Healthcare Resource Use and Costs Among Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Abstract Background Few studies have assessed HRU and costs in RRMM. A prior study reported 1-yr total healthcare costs of $113,000 (2013 US $) among non-transplant patients with newly diagnosed MM (DaCosta Byfield ASCO 2015). Real-world data on economic burden in the era of new MM therapeutic options could provide insight for directing efficient resource utilization. We examined HRU and costs associated with second-line therapy (SLT) in RRMM. Methods We identified adult pts with MM between Jan 2008 and Feb 2014 in a large, national, healthcare claims database of commercially insured and Medicare Advantage beneficiaries. Newly diagnosed pts were followed from first claim for MM (+12-mo wash out period). Pts with continuous enrollment from 12 mos pre-diagnosis through 12 mos post-initiation of SLT for RRMM were included (including pts who died within 12 mos post SLT start). Those with a claim for transplants were excluded. Front-line therapy (FLT) began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 d of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 mos of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 mos between end of FLT and start of a 2nd regimen (retreatment or switch), 2) start of a follow-up regimen (retreatment) with treatment gap >3 and ≤6 mos after end of FLT, or 3) a switch to another drug combination after FLT. The first claim for SLT was the index date. Healthcare costs and HRU were determined for the 1-yr period following SLT start. Healthcare costs were calculated as total reimbursed amount to the provider paid by the health plan, the pt, and other payers, including treatment with subsequent lines of therapy if falling within the 1-yr period. Drug and drug-administration costs were captured from a) all pharmacy claims for MM-directed systemic therapy, and b) medical claims with CPT codes indicating chemotherapy drug administration if, on the same date of service, there was a claim with a HCPCS for any drug of interest. Results We identified 160 of 249 pts receiving SLT. The majority (55%) were female, 72% were aged ≥65 yrs, 10% received triplet SLT, and 53% were enrolled in a Medicare Advantage plan. Most common SLT regimens were bortezomib- (39%) or lenalidomide-based (38%) (Table 1). RRMM pts averaged 58 ambulatory visits and 1.2 hospitalizations in the yr following start of SLT, with 5.1 ICU and 7.9 non-ICU days. Mean 1-yr healthcare costs were $123,922 with 59% of total costs attributable to non-drug costs (mean: $72,718; Table 2). Conclusions The healthcare and economic burden of illness among pts with RRMM receiving SLT is substantial. The main cost driver in RRMM was non-drug related. While this research did not examine indirect costs, rates of ambulatory visits and hospitalization days occurring within 1 yr of the start of SLT were high and likely correlated with indirect costs to both the pt and caregiver. New treatment options with a more favorable side-effect and efficacy profile may mitigate this burden. At study completion, a statistical analysis will be conducted to assess the determinants and drivers of economic burden in RRMM. Table 1. RRMM pt Characteristics and SLT patterns Total (N=160)n (%)* Died during 1-yr following start of SLT 36 (22.5) Age, yrs <65 45 (28.1) 65-74 45 (28.1) ≥75 70 (43.8) Male 72 (45) Insurance type Commercial 76 (47.5) Medicare Advantage 84 (52.5) SLT regimens Bortezomib-based 62 (38.8) IMiD-based 60 (37.5) Bortezomib + IMiD 3 (1.9) Other† 35 (21.9) Start of a new regimen within 1 yr (3rd line) 68 (42.5) *unless otherwise noted †including cyclophosphamide, melphalan, vincristine, doxorubicin, interferon-alpha, pomalidomide, thalidomide, carfilzomib, dexamethasone, prednisone ‡among non-censored pts Table 2. Healthcare costs and encounters among pts with RRMM after initiation of SLT 1-yr healthcare costs (2014 US$) Mean (SD)(N=160) Total 123,922 (114,052) Drug 51,204 (40,997) Non-drug 72,718 (102,169) Total 123,922 (114,052) During SLT 81,590 (90,151) After 3rd Line initiation* 33,573 (64,832) SLT end to start of 3rd Line 8,759 (28,046) Healthcare encounters per pt Ambulatory visits 58.5 (32.6) ER visits 1.7 (2.2) Hospitalizations 1.2 (1.7) Inpatient length of stay, days 13.0 (26.6) Non-ICU 7.9 (21) ICU 5.1 (12.7) *censored at 12 mos after SLT initiation Disclosures Romanus: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Takeda Pharmaceutical Company Limited: Equity Ownership; Sanofi: Equity Ownership. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment.

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Predictors of Second-Line Treatment Choice with Triplet Therapy in Routine Care Among Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood.v126.23.3309.3309 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3309-3309

Author(s):

Dorothy Romanus ◽

Mehul Jhaveri ◽

Richard Labotka ◽

Henry Henk ◽

Brian Seal

Keyword(s):

