or better; and patients without poor risk cytogenetic features at diagnosis. OS was longer in patients who received maintenance therapy post allo HCT (N=12) versus the patients who did not, although it did not reach statistical significance (2.9 years versus 8.4 months; p 0.06). Conclusion: Allo HCT for MM can offer long term disease control in a subset of MM patients. TRM has declined and outcomes have significantly improved over the last decade. Maintenance therapy may have a role post allo HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Qazilbash:Celgene: Speakers Bureau.

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AB0330 HIGH REMISSION RATES IN RA – REAL LIFE DATA FROM BARITICINIB

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5263 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1463.2-1464

Author(s):

S. Bayat ◽

K. Tascilar ◽

V. Kaufmann ◽

A. Kleyer ◽

D. Simon ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Cox Regression ◽

Real Life ◽

Inadequate Response ◽

Research Support ◽

Das 28 ◽

Patient Reported ◽

One Year

Background:Recent developments of targeted treatments such as targeted synthetic DMARDs (tsDMARDs) increase the chances of a sustained low disease activity (LDA) or remission state for patients suffering rheumatoid arthritis (RA). tsDMARDs such as baricitinib, an oral inhibitor of the Janus Kinases (JAK1/JAK2) was recently approved for the treatment of RA with an inadequate response to conventional (cDMARD) and biological (bDMARD) therapy. (1, 2).Objectives:Aim of this study is to analyze the effect of baricitinb on disease activity (DAS28, LDA) in patients with RA in real life, to analyze drug persistance and associate these effects with various baseline characteristics.Methods:All RA patients were seen in our outpatient clinic. If a patient was switched to a baricitinib due to medical reasons, these patients were included in our prospective, observational study which started in April 2017. Clinical scores (SJC/TJC 76/78), composite scores (DAS28), PROs (HAQ-DI; RAID; FACIT), safety parameters (not reported in this abstract) as well as laboratory biomarkers were collected at each visit every three months. Linear mixed effects models for repeated measurements were used to analyze the time course of disease activity, patient reported outcomes and laboratory results. We estimated the probabilities of continued baricitinib treatment and the probabilities of LDA and remission by DAS-28 as well as Boolean remission up to one year using survival analysis and explored their association with disease characteristics using multivariable Cox regression. All patients gave informed consent. The study is approved by the local ethics.Results:95 patients were included and 85 analyzed with available follow-up data until November 2019. Demographics are shown in table 1. Mean follow-up duration after starting baricitinib was 49.3 (28.9) weeks. 51 patients (60%) were on monotherapy. Baricitinib survival (95%CI) was 82% (73% to 91%) at one year. Cumulative number (%probability, 95%CI) of patients that attained DAS-28 LDA at least once up to one year was 67 (92%, 80% to 97%) and the number of patients attaining DAS-28 and Boolean remission were 31 (50%, 34% to 61%) and 12(20%, 9% to 30%) respectively. Median time to DAS-28 LDA was 16 weeks (Figure 1). Cox regression analyses did not show any sufficiently precise association of remission or LDA with age, gender, seropositivity, disease duration, concomitant DMARD use and number of previous bDMARDs. Increasing number of previous bDMARDs was associated with poor baricitinib survival (HR=1.5, 95%CI 1.1 to 2.2) while this association was not robust to adjustment for baseline disease activity. Favorable changes were observed in tender and swollen joint counts, pain-VAS, patient and physician disease assessment scores, RAID, FACIT and the acute phase response.Conclusion:In this prospective observational study, we observed high rates of LDA and DAS-28 remission and significant improvements in disease activity and patient reported outcome measurements over time.References:[1]Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Annals of the rheumatic diseases. 2015 Feb;74(2):333-40.[2]Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. The New England journal of medicine. 2016 Mar 31;374(13):1243-52.Figure 1.Cumulative probability of low disease activity or remission under treatment with baricitinib.Disclosure of Interests:Sara Bayat Speakers bureau: Novartis, Koray Tascilar: None declared, Veronica Kaufmann: None declared, Arnd Kleyer Consultant of: Lilly, Gilead, Novartis,Abbvie, Speakers bureau: Novartis, Lilly, David Simon Grant/research support from: Else Kröner-Memorial Scholarship, Novartis, Consultant of: Novartis, Lilly, Johannes Knitza Grant/research support from: Research Grant: Novartis, Fabian Hartmann: None declared, Susanne Adam: None declared, Axel Hueber Grant/research support from: Novartis, Lilly, Pfizer, EIT Health, EU-IMI, DFG, Universität Erlangen (EFI), Consultant of: Abbvie, BMS, Celgene, Gilead, GSK, Lilly, Novartis, Speakers bureau: GSK, Lilly, Novartis, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB

