Management of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Proteasome Inhibitor Based Therapy at First Relapse in Routine Clinical Practice in Germany

Abstract Background: Proteasome inhibitors (PI) represent an important therapeutic advance in the treatment of patients with relapsed/refractory multiple myeloma (RRMM). In 2017, three distinct PIs (bortezomib [BTZ], carfilzomib [CFZ] and ixazomib [IXA]) were available in Germany but real-world data describing their usage was scarce. Aim: To describe characteristics and treatment experience of PI-treated patients with RRMM in Germany. Methods: A national retrospective medical chart review included consecutive patients treated with at least one dose of PI-based regimen in participating hospitals/centers across Germany between January and June 2017. The following data were extracted until April 2018 or death of patient, whichever occurred first: patient demographics, disease characteristics and treatment history at diagnosis and at initiation of PI-based therapy. Physician assessed treatment response were also collected. Results: Physicians from 44 participating centers extracted 302 patient charts, including 219 patients in 2nd line (2L) and 83 in 3rd line treatment (3L), as shown in Figure 1. Results for 2L patients are described below (Table 1, Figure 2): BTZ-treated patients represented 42% of patients (n=92) with a PI-based therapy in 2L. BTZ was often combined with dexamethasone (dex) alone (77%). Median age was 74 years and 56.5% had an ECOG status ≥2 at 2L initiation. Most patients (86%) did not receive a prior transplant. Median treatment duration was 6 months among 40 patients who completed 2L; based on 38 narratives, 2L was ended as planned (47.4%). Where response was available (n=83), 25% of patients achieved a complete response/very good partial response [CR/VGPR]. Median time to next treatment (TTnT) was 7.5 months for 12 patients who moved to 3L. Patient profiles differed in terms of prior treatment exposure: 22% of patients had been treated with a BTZ-based therapy in both 1L and 2L and 62% switched therapies from 1L lenalidomide (len) to BTZ. None of the patients receiving len in 1L were transplanted. A CR/VGPR was achieved by 65% of prior BTZ-treated patients (13/20) and 30% of patients with prior len therapy (17/57). CFZ-treated patients: 48% (n=106) of patients received CFZ-based therapy in 2L. Of those, 56% (n=59) received CFZ in combination with len/dex (KRd) and 44% (n=47) with dex alone (Kd). Median age was 68 years, 60.4% had an ECOG status of 0-1 at 2L initiation and 49% had received a transplant. In 1L, 82% had received a BTZ-based regimen. Where response was mentioned (n=89), a CR/VGPR was reached in 53% of CFZ-treated patients. Median treatment duration was 6.5 months (24/106). Based on 21 narratives, the main reason for discontinuing CFZ in 2L was disease progression (47.6%). Median TTnT was 9.5 months for 10 patients who moved to 3L. The patient profiles by KRd or Kd combination were as follows: at KRd initiation, median age was 65 years, 10.2% of patients had an ECOG status ≥2 and 72.9% were transplanted. At Kd initiation, median age was 71 years, 76.6% of patients had an ECOG ≥2 and 19.1% were transplanted. IXA-treated patients (n=21) represented only 10% of PI-treated patients in 2L. Median age was 66 years, 71.4% had an ECOG status of 0-1 at 2L initiation, 33% were transplanted, and 72% had received a BTZ combination in 1L. Information on response was premature as it was only available for 13 patients with no CR reached (VGPR 77%). Median treatment duration was 4 months (n=9) and median TTnT was 10 months for 4 patients who moved into 3L. Limitation: The main limitation of the study was the sample size of IXA-treated patients due to open inclusion criteria to select patient charts. This analysis was not powered to compare between PIs. Hence, results are descriptive of the clinical experience with PI-based therapy to date and reflect current treatment practices in Germany in 2017. Conclusion: In Germany, distinct patient characteristics are observed in clinical practice by selected PI-based therapy. Patients treated with novel PI agents in 2L are generally younger and more transplanted than bortezomib-treated patients; these appear to be important considerations when tailoring therapy in RRMM. In addition, the choice between triplet or doublet therapy for CFZ-based combinations seems to reflect prior transplant status and patients' overall functional performance. Evidence suggests that use of novel PI agents such as CFZ can translate into deeper response in 2L. Disclosures Steinmetz: Amgen, Celgene, Novartis, Vifor: Research Funding; Amgen; BMS, Celgene, Hexal-Sandoz, Medice, Novartis; Janssen-Cilag; Pharmacosmos; Pfizer, Vifor; Ariad: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion, Amgen, Bayer, Celgene, Janssen-Cilag, Novartis: Other: Travel grants. Singh:Amgen: Employment, Equity Ownership. Lebioda:Amgen: Employment, Equity Ownership. Mantonnier:Kantar Health: Employment, Other: Received funding to conduct this research. Fink:Kantar Health: Employment, Other: Received funding to conduct this research. Rieth:Amgen: Employment, Equity Ownership. Suzan:Amgen: Employment, Equity Ownership. Gonzalez-McQuire:Amgen: Employment, Equity Ownership.