Pharmaceutical Company ◽

Routine Care ◽

Line Therapy ◽

Company Limited ◽

Younger Age ◽

Wholly Owned Subsidiary ◽

First Relapse ◽

Equity Ownership ◽

Baseline Characteristics ◽

Comorbidity Status

Abstract Background Beginning with the IFM 2005-04/MMVAR trial, three-drug combinations (TCs) have demonstrated superior clinical outcomes compared with two-drug regimens among patients with RRMM (Garderet JCO 2012). TCs are emerging as the standard of care at first relapse. We assessed factors that influenced treatment choice with TCs in a cohort of patients with RRMM who were managed in routine care. Methods We identified adult patients with MM between January 2008 and February 2014 in a large, national, US healthcare claims database of commercially insured and Medicare Advantage beneficiaries. Newly diagnosed patients were followed from the first claim with an ICD-9 code for MM (with a 12-month wash-out period). To ensure completeness of claim history, patients with continuous enrollment from 12 months pre-diagnosis through at least initiation of second-line therapy (SLT) for RRMM were included. Those with claims for transplants were excluded. Front-line therapy (FLT) began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 days of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 months of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 months between end of FLT and start of a second regimen (retreatment or switch), 2) start of a follow-up regimen (retreatment) with a treatment gap of >3 and up to 6 months after end of FLT, or 3) a switch to another drug combination after FLT regimen. The first claim for SLT was the index date. SLT ended at the earliest of: start of a new drug, death, or end of study period (February 2014). Patients were grouped into those receiving one-/two-(1-2) vs three-/four-drug (3+) combinations based on the number of unique cancer therapy agents received within the start and end date of SLT. A logistic multivariable model was used to identify factors independently associated with receipt of 1-2 vs 3+ SLT regimens. Results Baseline characteristics among 249 RRMM patients on SLT are shown in Table 1 according to receipt of 1-2 vs 3+ SLT regimens. Among 62 patients who initiated SLT in 2013-14, 14 (23%) received a 3+ SLT regimen (vs 19 (10%) prior to 2013). Adjusting for gender and CRAB symptoms (hypercalcemia, renal insufficiency, anemia, and bone disease), predictors of 3+ SLT included: younger age (<65 years), early relapse (time to next therapy [TTNT], interval from start of FLT to start of SLT, <6 months), 3+ agents in FLT and index year of SLT initiation (in 2013-14). Charlson Comorbidity Index (CCI) was not independently associated with receipt of 3+ SLT. Conclusions A majority of patients do not receive triplet-based SLT in routine care. Younger age, and not comorbidity status, appears to be the discriminatory patient characteristic for triplet therapy choice. Introduction of triplets with a favorable toxicity profile and assessment for comorbidity status in routine practice represent steps towards optimizing treatment choices in RRMM. Table 1. Baseline Characteristics among Patients with RRMM According to SLT Type (N=249) N (%) Monotherapy/Doublet (1-2) (N=216) Triplet/Quadruplet (3+) (N=33) Total (N=249) TTNT <6 months 44 (20.4%) 14 (42.4%) 58 (23.3%) ≥6 months 172 (79.6%) 19 (57.6%) 191 (76.7%) Age, years <65 53 (24.5%) 17 (51.5%) 70 (28.1%) 65-74 64 (29.6%) 8 (24.2%) 72 (28.9%) ≥75 99 (45.8%) 8 (24.2%) 107 (43%) Male 105 (48.6%) 16 (48.5%) 121 (48.6%) CCI 0 60 (27.8%) 10 (30.3%) 70 (28.1%) 1 52 (24.1%) 3 (9.1%) 55 (22.1%) 2+ 104 (48.1%) 20 (60.6%) 124 (49.8%) CRAB symptoms 147 (68.1%) 26 (78.8%) 173 (69.5%) Number of agents in FLT regimen 1-2 147 (68.1%) 12 (36.4%) 159 (63.9%) 3+ 69 (31.9%) 21 (63.6%) 90 (36.1%) Table 2. Predictors of 3+ SLT in RRMM (N=249) Odds Ratio (OR) for 3+ vs 1-2 SLT (95% CI for OR) Age, years <65 65-74 ≥75 3.10 1.36 Reference (1.13 - 8.51)* (0.45 - 4.09) - Male 1.13 (0.51 - 2.51) Index year 2008-2012 ≥2013 Reference 3.42 - (1.42 - 8.21)** TTNT, months ≥6 <6 Reference 2.54 - (1.05 - 6.17)* CRAB symptoms at baseline 1.69 (0.63 - 4.58) CCI 0 1 2+ Reference 0.41 0.98 - (0.10 - 1.62) (0.39 - 2.46) Number of agents in FLT regimen 1-2 3+ Reference 2.77 - (1.20 - 6.42)* *significant at 5%; **significant at 1% Disclosures Romanus: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Takeda Pharmaceutical Company Limited: Equity Ownership; Sanofi: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

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Treatment Patterns and Outcomes Among Patients with Higher-Risk Myelodysplastic Syndromes Treated in a Real-World Setting: Electronic Medical Record-Based Data

Blood ◽

10.1182/blood.v128.22.5540.5540 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5540-5540

Author(s):

Jill A Bell ◽

Aaron Galaznik ◽

Eileen Farrelly ◽

Marlo Blazer ◽

Brian Seal ◽

...

Keyword(s):