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FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors

Neuroendocrinology ◽

10.1159/000514339 ◽

2021 ◽

Author(s):

Jane E. Rogers ◽

Michael Lam ◽

Daniel M. Halperin ◽

Cecile G. Dagohoy ◽

James C. Yao ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Cox Regression ◽

Progression Free Survival ◽

Pancreatic Neuroendocrine Tumors ◽

Free Survival ◽

Prior Therapy ◽

Well Differentiated ◽

Grade 3 ◽

Line Of Therapy

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

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The Necessary for Long-Term Follow-up of Mutated Genes and Clonal Evolutions in Multiple Myeloma Combined with cfDNA Assay

Blood ◽

10.1182/blood-2019-122977 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5515-5515

Author(s):

Yuko Mishima ◽

Yuji Mishima ◽

Masahiro Yokoyama ◽

Noriko Nishimura ◽

Yoshiharu Kusano ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Genomic Dna ◽

Research Funding ◽

Somatic Mutations ◽

Clinical Course ◽

Bone Marrow Aspiration ◽

Long Term Follow Up

Introduction)Somatic mutations in multiple myeloma (MM) are strongly related to the clinical outcome and clonal evolution over the clinical course, and are a major problem. From a clinical viewpoint, although numerous novel drugs have been utilized, achieving long-lasting and complete remission remains difficult. Recent studies have elucidated the mutated genes using next-generation sequencing, and have examined how clonal change can be acquired in myeloma. In this study, we traced the transition of the somatic mutations of bone marrow tumor cells in patients with MM over a long-term follow-up. Furthermore, we compared the somatic mutations found in serum cell-free DNA (cfDNA) and mutated genes obtained from bone marrow myeloma cells. Material and Methods)Patients diagnosed with multiple myeloma who provided written informed consent to participate in the study were enrolled. Patients were treated by immuno-chemotherapy with or without radiation between 2000 and 2017 at our institute. Bone marrow aspiration and biopsy were performed at the time of diagnosis and upon disease progression. Around the time of bone marrow aspiration, serum was obtained from a peripheral blood sample for cfDNA analysis. Myeloma cells were separated from bone marrow samples with MicroBeads of CD138 antibody and genomic DNA was extracted. The peripheral blood samples derived from myeloma patients. The cfDNA was extracted from the serum using a Maxwell RSC cfDNA Plasma kit. Using genomic DNA derived from cfDNA and bone marrow, multiplex polymerase chain reaction (PCR) was performed, and a sequence library was then constructed with an Ion Custom Amplicon panel. The panel for the sequence library was designed using an Ion AmpliSeq DesignerTM. 126 targeted genes were selected. The genomes were sequenced using the Ion ProtonTM System. This protocol was approved by the institutional review board and the Genomic Review Board of the Japanese Foundation for Cancer Research. Result)We followed 7 patients' long term-clinical course and the transition of mutations (8.5 year average). The expression of myeloma driver genes, such as RAS, BRAF, and MYC, were not critical. We did, however, detect a relationship between an increase in the dominant mutated gene, such as TP53, DIS3, FAM46C, KDM6B, and EGR1 and poor prognosis in patients with myeloma. Next, we calculated the cfDNA concentrations from 34 cases. The cfDNA concentrations were significantly higher than 10 control cases (average 62.0 ng/mL (0-200 ng/mL) and 8.18 ng/mL (4.3-14.1 ng/mL), P=0.0046). The 2.5 year-progression free survival (PFS) during the first treatment of MM were tend to be poorer in the group with cfDNA>50 ng/mL (72.9%) than the group with cfDNA<50 ng/mL(25.9%), however there are no statistical significance (P = 0.15).We caluculated concordance rate of derived mutations from bone marrow MM cells and cfDNA in 7 cases. The somatic mutations found in serum cell-free DNA (cfDNA) and bone marrow MM cells were determined the correlation coefficients. However, there are few difference expression pattern in each source. In cfDNA assay, CREEP, EGR1, HDAC4, HDAC6, and JMJD1C were highly expressed as 57.1% (4/7) - 85.7% (6/7), and these results were almost the same as those for bone marrow MM cells. On the other hand, KDM1A (85.7%), PI3KCD (71.4%), and KDM3B (57.1%) were highly detected in cfDNA, although those were not frequently expressed in bone marrow. Discussion)Our data demonstrate the importance of the long-term follow-up of somatic mutations during the clinical course of myeloma. Serum cfDNA is a useful alternative source for detecting somatic mutations in MM patients during long-term follow-up. Disclosures Mishima: Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Yokoyama:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy. Nishimura:Chugai-Roche Pharmaceuticals Co.,Ltd.: Consultancy; Celgene K.K.: Honoraria. Hatake:Celgene K.K.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Takeda Pharmaceutical Co.,Ltd.: Honoraria. Terui:Bristol-Myers Squibb K.K.: Research Funding; Bristol-Myers Squibb, Celgene, Janssen, Takeda, MSD, Eisai, Ono, and Chugai-Roche Pharmaceuticals Co.,Ltd.: Honoraria.

