scholarly journals Evaluation of Functional and Cytogenetic High-Risk Multiple Myeloma Using Real-World Data

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4093-4093
Author(s):  
Ankit Kansagra ◽  
Eric Hansen ◽  
Andrew J. Belli ◽  
Stefanie Goran ◽  
Ching-Kun Wang
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Disease Progression ◽  
Real World ◽  
Multivariate Analyses ◽  
Rapid Disease Progression ◽  
High Risk Patients ◽  
Risk Patients ◽  
High Risk Populations ◽  
Equity Ownership

Abstract Introduction: Multiple myeloma (MM) is a heterogeneous disease with wide variability in outcomes. The presence of cytogenetic abnormalities in MM is of critical importance for prognosis and risk stratification. However, patients who may or may not have sufficient cytogenetic abnormalities to classify as high-risk can still experience rapid disease progression despite therapy, or functional high risk (FHR) disease. These two high risk cohorts comprise vulnerable subpopulations who have a significant burden of disease, and it is critical that we understand the underlying patient characteristics and optimal treatment sequence. We sought to investigate these two high risk patient populations treated in the contemporary real-world practice setting. Methods: A total of 1719 patients were identified in the COTA real-world database as having been diagnosed with active MM on or after January 1, 2015 and classified as either FHR, cytogenetic high risk (CHR), or both. The COTA real-world database is a USA-based real-world evidence database comprised of longitudinal, Health Insurance Portability and Accountability Act (HIPAA)-compliant, data on the diagnosis, clinical management, and outcomes of patients with cancer. Of the 1719 patients, 1260 were identified to be FHR, defined as relapse <18 months from initial active MM diagnosis. A total of 459 patients were identified as CHR, among which 347 were both FHR and CHR. CHR was defined as a patient having at least one of the following abnormalities: t(4;14), t(14;16), t(14;20), del(17p), 1q gain, or hypoploid. Line of therapy was applied programmatically using an algorithm based on International Myeloma Working Group criteria and clinical guidance. The primary outcome was time to next treatment (TTNT) calculated using the Kaplain Meier method. Univariate and multivariate analyses were conducted to understand predictors of rapid disease progression among high-risk patients. Results: In our real-world population, FHR patients tended to be slightly younger, African American, and treated predominantly in the academic setting (Table 1). First-line (1L) and second-line (2L) treatment patterns by category are shown in Table 2. A lower proportion of FHR patients received 1L immunomodulators as compared to the other high-risk groups, while almost half of the CHR patients received 1L stem cell transplant (SCT). In 2L, among patients not receiving 2L SCT, a higher proportion of CHR patients received a daratumamab-based treatment as compared to FHR (23.2% vs. 12.0%, respectively). We observed a longer median (95% CI) TTNT for high-risk patients receiving 2L daratumamab-based treatment as compared to patients who did not: 8.5 months (6.4-13.0) vs. 6.0 months (5.3-6.9), p=0.07 (Figure 1). Univariate and multivariate analyses showed age at diagnosis (HR: 0.98, CI: 0.97, 0.99), normal cytogenetics (HR: 0.78, CI: 0.63, 0.97), 1L immunomodulator (HR: 0.39, CI: 0.22, 0.69), 1L proteasome inhibitor (HR: 1.4, CI: 1.1, 1.8), and 1L SCT (HR: 0.22, CI: 0.15, 0.32) as significant predictors of rapid disease progression. Conclusions: Our study provides important insights comparing high risk populations with MM treated in the real-world setting. A higher proportion of CHR patients received 1L SCT and this provided the longest 1L TTNT as compared to other treatments. In 2L, among patients not receiving 2L SCT, we observed a trend towards significantly longer TTNT provided by dara-based treatment as compared to non-dara based treatment; however, our TTNT is lower than progression-free survival results observed in pivotal trials. We identified potential underlying differences in our patient populations that may be driving the predictors of rapid disease progression, including 1L SCT eligibility and renal disease, and these will be further investigated in propensity score matched populations. Future research will continue to explore optimal treatment sequences in high-risk populations with multiple myeloma to improve patient outcomes. These data highlight an urgent need to better predict FHR patients at diagnosis and develop clinical trials incorporating novel compounds in high risk patients. Figure 1 Figure 1. Disclosures Hansen: COTA, Inc.: Current Employment. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Goran: COTA, Inc.: Current Employment. Wang: COTA, Inc.: Current Employment, Other: Equity ownership.

scholarly journals Real-World Treatment Patterns and Outcomes of Patients with Functional High-Risk (Early Relapse) Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Andrew J. Belli ◽  
Eric Hansen ◽  
Ankit Kansagra ◽  
Keshava Dilwali ◽  
Ching-Kun Wang
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Real World ◽  
Treatment Patterns ◽  
Practice Setting ◽  
Private Company ◽  
Early Relapse ◽  
High Risk Patients ◽  
Risk Patients ◽  
Insight Into