Pharmaceutical Company ◽

Research Funding ◽

Employment Equity ◽

Line Therapy ◽

Company Limited ◽

Induction Type ◽

Wholly Owned Subsidiary ◽

Equity Ownership ◽

Diagnosis Date

Abstract Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders resulting in ineffective hematopoiesis primarily affecting older adults; median age of diagnosis is >70 years. Treatment decisions in MDS are largely based on a prognostic scoring system that has been incorporated into some drug labeling (NCCN 2016). The use of hypomethylating agents (HMAs) in patients with higher-risk (HR) MDS is supported by consensus guidelines, thus the purpose of this study was to examine factors influencing prescribing patterns in this subset of patients. Methods: This was a retrospective cohort study using a large United States electronic medical record database. Newly diagnosed HR MDS patients initiating first-line therapy (1LT) between 1/2008 and 7/2015 were followed for 1 year prior to and ≥ 60 days after diagnosis. Included patients were ≥18 years old with evidence of HR MDS identified as follows: 1) ≥1 inpatient claim with an HR MDS diagnosis code (ICD-9 code: 238.73; ICD-10 codes: D46.20, D46.21, D46.22), or 2) ≥2 outpatient claims with an MDS diagnosis code, with the first one coded for HR MDS ≥60 days but <1 year apart during the identification period. The date of the first HR MDS claim served as the index diagnosis date. 1LT was defined as an MDS-specific systemic agent initiated on or after the index diagnosis date and included all agents received within 30 days following the first infusion or fill date. Subsequent lines of therapy (LOT) were defined as an addition of a new MDS-specific agent >30 days after the initial chemotherapy agent(s) or a switch to another drug combination. Stem cell transplantation (SCT) was considered part of the LOT in which it occurred. All patients were followed until death or progression to acute myeloid leukemia (AML), loss to follow-up, or the end of study period (9/30/2015). Results: 345 patients newly diagnosed with HR MDS met the study criteria; 218 (63%) were treated with supportive care (including transfusions, hydroxyurea, colony-stimulating factors [CSFs], azole antifungals, erythropoiesis-stimulating agents [ESAs], or pain medications) or observation only and 127 (37%) were treated with MDS-directed therapy (HMAs, immunosuppressive therapy, induction-type therapy, SCT, or lenalidomide) ± supportive care (Table 1). Compared to untreated patients, a greater proportion of treated patients were male, had severe cytopenias (specifically, neutrophils <0.8 K/L and/or platelets <50 K/L), and had received a transfusion of either red blood cells or platelets during the baseline period (Table 1). In the treated population, most patients received only 1LT (n=111, 87%); 16 patients (13%) went on to second-line therapy, and 3 (2.3%) to third-line therapy. HMAs were the most utilized agents in 1LT, with 84 (66%) and 29 (23%) patients receiving azacitidine and decitabine, respectively. Lenalidomide was used in 6.3% of patients (n=8), and induction-type chemotherapy in 3.2% (n=4); no patients received immunosuppressive therapy only (cyclosporine or anti-thymocyte globulin). At median follow-up of 9 months (interquartile range [IQR]: 4, 16) for the treated population, 46 (36%) had died and 36 (28%) had progressed to AML. Within the population that received an HMA (n=113), age ≥75 years was approximately 50% for each agent; however, a greater proportion of patients who received azacitidine had a known marrow blast count of >5%, hemoglobin <10 gm/dL, and platelets <50 K/L at baseline (Table 2). At end of follow-up, 27% (n=23) and 36% (n=30) of azacitidine-treated patients had progressed to AML or died whereas 28% (n=8) and 41% (n=12) of decitabine-treated patients progressed to AML or died, respectively. Conclusions: Despite the existence of treatment guidelines for HR MDS patients and given the limitations of a retrospective study, the majority of patients in a real-world setting are not treated with MDS-specific agents. Younger age (<75 years) and more severe cytopenias may be factors considered in the decision of whether or not to treat HR MDS. If treated, HMAs are the most utilized therapy in these patients, with azacitidine predominating. Cytopenias at baseline may also influence the choice between azacitidine and decitabine, although survival and progression to AML appear similar between groups. References: National Comprehensive Cancer Network (NCCN) Guidelines in Oncology for MDS v.1.2016. Disclosures Bell: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Galaznik:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Farrelly:Takeda: Research Funding. Blazer:Takeda: Research Funding. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Shih:Takeda: Research Funding. Ogbonnaya:Takeda: Research Funding. Dezube:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership.

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Treatment Patterns and Outcomes Among Patients Who Initiate Therapy for Relapsed/Refractory Multiple Myeloma (RRMM) in Routine Care

Blood ◽

10.1182/blood.v126.23.4515.4515 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4515-4515

Author(s):

Dorothy Romanus ◽

Mehul Jhaveri ◽

Richard Labotka ◽

Henry Henk ◽

Brian Seal

Keyword(s):

Pharmaceutical Company ◽

Primary Therapy ◽

Treatment Gap ◽

Nccn Guidelines ◽

Line Therapy ◽

Company Limited ◽

Asco 2012 ◽

Wholly Owned Subsidiary ◽

First Relapse ◽

Equity Ownership

Abstract Background Multiple myeloma (MM) is the second most common hematologic cancer in adults. Novel agents, including thalidomide, bortezomib, and lenalidomide, have led to improved overall survival (OS) in MM, but the disease remains generally incurable with the majority of patients inevitably relapsing after front-line therapy (FLT). In a multi-center observational analysis of 383 MM patients (treated between 2007 and 2010), median progression-free survival (PFS) and OS from treatment after first relapse were 13 and 35 mos (Durie ASCO 2012; abs 8095). According to NCCN guidelines, retreatment with primary therapy may be considered if relapse occurs more than 6 mos after discontinuation of primary therapy, otherwise a switch in regimen is recommended (NCCN MM Guidelines v.4 2015). Treatment patterns and outcomes in RRMM remain to be elucidated. We examined treatment use, retreatment and therapy switch patterns, and outcomes among patients with RRMM initiating second-line therapy (SLT). Methods We conducted a retrospective cohort study using a large, national, US claims database. Adult patients with MM who initiated cancer-specific systemic therapy between Jan 2008 and Feb 2014, without evidence of transplantation, were identified. Newly diagnosed MM patients were followed from the first claim for MM. Continuous enrollment in the health plan for 12 mos pre-diagnosis (with no claim for MM) through at least the start of SLT was required. FLT began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 days of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 mos of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 mos between end of FLT and start of a second regimen (retreatment or switch), 2) start of a follow up regimen (retreatment) with a treatment gap of >3 and up to 6 mos after end of FLT, or 3) a switch to another drug combination after FLT regimen. Analyses were conducted from the first claim for SLT. SLT ended at the earliest of start of a new drug, death, or end of study period (Feb 2014). MM drug combinations were based on all unique MM systemic therapy agents received within start and end date for SLT. Vital status information was ascertained from the Social Security Death Index. Results We identified 249 patients with RRMM receiving SLT. Approximately half (49%) were male; 29% and 43% were aged 65-74 and 75 years or older, respectively. SLT regimens were: lenalidomide±dexamethasone (R±d, n=70 [28%]), bortezomib±d (V±d 61 [25%]), other (58 [23%], see Table 1), V+other (25 [10%]), R+other (14 [6%]), V-cyclophosphamide±d (VC±d, 13 [5%]), and VR±d (8 [3%]). The switch and retreatment patterns from FLT to SLT are depicted in Table 1. Among patients with treatment-free interval (TFI, time from end of FLT to start of SLT) >6 mos (n=64) vs ≤6 mos (n=185), 18 (28%) vs 17 (9%) were retreated with the same primary regimen in SLT, respectively. Median duration of SLT was 6.3 (95% CI: 5.6, 6.9) mos (Fig. 1) and of FLT was 6.8 (95% CI: 6.0, 7.8) mos. The 1-year OS probability from initiation of SLT for RRMM was 82% (95% CI: 76%, 86%). Conclusions Among patients with RRMM treated in the USA, V- and R-based regimens were the most common at first relapse. The vast majority of patients (91%) with TFI ≤6 mos switched therapy at time of relapse in concordance with NCCN guidelines. The relatively short duration of SLT (median 6.3 mos) in this study compared with PFS from treatment after first relapse (median 13 mos, Durie ASCO 2012; abs 8095) in a cohort of patients with RRMM, suggests that the majority of patients discontinue SLT prior to disease progression. These findings highlight the need for newer SLT regimens that are effective and more sustainable compared with current treatment choices. Table 1. Switch and Retreatment Patterns from FLT to SLT among Patients with RRMM. SLT V-based R-based VR-based Other FLT V-based 41 (41%) 49 (58%) 4 (50%) 15 (26%) R-based 33 (33%) 13 (15%) 2 (25%) 12 (21%) VR-based 9 (9%) 6 (7%) 2 (25%) 19 (33%) Other* 16 (16%) 16 (19%) 0 (0%) 12 (21%) Total 99 (100%) 84 (100%) 8 (100%) 58 (100%) *Other combinations consisted of a subset of the following agents: cyclophosphamide, melphalan, vincristine, doxorubicin, interferon-alpha, pomalidomide, thalidomide, carfilzomib, dexamethasone, prednisone Disclosures Romanus: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Sanofi: Equity Ownership; Takeda Pharmaceutical Company Limited: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