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MM-008: A Phase 1 Trial Evaluating Pharmacokinetics and Tolerability of Pomalidomide + Low-Dose Dexamethasone in Patients with Relapsed or Refractory and Refractory Multiple Myeloma and Renal Impairment

Blood ◽

10.1182/blood.v124.21.4730.4730 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4730-4730 ◽

Cited By ~ 1

Author(s):

Jeffrey Matous ◽

David S Siegel ◽

Sagar Lonial ◽

R. Donald Harvey ◽

Claudia Kasserra ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Impairment ◽

Creatinine Clearance ◽

Research Funding ◽

Platelet Transfusion ◽

Low Dose ◽

Phase 1 ◽

Employment Equity ◽

Refractory Multiple Myeloma ◽

Equity Ownership

Abstract Background: Pomalidomide (POM) is indicated for patients (pts) with relapsed or refractory multiple myeloma (RRMM) who received ≥ 2 prior therapies including lenalidomide and bortezomib and demonstrated progression on or within 60 days of completion of the last treatment (Tx). Renal impairment (RI) is a common comorbidity of multiple myeloma (MM) occurring in 20% to 40% of pts (Eleutherakis-Papaikovou, et al. Leuk Lymphom, 2007; Knudsen, et al., Eur J Haematol, 2000). POM is extensively metabolized, with < 5% eliminated renally as the parent drug (Hoffmann, et al., Cancer Chemother Pharmacol, 2013). POM in combination with low-dose dexamethasone (LoDEX) has shown efficacy in pts with RRMM and moderate RI (creatinine clearance [CrCl] < 30-44 mL/min), but pts with severe RI (CrCl < 30 mL/min; serum creatinine> 3 mg/dL) were excluded from most trials (Siegel, et al., Blood. 2012; Weisel, et al., J Clin Oncol, 2013). MM-008 is a multicenter, open-label, phase 1 study assessing the pharmacokinetics (PK) and safety of POM + LoDEX in pts with RRMM and normal or severely impaired renal function. Methods: Pts withRRMM (≥ 1 prior Tx) and normal kidney function or mild RI (creatinine clearance [CrCl] ≥ 60 mL/min; Cohort A—control arm), severe RI (CrCl < 30 mL/min) not requiring dialysis (Cohort B), and severe RI requiring dialysis (Cohort C) were eligible. Cohort A received POM 4 mg, and Cohort B received POM 2 or 4 mg on days 1-21 of a 28-day cycle, following a 3 + 3 dose-escalation design. Cohort B results informed the 4 mg dosing of Cohort C. All cohorts received DEX 40 mg (20 mg for pts aged > 75 yrs) on days 1, 8, 15, and 22. Tx continued until progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) were defined as any of the following: grade (Gr) 4 neutropenia, febrile neutropenia, Gr 4 thrombocytopenia that is a ≥ 30% decrease in platelets from baseline and requires > 1 platelet transfusion, Gr 3 thrombocytopenia with significant bleeding (requiring hospitalization and/or platelet transfusion), Gr 4 infection, or ≥ Gr 3 other non-hematologic toxicity related to POM. Serial plasma samples were analyzed to generate PK parameters. Updated PK and AE data for all cohorts will be presented. Results: As of July 17, 2014, updated data for 16 treated pts were available (8 in Cohort A; 3 in Cohort B at 2 mg; 4 in Cohort B at 4 mg; and 1 in Cohort C). Median age was 67 yrs (range, 46-76 yrs), 56% were male, all had Eastern Cooperative Oncology Group performance status 0 or 1, and a median time from diagnosis of 3.8 yrs (range, 0.6-12.5). No DLTs in cycle 1 were reported for any cohort. The most common Gr ≥ 3 adverse events (AEs) were neutropenia, anemia, infection, and fatigue (Table). Median relative dose intensity was consistent across cohorts: 90% (Cohort A), 90% (Cohort B; 2 mg), 100% (Cohort B; 4 mg) and 100% (Cohort C). Three pts discontinued due to AEs (2 in Cohort A and 1 in Cohort B 4 mg); no deaths have occurred during treatment phase. Conclusion: MM-008 is an ongoing trial prospectively evaluating the PK and safety of POM + LoDEX in pts with RRMM and severe RI. Preliminary PK data support mean dose-normalized exposure in pts with RRMM being similar between those with severe RI and those with no or mild RI at the clinical dose of 4 mg; early tolerability data (after one cycle) are encouraging. Table Cohort A(n = 8) Cohort B(n = 3) Cohort B(n = 4) Cohort C(n = 1) Cohort Characteristics POM dose 4 mg 2 mg 4 mg 4 mg CrCl (mL/min) ≥ 60 mL/min < 30 mL/min without dialysis < 30 mL/min without dialysis < 30 mL/min with dialysis Safety Dose-limiting toxicities (n) N/A 0 0 0 Grade 3/4 AEs (n) Neutropenia 4 2 1 0 Anemia 3 1 2 0 Infection 3 2 0 0 Fatigue 2 0 0 0 N/A: Not applicable (4 mg POM is approved dose for population) Disclosures Matous: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siegel:Celgene Corp: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Lonial:Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy. Harvey:Celgene Corp: Research Funding. Kasserra:Celgene Corp: Employment, Equity Ownership. Li:Celgene Corp: Employment, Equity Ownership. Chen:Celgene Corp: Employment. Doerr:Celgene Corporation: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene : Employment, Equity Ownership. Jacques:Celgene Corp: Employment, Equity Ownership. Shah:Celgene Corp: Consultancy, Research Funding.