Background: There have been significant advancements in the treatment of multiple myeloma (MM) over the last 20 years including an influx of recently approved novel therapies. However, with these advances in treatment, the optimal combination and sequence of agents remain largely unknown especially in relapsed/refractory MM. A major unmet need in MM is patients with high-risk disease. Revised International Staging System is used to identify patients with high-risk MM, however a better definition of high risk includes "functional high risk" (i.e. patients relapsing within 18 months from diagnosis). As it has been previously shown that clinical trial populations are not universally representative of those in the routine practice setting, real-world data (RWD) can provide valuable insight into this rapidly evolving treatment landscape and high-risk population. Here we explore treatment patterns and outcomes of functional high-risk MM, patients who relapse within 18 months of initial diagnosis. Methods: This retrospective study utilized the COTA real-world database, a de-identified database of RWD derived from the electronic health records of partnered healthcare providers in the United States. A total of 958 patients were identified as having been diagnosed with active MM between Jan. 1, 2015 and Jan. 1, 2020 and experienced early relapse (defined as relapse within 18 months of initial active MM diagnosis and treatment). Practice setting distribution of this cohort was 84% academic and 16% community. Line of therapy was assigned programmatically utilizing IMWG definitions and guidelines. Patient characteristics and treatment patterns across the first (1L) and second lines (2L) of treatment were assessed using descriptive statistics. Time to next treatment (TTNT) was calculated overall and within treatment subgroups of interest as a surrogate for progression-free survival. Results: Among this functional high-risk patient population, the mean age was 64 yrs. (SD ±11.3) and the patients were predominantly white (72.6%). The most common cytogenetic abnormalities at diagnosis were del(13) (46.0% positive), 1q (36.4%), and t(11;14) (25.4%). In 1L, the majority of patients received a triplet regimen (75.4%), most commonly proteosome inhibitor (PI) + immunomodulator (IMiD) + steroids (45.0%). A total of 56 patients (5.9%) received stem-cell transplant (SCT) in 1L. Overall, 16.3% of the population did not receive 2L therapy due to death. Among the patients who received 2L therapy after early relapse (N=869), 50.5% received an SCT. TTNT was significantly longer for patients receiving SCT in 2L as compared to those who did not (34.8 vs. 5.8 months, respectively). Among patients who did not receive SCT (N=430), triplet therapy was most common (61.2%) with PI + IMiD + steroids representing the largest regimen group (30.2%). Table 1 shows the distribution of PI drugs within the 2L PI + IMID + steroids group and their associated median TTNT. No significant differences were observed when comparing median TTNT of 2L PI + IMID + steroids to daratumumab-based regimens (5.3 vs. 5.6 months, respectively). Conclusions: In our real-world population, median TTNT for functional high-risk patients was 17.8 months. 50.5% of these functional high-risk patients received SCT in 2L with the most common induction regimen containing cyclophosphamide + etoposide + dexamethasone (CED). For patients not receiving SCT in 2L, the most common regimen type included PI + IMID + Steroids. In comparing antibody-based therapy vs. PI + IMID + dexamethasone-based therapy, daratumumab-based combinations showed no significant difference in unadjusted analysis. Our study highlights some very important observations in functional high-risk patients. First, if patients are SCT eligible and it is not performed as part of first line treatment, SCT still provides the best outcomes in regard to TTNT in the second line setting. For patients not receiving SCT, our RWD demonstrates that 30.2% receive PI + IMID + dexamethasone as 2L treatment with only 13% receiving carfilzomib-based combination. Our study highlights the poor outcome of functional high-risk patients and provides insight into treatment patterns in 2L therapy. Further research is needed to explore patient and disease characteristics of functional high-risk patients and study novel treatment strategies like CAR T cell therapy or T-cell engagers in these patient population. Disclosures Belli: COTA, Inc.: Current Employment, Current equity holder in private company. Hansen:COTA, Inc.: Current Employment, Current equity holder in private company. Kansagra:Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Dilwali:COTA, Inc.: Current Employment, Current equity holder in private company. Wang:COTA, Inc.: Current Employment, Current equity holder in private company.

scholarly journals Daratumumab Single Agent and Daratumumab Plus Pomalidomide and Dexametasone in Relapsed/Refractory Multiple Myeloma: A Real Life Retrospective Evaluation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4516-4516 ◽  
Author(s):  
Antonio Branca ◽  
Amy Buros ◽  
Donghoon Yoon ◽  
Larry J Suva ◽  
Niels Weinhold ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Event ◽  
High Risk ◽  
Disease Progression ◽  
Single Agent ◽  
Low Risk ◽  
High Risk Patients ◽  
Risk Patients ◽  
Group 2 ◽  
Group 1