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A Randomized Phase 2 Study of Pevonedistat, Venetoclax, and Azacitidine Versus Venetoclax Plus Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) Who Are Unfit for Intensive Chemotherapy

Blood ◽

10.1182/blood-2020-136968 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-35

Author(s):

Nicholas J. Short ◽

Farhad Sedarati ◽

Dan Zhao ◽

Olga Tsukurov ◽

Sharon Friedlander ◽

...

Keyword(s):

Pharmaceutical Company ◽

Board Of Directors ◽

Small Molecule ◽

Phase 2 ◽

Newly Diagnosed ◽

Private Company ◽

Advisory Committees ◽

Limited Current ◽

Company Limited ◽

Wholly Owned Subsidiary

Background Pevonedistat is the first small-molecule inhibitor of neural precursor cell expressed, developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE). Inhibiting NAE blocks ubiquitination of select proteins upstream of the proteasome. Treatment with pevonedistat disrupts cell cycle progression and cell survival, leading to cell death in cancers, including myeloid malignancies. In a phase 1b study in patients aged ≥60 yrs with untreated AML, pevonedistat in combination with azacitidine (AZA) was tolerable and showed clinical activity (Swords et al. Blood 2018). In a randomized phase 2 study of pevonedistat + AZA vs AZA alone in patients with higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia and low-blast AML, pevonedistat + AZA improved event-free survival (EFS) and overall survival (OS), had a similar safety profile to AZA alone, did not increase myelosuppression, and maintained AZA dose intensity (Adès et al. ASCO 2020). Venetoclax (VEN) is a small-molecule inhibitor of B-cell lymphoma 2 that is approved in the United States in combination with low-dose cytarabine or hypomethylating agents for the treatment of patients with AML. VEN + AZA has been shown to improve OS vs AZA alone, and the combination is emerging as a standard of care for older patients with newly diagnosed AML who are unfit for standard intensive chemotherapy. Despite recent advances, outcomes for these patients remain poor; novel therapies that increase duration of response (DOR) or reduce relapse rates are needed. Pevonedistat in combination with VEN has shown synergistic cytotoxic effects in AML cell lines and primary clinical AML samples (Knorr et al. Cell Death Differ 2015). This is likely mediated through pevonedistat-induced neutralization of prosurvival proteins including myeloid leukemia cell differentiation protein (MCL-1). Upregulation of MCL-1 is thought to be a primary mode of resistance to VEN. Therefore, treatment with pevonedistat + VEN may help to prevent or overcome resistance to VEN and prolong DOR. The reported clinical benefit of both pevonedistat + AZA and VEN + AZA in AML, and preclinical evidence of synergy between pevonedistat and VEN, suggest that combination treatment with all 3 therapies may result in improved outcomes compared with VEN + AZA in patients with newly diagnosed AML who are unfit for intensive chemotherapy. A phase 1/2 study of the triplet combination of pevonedistat, VEN, and AZA in secondary AML established the recommended phase 2 dose and demonstrated a high response rate in this relatively refractory population (Short et al. EHA 2020). Methods NCT04266795 is a randomized, open-label, controlled, phase 2 study (Figure) that is being conducted across ~85 sites globally. Eligible patients are those aged ≥18 yrs with morphologically confirmed newly diagnosed AML (World Health Organization criteria 2008) and considered unfit for treatment with cytarabine and anthracycline induction due to age and/or comorbidities. Patients are being randomized 1:1 to receive the combination of pevonedistat 20 mg/m2 intravenously (IV) on days 1, 3, and 5, VEN 400 mg by mouth on days 1-28 in cycle 1 (ramp up schedule of 100 mg on day 1, 200 mg on day 2, 400 mg on days 3-28) and then on days 1-28 (days 1-21 if remission is confirmed; can return to 28-day dosing if well tolerated) in cycle 2 onwards, and AZA 75 mg/m2 (IV or subcutaneously) on days 1-7 or 1-5, 8, and 9, or VEN + AZA, in 28-day cycles until unacceptable toxicity, relapse, or progressive disease. Randomization is stratified by age (18-<75 yrs vs ≥75 yrs) and AML subtype (de novo vs secondary). The primary endpoint is EFS (time from randomization to relapse from complete remission [CR] or CR with incomplete blood count recovery [CRi], treatment failure, or death from any cause, whichever occurs first). Secondary endpoints include: OS; OS at 6 months, 1 yr, and 2 yrs; 30- and 60-day mortality; CR rate; EFS after cycle 6; DOR; time to first response; time to relapse from CR/CRi or death; health-related quality of life; pharmacokinetics; rate of red blood cell and platelet transfusion independence; and rate of hospitalization. Molecular characterization of bone marrow aspirates will be performed for measurable residual disease and mechanism of action studies. Elimination of leukemic stem cells and predictive biomarkers of response will be assessed. The study is planned to enroll ~150 patients; recruitment is ongoing. Figure Disclosures Short: Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding. Sedarati:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Zhao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Tsukurov:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Friedlander:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Faller:Phoenicia Biosciences: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Briacell Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Viracta Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. OffLabel Disclosure: Pevonedistat is the first small molecule inhibitor of the neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme (NAE)