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An Experience on Pomalidomide in Patients within Relapsed/Refractory Multiple Myeloma - A Multicenter Study in Turkey

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2020/v32i4131047 ◽

2021 ◽

pp. 92-98

Author(s):

Mehmet Ali Erkurt ◽

Fehmi Hindilerden ◽

Omer Ekinci ◽

Jale Yildiz ◽

Mehmet Sinan Dal ◽

...

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Cox Regression ◽

Single Agent ◽

Eastern Cooperative Oncology Group ◽

Cox Regression Analysis ◽

Refractory Multiple Myeloma ◽

Thalidomide Analogue ◽

New Generation

Objective: Pomalidomide is a new generation thalidomide analogue. Effectiveness as a single agent or combination with low dose dexamethasone has been in the treatment of relapse/refractory Multiple Myeloma (MM). The aim of the present study was to share the experience of different oncology centres with pomalidomide treatment in patients with relapsed/refractory MM. Materials and Methods: Seventy-three patients from 16 centres were enrolled into the study. The patients were followed for a median of 6 months. Relapsed/refractory MM patients who received at least one line of treatment before pomalidomide were included into the study. ISS, R-ISS and Eastern Cooperative Oncology Group (ECOG) scores of the patients and treatment-related side effects were evaluated. Results: As a result of the median follow-up for 6 months, 36% (26/72) of the patients presented progression. The estimated median PFS was found 29 months. The Cox regression analysis revealed that ECOG affected PFS only, myeloma subtype; ISS and R-ISS scores did not affect PFS. The most common side effects with pomalidomide treatment in our population include neutropenia, infections, anaemia and thrombocytopenia. Conclusion: In our study, it was statistically shown that the ECOG score was effective in survival in relapsed / refractory MM patients treated by pomalidomide. Therefore, we recommend evaluation of the ECOG score for each patient before treatment in eligible cases.

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Factors Associated with Persistence with Teriparatide Therapy: Results from the DANCE Observational Study

Journal of Osteoporosis ◽

10.4061/2011/314970 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Deborah T. Gold ◽

David L. Weinstein ◽

Gerhardt Pohl ◽

Kelly D. Krohn ◽

Yi Chen ◽

...

Keyword(s):

Side Effects ◽

Observational Study ◽

Trend Test ◽

Factors Associated ◽

Treatment Side Effects ◽

Patient Reported ◽

Proper Training ◽

Improper Use ◽

Armitage Trend Test

Purpose. Determine patient-reported reasons for discontinuation with teriparatide.Methods. Patients taking teriparatide in a multicenter, prospective, and observational study were given three questionnaires: baseline, follow-up questionnaire 1 (QF1, 2 to 6 months), and follow-up questionnaire 2 (QF2, 12 months). Discontinuation reported at QF1 and QF2 was defined as “early” and “late,” respectively, and remaining patients were considered persistent. Cochran-Armitage trend test was used to identify factors associated with discontinuation.Results. Side effects, concern about improper use, injection difficulties, and several patient-perceived physician issues were associated with early discontinuation. Low patient-perceived importance of continuing treatment, side effects, difficulty paying, and low patient-perceived physician knowledge were associated with late discontinuation. The most common specific reasons selected for discontinuing treatment were “concerns about treatment outweighing the benefits” (n=53) and “difficulty paying” (n=47).Conclusions. Persistence with teriparatide is dependent on managing side effects, addressing financial challenges, proper training, and obtaining support from the healthcare provider.

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