Abstract Background. In the last twenty years, the outcome of multiple myeloma (MM) has markedly improved. Daratumumab is the first anti-CD38 monoclonal antibody (mAb) recently approved for the treatment of relapsed refractory multiple myeloma (RRMM). In this study we have evaluated the efficacy of daratumumab single agent and daratumumab plus pomalidomide and dexamethasone in low and high risk RRMM patients. Design and Methods. From November 2015 to March 2016, 25 and 39 RRMM patients were treated with therapy using daratumumab single agent (Group 1: median age 67, range 40-83) and daratumumab plus pomalidomide and dexamethasone respectively (Group 2: median age 71, range 45-87). In both groups, patients received daratumumab IV 16 mg/kg once a week (weeks 1-8), followed by every other week (weeks 9-24) and then once a month until disease progression or unacceptable toxicities. In Group 2 pomalidomide was administered at dosages from 1 mg to 4 mg daily according to tolerability for 21 days every 28 days, along with dexamethasone 40 mg weekly. The median time form the time of diagnosis was 7.1 years and 5.5 years in Group 1 and Group 2 respectively. In both groups, patients had received a median of 4 prior treatments. In Group 1, 80% of the patients had disease refractory to the last therapy received, 68% had disease double refractory to IMiDs and PIs, and 28% (7 patients) had GEP high risk signature. In Group 2, 78% of the patients had disease refractory to last therapy, 84% had double refractory disease and 37% (14 patients) had high GEP risk signature. Results. In the single agent group, the overall response rate (ORR) was 28%: CR 4% (1 patient), 4% VGPR (1 patient), PR 20% (5 patients). With a median follow up of 3.5 months, 48% of patients were still on treatment and 52% had discontinued treatment for disease progression. The ORR according to last GEP70 was 40% and 0% in the low risk and high risk patients respectively. All high risk patients had discontinued treatment for disease progression within the second month of treatment. In the second group, the ORR was 41%: CR 5% (2 patients), 3% VGPR (1 patient), and 33% PR (13 patients). After a median follow up of 4 months, 77% (30 patients) of patients were still on treatment, 20% (8 patients) discontinued treatment for disease progression and 3% (1 patient) of patients had discontinued treatment for adverse event grade 4. The ORR was 50% (4% CR, 4% VGPR, and 42% PR) in low risk patients and 21% (7% CR and 14% PR) in high risk patients. Infusion-related reactions were mild (54% of patients had an event of any grade, and 4% and 2% had an adverse event of grade 3 in Group 1 and Group 2 respectively). The most common non hematological adverse event of grade 3 or 4 was pneumonia (4% and 8% in Group 1 and Group 2 respectively). PFS of Group 1 and 2 are shown in Figure 1. Conclusion. Daratumumab single agent had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma, and the combination of daratumumab with pomalidomide and dexamethasone was well tolerated and improved the outcome in low risk patients, even in double refractory disease. Encouraging results have been observed as well in patients with high risk GEP 70 signature. Figure 1 Figure 1. Disclosures Davies: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Morgan:Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding.

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

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

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

scholarly journals Predictors of coronary artery disease progression among high-risk patients with recurrent symptoms

Heart Views ◽  
2018 ◽  
Vol 19 (2) ◽  
pp. 45
Author(s):  
MouazH Al-Mallah ◽  
Iyad Farah ◽  
AmjadM Ahmed ◽  
Raed Odeh ◽  
Eltayyeb Alameen ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
High Risk ◽  
Disease Progression ◽  
High Risk Patients ◽  
Risk Patients ◽  
Artery Disease ◽  
Coronary Artery Disease Progression

scholarly journals Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 804-804 ◽  
Author(s):  
Mark Bustoros ◽  
Chia-jen Liu ◽  
Kaitlen Reyes ◽  
Kalvis Hornburg ◽  
Kathleen Guimond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Rna Sequencing ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

scholarly journals Use of a Combination of CEA and Tumor Budding to Identify High-risk Patients with Stage II Colon Cancer

2017 ◽  
Vol 32 (3) ◽  
pp. 267-273 ◽  
Author(s):  
Changzheng Du ◽  
Weicheng Xue ◽  
Fangyuan Dou ◽  
Yifan Peng ◽  
Yunfeng Yao ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Disease Progression ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Tumor Budding ◽  
High Risk Patients ◽  
Prognostic Accuracy ◽  
Risk Patients ◽  
Stage Ii Colon Cancer

Background High-risk patients with stage II colon cancer may benefit from adjuvant chemotherapy, but identifying this patient population can be difficult. We assessed the prognosis value for predicting tumor progression in patients with stage II colon cancer, of a panel of 2 biomarkers for colon cancer: tumor budding and preoperative carcinoembryonic antigen (CEA). Methods Consecutive patients (N = 134) with stage II colon cancer who underwent curative surgery from 2000 to 2007 were included. Multivariate analysis was used to evaluate the association of CEA and tumor budding grade with 5-year disease-free survival (DFS). The prognostic accuracy of CEA, tumor budding grade and the combination of both (CEA-budding panel) was determined. Results The study found that both CEA and tumor budding grade were associated with 5-year DFS. The prognostic accuracy for disease progression was higher for the CEA-budding panel (82.1%) than either CEA (70.9%) or tumor budding grade (72.4%) alone. Conclusions The findings indicate that the combination of CEA levels and tumor budding grade has greater prognostic value for identifying patients with stage II colon cancer who are at high-risk for disease progression, than either marker alone.

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