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Randomized Phase 2 Study of the All-Oral Combination of Investigational Proteasome Inhibitor (PI) Ixazomib Plus Cyclophosphamide and Low-Dose Dexamethasone (ICd) in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Transplant-Ineligible (NCT02046070)

Blood ◽

10.1182/blood.v126.23.26.26 ◽

2015 ◽

Vol 126 (23) ◽

pp. 26-26 ◽

Cited By ~ 6

Author(s):

Meletios A. Dimopoulos ◽

Sebastian Grosicki ◽

Wieslaw W Jedrzejczak ◽

Hareth Nahi ◽

Astrid Gruber ◽

...

Keyword(s):

Pharmaceutical Company ◽

Proteasome Inhibitor ◽

Low Dose ◽

Phase 2 ◽

Newly Diagnosed ◽

Advisory Committees ◽

Company Limited ◽

Phase 2 Study ◽

Wholly Owned Subsidiary

Abstract Background Ixazomib is the first orally administered PI to be studied in the clinic. The feasibility of combining a PI with cyclophosphamide and dexamethasone has been demonstrated with the PI bortezomib (Reeder et al Leukemia 2009; Mai et al Leukemia 2015). This open-label, multicenter, phase 2 study is evaluating the all-oral triplet combination of ICd, with two different doses of cyclophosphamide, as a 12-month induction therapy in previously untreated, transplant-ineligible pts with NDMM, and is the first study to assess ICd for the frontline treatment of MM. Methods Adult pts with previously untreated, symptomatic NDMM who were ineligible for stem cell transplantation due to age and/or comorbidities, had ECOG PS 0-2, and adequate hematologic, hepatic, and renal function, were included. Pts were randomized 1:1 to receive up to 13 x 28-day cycles of induction therapy with ixazomib 4.0 mg PO on days 1, 8, and 15, plus cyclophosphamide 300 mg/m2 (ICd-300 arm) or 400 mg/m2 (ICd-400 arm) PO on days 1, 8, and 15, plus dexamethasone 40 mg PO (20 mg in pts aged >75 years) on days 1, 8, 15, and 22. A safety lead-in evaluation of dose-limiting toxicities (DLTs) was performed in 6 evaluable pts in each arm after cycle 1. The primary endpoint was the combined rate of complete response plus very good partial response (CR+VGPR). Secondary endpoints included overall response rate (ORR; CR+VGPR+ partial response [PR]) and safety (adverse events [AEs]). Response was investigator-assessed at the end of every cycle per IMWG criteria. Sample size (n=70) was determined to provide 80% power for the primary endpoint of CR+VGPR rate (1-sided alpha=0.10). Here we present a preliminary analysis of data post-induction (data cut-off: July 1, 2015). Results 70 pts were randomized (36 to ICd-300, 34 to ICd-400): median age 72.5 and 75.5 years; 42% and 53% male; 64% and 59% ISS stage II/III (92% and 79% Durie-Salmon stage II/III), respectively. Mean duration of follow-up was 7.0 months in both arms. Response data are summarized in the Table. Best unconfirmed CR+VGPR rates across all 13 cycles were 27% (ICd-300) and 23% (ICd-400); ORRs were 80% and 73%. Best M-protein reductions are shown in the Figure. Twelve pts (6 ICd-300; 6 ICd-400) were DLT-evaluable; no DLTs were observed in either arm. Pts received a median of 6.0 (1-13) and 6.5 (1-13) cycles in the ICd-300 and ICd-400 arms, respectively. Mean ixazomib relative dose intensity was 90.7% in the ICd-300 arm and 89.8% in the ICd-400 arm. Across all 13 cycles of treatment (ICd-300 and ICd-400, respectively), rates of Gr ≥3 AEs were 53% and 62%, serious AEs 33% and 53%, AEs leading to dose reduction in any study drug 17% and 21%, discontinuation of all study drugs due to AEs 14% and 12%, and on-treatment deaths 2 pts (cardiac arrest; upper gastrointestinal hemorrhage) and 1 pt (pneumonia) which were not deemed as treatment-related. In the ICd-300 and ICd-400 arms, respectively, rates of anti-emetic use were 36% and 44% (8% and 18% for AEs) and G-CSF use 11% and 50% (11% and 35% for AEs); erythropoietin was used in only 1 pt (ICd-300 arm). Thrombocytopenia events occurred in 5 pts (no Gr ≥3) in the ICd-300 arm and 4 pts (3 Gr ≥3) in the ICd-400 arm. Most common AEs (>15% all pts) were anemia (19% and 29%), neutropenia (17% and 32%), nausea (14% and 24%), peripheral neuropathy (PN; 17% and 21%), diarrhea (19% and 15%), vomiting (14% and 21%), constipation (17% and 15%), and fatigue (14% and 18%). Most common Gr ≥3 AEs were neutropenia (14% and 32%), anemia (11% and 15%), and pneumonia (8% and 9%); no Gr ≥3 PN was observed. Conclusion These preliminary data suggest that the all-oral triplet combination of ICd is tolerable in transplant-ineligible pts with NDMM, with a manageable toxicity profile in line with that previously seen with ixazomib and with manageable myelosuppression. Comparably high response rates were reported in both the ICd-300 and ICd-400 arms. Toxicity rates appeared higher with ICd-400, suggesting that ICd-300 may be a more preferable regimen for elderly NDMM pts. Updated data, including long-term outcomes after additional follow-up will be presented at the meeting. Table. Best unconfirmed response by IMWG criteria during cycles 1-13 (response-evaluable pts) Response, n (%) ICd-300(n=30) ICd-400(n=30) CR 3 (10) 3 (10) PR 21 (70) 19 (63) VGPR 5 (17) 4 (13) CR+VGPR 8 (27) 7 (23) ORR (CR+VGPR+PR) 24 (80) 22 (73) SD 6 (20) 8 (27) SD, stable disease Disclosures Dimopoulos: Amgen: Honoraria; Onyx: Honoraria; Celgene: Honoraria; Genesis: Honoraria; Novartis: Honoraria; Janssen-Cilag: Honoraria; Janssen: Honoraria. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with cyclophosphamide and low-dose dexamethasone for patients with newly diagnosed multiple myeloma who are transplant-ineligible.. Nahi:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Byrne:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

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Systematic Review of Therapy Used in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.3562.3562 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3562-3562

Author(s):

Aaron Galaznik ◽

Jill A Bell ◽

Meredith M Hoog ◽

Michael E Stokes ◽

Anna W Steenrod ◽

...

Keyword(s):

Pharmaceutical Company ◽

Phase Ii ◽

B Cell Lymphoma ◽

Employment Equity ◽

The Past ◽

Large B Cell Lymphoma ◽

Company Limited ◽

The Us ◽

Wholly Owned Subsidiary ◽

Equity Ownership

Abstract INTRODUCTION: Non-Hodgkin's lymphoma is a heterogeneous group of diseases originating in the lymphoid system. The most common subtype, constituting up to 40% of all cases globally, is diffuse large B cell lymphoma (DLBCL).1 Approximately one-third of DLBCL patients treated with standard therapy (since 1998, a combination of chemotherapy plus immunotherapy with the CD20-directed humanized monoclonal antibody rituximab [RCHOP]) at diagnosis will develop relapsed or refractory (R/R) disease.1 Relapsed or refractory disease is defined as those whose disease does not respond to therapy (refractory) or whose disease returns after achieving remission (relapse), requiring secondary therapies. In this systematic review we examine outcomes associated with therapies used to treat R/R DLBCL including autologous (auto) stem cell transplant (SCT) and allogeneic SCT (alloSCT), plus various chemotherapy regimens in patients not eligible for SCT. METHODS: Literature databases (Medline and EMBASE) were searched for the past five years (from January 1, 2012-May 11, 2016) to identify studies reporting treatment outcomes in R/R DLBCL (including patients who had failed at least one prior treatment line). The searches applied terms to targeted publications on relapsed/refractory DLBCL and were limited to studies conducted in humans and articles published in English, including an abstract. To ensure the latest information available was included, the database searches were supplemented by reviewing American Society of Hematology (ASH) conference abstracts from the last two years. Only studies clearly (as denoted in the abstract) enrolling R/R patients with a sample size of at least 50 were included to ensure the evidence collected was well powered to detect meaningful findings. Furthermore, the review was limited by geographic location to studies primarily conducted in the European Union 5 (EU5), United States (US), and Japan. RESULTS: Of the 590 abstracts identified through Medline and EMBASE and the 325 ASH abstracts, 21 studies met the inclusion criteria after reviewing the full-text articles. Those studies meeting the criteria clearly presented clinical results for at least 50 patients with R/R DLBCL. The evidence was primarily available in observational (16/21) study designs; most of the data was presented in ASH abstracts (13/21) from the past two years. Of the clinical trials (four Phase II, one Phase II/III), many evaluated chemotherapy in patients ineligible for SCT or high dose salvage regimens. Among the studies included, 8 enrolled patients from the EU, 7 from the US, 4 from Japan, and 2 with sites in both the US and EU. Of the identified studies, there were 7 real-world observational studies evaluating SCT in R/R DLBCL. The majority (71%) investigated alloSCT with reported overall survival (OS) rates ranging from 18-52%. Among the three studies examining autoSCT, OS ranged from 54-71% (Table 1). Only one study (Rigacci, 2012) reported data on response after transplant (overall response [OR] 49%; complete response [CR] 43%). For post-SCT or SCT-ineligible patients, various chemotherapy regimens were used. Three articles were identified examining chemotherapy regimens in this setting, two of which were Phase II clinical trials. OR rates ranged widely from 3% to 62.7% for trials investigating fostamatinib and rituximab + bendamustine, respectively (Table 2). Limited data on survival were available, with only Arcari, 2015 reporting median survival of 10.8 months for patients receiving rituximab + bendamustine. CONCLUSIONS: In the past five years, only limited clinical evidence has been reported specifically for patients with R/R DLBCL. Among studies examining DLBCL, treatment courses ranged from SCT to combination chemotherapy. Survival outcomes were more often reported in studies evaluating patients treated with SCT (auto or allo) than in studies evaluating those post-SCT or SCT-ineligible. Rates of survival at three or four years varied widely from 18% to nearly two-thirds to three-quarters of patients treated with SCT; survival was higher in patients treated with autoSCT. Response rates in those ineligible for SCT were also highly variable. Studies examining SCT that were included in the review had only limited information on response. 1 World Cancer Report 2014. International Agency for Research on Cancer. (2014) Accessed July 2014. Disclosures Galaznik: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Bell:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Hoog:Evidera Inc.: Employment. Stokes:Evidera Inc.: Employment. Steenrod:Evidera Inc.: Employment. Knopf:Sutter Health Care: Employment; Exeltis: Speakers Bureau; Evidera Inc.: Consultancy. Seal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Shou:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

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Treatment patterns and healthcare costs among newly-diagnosed patients with chronic myeloid leukemia receiving dasatinib or nilotinib as first-line therapy in the United States

Journal of Medical Economics ◽

10.1080/13696998.2016.1225578 ◽

2016 ◽

Vol 20 (1) ◽

pp. 63-71 ◽

Cited By ~ 3

Author(s):

Dominick Latremouille-Viau ◽

Annie Guerin ◽

Roy Nitulescu ◽

Patrick S. Gagnon ◽

George J. Joseph ◽

...

Keyword(s):

United States ◽

Chronic Myeloid Leukemia ◽

Healthcare Costs ◽

Myeloid Leukemia ◽

The United States ◽

Treatment Patterns ◽

Newly Diagnosed ◽

First Line ◽

First Line Therapy ◽

Line Therapy

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a Phase 1b/2 Study of TAK-659, an Investigational Dual SYK and FLT-3 Inhibitor, in Patients (Pts) with Relapsed or Refractory Acute Myelogenous Leukemia (R/R AML)

Blood ◽

10.1182/blood.v128.22.2834.2834 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2834-2834 ◽

Cited By ~ 9

Author(s):

Jason B Kaplan ◽

Dale L. Bixby ◽

John C Morris ◽

Olga Frankfurt ◽

Jessica Altman ◽

...

Keyword(s):

Tyrosine Kinase ◽

Pharmaceutical Company ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Advisory Committees ◽

Company Limited ◽

Safety Population ◽

Wholly Owned Subsidiary ◽

Phase 1B

Abstract Background Spleen tyrosine kinase (SYK) is a nonreceptor cytoplasmic protein kinase and a key mediator of immunoreceptor signaling that has been shown to play an important role in the pathogenesis of both B-cell and myeloid malignancies. SYK has also been shown to directly bind and activate FMS-like tyrosine kinase 3 (FLT-3), a Class III receptor tyrosine kinase that is commonly mutated in approximately 30% of pts with AML (Puissant et al. Cancer Cell 2014;25:226-42). TAK-659 is an investigational, reversible, and potent dual inhibitor of SYK and FLT-3. Preclinical studies with TAK-659 have demonstrated growth inhibition of cell lines and xenograft tumor models of B-cell lymphoma or AML origin. Moreover, TAK-659 has exhibited antitumor activity in lymphoma pts in an ongoing clinical trial (Petrich et al. Blood 2015;126:2693). The primary objectives of the phase 1b dose-finding portion of this study are to evaluate the safety, tolerability, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659, as well as preliminary efficacy in the phase 2 expansion study. Secondary objectives include evaluation of TAK-659 pharmacokinetics (PK) in this pt population. Methods During dose escalation using a 3x3 schema, adult pts with R/R AML received oral TAK-659 daily (QD) in 28-d cycles (C) starting with a dose of 60 mg. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Response per IWG criteria for AML was assessed between d22 and d28 of C1, C2, and C4. Blood samples for plasma pharmacokinetic (PK) assessments were collected pre-dose and at multiple times post-dose on d1 and d15 of C1. The pharmacodynamic effect of TAK-659 was assessed at multiple time points by measuring the phosphorylation of ribosomal protein S6 (pS6) in peripheral AML blasts using flow cytometry. FLT-3 mutation status (wild type [FLT-3-WT], FLT-3-ITD, or point mutation [FLT-3-D835Y]) was assessed using a PCR-based assay at a central laboratory. The effect of TAK-659 treatment on FLT-3-ITD phosphorylation was evaluated using a plasma inhibitory assay (PIA) as previously described (Levis et al. Blood 2006;108:3477-83). Results At data cut-off (June 9, 2016), 15 pts had been enrolled at TAK-659 QD 60 mg (n=4), 100 mg (n=7), or 120 mg (n=4). No dose-limiting toxicity per protocol has been observed. Dose escalation is currently ongoing at 160 mg QD. In the safety population (n=13), median age was 67 yrs (range 25-86), 69% of pts were male, and 38% had received ≥4 prior lines of therapy. Baseline mutation data was available for 12 pts: 6 pts were FLT-3-WT, 3 pts had FLT-3-ITD, 1 pt had FLT-3-D835Y, and 2 pts had concurrent FLT-3-ITD/D835Y mutations. In the safety population, all-grade drug-related AEs occurred in 12 (92%) pts overall; the most common were elevated AST (31%), ALT (23%), and amylase levels (23%). Grade ≥3 drug-related AEs occurred in 7 (54%) pts including: increased ALT, AST, and amylase levels, cataract, positive fungal test, macular fibrosis, pancreatitis, pneumocystis jirovecii pneumonia, rash, and fungal sinusitis (each 1pt). Blood LDH levels were increased in almost all pts (significance unknown). Three pts discontinued TAK-659 due to AEs and 3 pts died on study; none of these events were considered related to the study drug. Preliminary plasma PK of TAK-659 (n=11, 60-100 mg) was characterized by rapid absorption (median Tmax of 2 hours), moderate variability in steady-state exposures (42% coefficient of variation for C1 d15 dose-normalized AUCtau), and mean accumulation of 2.1-fold after repeated QD dosing for 15 days. Of 9 pts evaluated to date, pS6 was detected at baseline and reduced after dosing in 4 pts (2 FLT-3-ITD; 2 FLT-3-WT). At 60 mg and 100 mg TAK-659, up to 70% inhibition of FLT-3-ITD phosphorylation was observed as assessed by PIA. Early signs of clinical activity were observed, with decreases in peripheral blood myeloblasts observed in some pts. Assessment is ongoing and preliminary efficacy data will be presented. Conclusions TAK-659 has a unique mechanism of action with dual inhibition of SYK and FLT-3. Dose escalation to determine the MTD/RP2D is ongoing. TAK-659 exhibits an acceptable PK profile in R/R AML pts, supporting continuous oral QD dosing. Disclosures Kaplan: Seattle Genetics: Research Funding; Janssen: Research Funding. Morris:Boehringer-Ingelheim: Speakers Bureau. Altman:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wise-Draper:Merck: Research Funding. Collins:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kannan:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Wang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faucette:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lee:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shou:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Levis:Millennium: Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria.

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Overall Survival (OS) Benefit of Oral Ixazomib in Combination with Lenalidomide and Dexamethasone (IRd) Vs Lenalidomide and Dexamethasone (Rd) in Asian Patients (pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): Pooled-Analysis from the Tourmaline-MM1 and the China Continuation Studies

Blood ◽

10.1182/blood-2018-99-116844 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5637-5637

Author(s):

Weijun Fu ◽

Jin Lu ◽

Jie Jin ◽

Yan Xu ◽

Depei Wu ◽

...

Keyword(s):

Pharmaceutical Company ◽

Research Funding ◽

Pooled Analysis ◽

Prior Exposure ◽

Treatment Groups ◽

Asian Patients ◽

Company Limited ◽

Global Study ◽

Wholly Owned Subsidiary ◽

Grade 3

Abstract Introduction: Ixazomib (Ninlaro) is the first orally administered proteasome inhibitor (PI) approved in more than 50 countries worldwide, including China. The TOURMALINE-MM1 study was a large randomized, double-blind, global registration study assessing treatment with either ixazomib or placebo added to lenalidomide and dexamethasone. The China Continuation Study (CCS) was a separate regional expansion of the global study that used the same study design. (Panel A) In the global study, IRd treatment extended progression-free survival (PFS), the primary endpoint, by 35% (HR=0.74) vs Rd. Here we report results of a pooled analysis of data from a subgroup of Asian patients enrolled in these two studies. Demographics and Methods: Asian patients from China (n=6 from the global study; n=115 from the CCS), Singapore (n=6), South Korea (n=6), and 3 non-Asian countries (n=5) were included in this pooled analysis. Overall response rate (ORR) was based on the International Myeloma Working Group criteria. The median OS and PFS were calculated using the Kaplan-Meier method. Comparative analysis of treatment groups used stratified log rank tests and the Cox proportional hazard regression model. Safety assessments were based on treatment-emergent adverse events (TEAEs), changes in laboratory parameters, and 12-lead electrocardiogram results. Results: Data from 138 pts were analyzed (67 IRd; 71 Rd). Baseline characteristics were balanced between the treatment groups; overall median age was 61 (range, 30-80) years, 67% of pts were < 65 years; 97% of pts had Eastern Cooperative Oncology Group Performance Scores 0-1; 37% had International Staging System (ISS) stages II/III; and 72% had lytic bone disease. The median number of prior treatments was 2, with 82% exposed to thalidomide of which 61% were thalidomide refractory, 61% were exposed to bortezomib, and 48% exposed to both drugs. The ORR was 57% in the IRd group vs 37% in the Rd group. Median OS was 25.8 mos and 15.8 mos in the IRd and Rd treatment groups, respectively (HR=0.346). (Panel B). OS also was longer with IRd therapy regardless of prior exposure to bortezomib (HR=0.322) or thalidomide (HR=0.317) as well as in pts with thalidomide refractory tumors (HR=0.273). (Panel C). The median PFS was 7.3 mos and 4.6 mos in the IRd and Rd treatment groups, respectively (HR=0.559). Longer PFS was also observed with IRd treatment in pts with prior exposure to bortezomib (HR=0.467) or thalidomide (HR= 0.580) as well as pts with thalidomide refractory tumors (HR= 0.631). The rates of drug-related TEAEs (IRd, 96%; Rd, 97%), serious TEAEs (IRd, 37%; Rd, 34%), Grade 3/4 TEAEs (IRd, 74%; Rd, 73%) and discontinuations due to AEs (IRd, 12%; Rd, 13%) were similar in both treatment groups. Grade 3/4 TEAEs reported in ≥10% of either treatment group were anemia (IRd, 14%; Rd, 31%), lower respiratory infection (IRd, 23%; Rd, 21%), neutrophil count decrease (IRd, 13%; Rd, 16%), platelet count decrease (IRd, 15%; Rd, 13%), neutropenia (IRd, 17%; Rd, 9%), thrombocytopenia (IRd 11%; Rd 6%). There was no increased cardiotoxicity, renal toxicity, hepatoxicity or secondary primary malignancy in the IRd group. Conclusions: Asian pts with RRMM treated with oral IRd showed superior OS and PFS vs those treated with Rd. The benefit was consistent regardless of prior exposure to thalidomide and bortezomib. The addition of ixazomib to Rd was well-tolerated, and no new safety signals were identified. The safety profile of IRd was consistent with the safety findings of the large global study (Moreau P, Masszi T, Grzasko N, et al. for the TOURMALINE-MM1 Study group. N Engl J Med. 2016;374:1621-1634.) Disclosures Jin: College of Medicine, Zhejiang University: Employment; The National Natural Science Foundation of China: Research Funding. Chng:Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Merck: Research Funding; Aslan: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses. Goh:Johnson & Johnson: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi-Aventis: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Wu:Takeda Pharmaceuticals: Employment. Wang:Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda: Employment. Liu:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Skacel:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Department of Hematology, Charles University General Hospital, Prague, Czech Republic: Other: Affiliation. Wan:Takeda Pharmaceuticals International Co.: Employment. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

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Economic burden of Huntington’s disease in Peru

BMC Health Services Research ◽

10.1186/s12913-019-4806-6 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Gustavo Silva-Paredes ◽

Rosa M. Urbanos-Garrido ◽

Miguel Inca-Martinez ◽

Danielle Rabinowitz ◽

Mario R. Cornejo-Olivas

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Economic Burden ◽

Annual Cost ◽

Healthcare Costs ◽

Neurodegenerative Disorder ◽

Indirect Costs ◽

Direct Costs ◽

Cross Sectional ◽

Direct And Indirect Costs

Abstract Background Huntington’s disease (HD) is a devastating and fatal neurodegenerative disorder that leads to progressive disability, and over time to total dependence. The economic impact of HD on patients living in developing countries like Peru is still unknown. This study aims to estimate the economic burden by estimating direct and indirect costs of Huntington’s disease in Peru, as well as the proportion of direct costs borne by patients and their families. Methods Disease-cost cross-sectional study where 97 participants and their primary caregivers were interviewed using a common questionnaire. Prevalence and human capital approaches were used to estimate direct and indirect costs, respectively. Results The average annual cost of HD reached USD 8120 per patient in 2015. Direct non-healthcare costs represented 78.3% of total cost, indirect costs 14.4% and direct healthcare costs the remaining 7.3%. The mean cost of HD increased with the degree of patient dependency: from USD 6572 for Barthel 4 & 5 (slight dependency and total independency, respectively) to USD 23,251 for Barthel 1 (total dependency). Direct costs were primarily financed by patients and their families. Conclusions The estimated annual cost of HD for Peruvian society reached USD 1.2 million in 2015. The cost impact of HD on patients and their families is very high, becoming catastrophic for most dependent patients, and thus making it essential to prioritize full coverage by the State.

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