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Pmd-107: Marizomib, Pomalidomide and Low Dose-Dexamethasone Combination Study in Relapsed/Refractory Multiple Myeloma (NCT02103335): Full Enrollment Results from a Phase-1 Multicenter, Open Label Study

Blood ◽

10.1182/blood.v128.22.3326.3326 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3326-3326 ◽

Cited By ~ 4

Author(s):

Andrew Spencer ◽

Simon Harrison ◽

Jacob P. Laubach ◽

Jeffrey Zonder ◽

Ashraf Z Badros ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Employment Equity ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Marizomib (MRZ) is a novel, irreversible, pan subunit proteasome inhibitor (PI) with preclinical evidence demonstrating in vitro and in vivo activity in multiple myeloma (MM). This study was designed to evaluate the safety and antimyeloma activity of pomalidomide (POM), MRZ and low dose dexamethasone (Lo-DEX) (PMD) in patients with relapsed and refractory multiple myeloma (RRMM). Thirty-eight heavily pretreated patients with RRMM were enrolled [dose-escalation cohort (n=14); recommended Phase 2 dose (RP2D) cohort (n=24)]. IV MRZ (0.3 to 0.5 mg/m2) was administered on Days (D) 1, 4, 8, 11; POM (3 or 4 mg) on D1 through 21; and Lo-DEX (5 or 10 mg) on D1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23 of every 28-D cycle. Patients received a median of 4 (range 1-9) prior lines of therapy; 100% received prior lenalidomide (LEN) and bortezomib (BTZ), 34% carfilzomib (CFZ), and 50% thalidomide. 53% of patients were refractory to both LEN and BTZ and 21% were refractory to LEN, BTZ, and CFZ. There were no dose limiting toxicities during the study. The most common study treatment related ≥Grade 3 adverse events (AEs) were neutropenia (11/38 pts: 29%), pneumonia (4/38 pts 11%), anemia (4/38 pts; 11%), thrombocytopenia (4/38 pts; 11%), and febrile neutropenia (2/38 pts; 5%), with two grade 4 AEs (neutropenia related to POM and viral infection related to DEX), and one grade 5 AE (cardio-respiratory arrest from a suspected PE related to POM). Overall, MRZ was well tolerated, did not add to the incidence or severity of POM/Lo-DEX AEs and the regimen may have fewer hematological and infectious AEs compared to that observed with POM/Lo-DEX. MRZ pharmacokinetic analysis revealed that it was rapidly cleared with a short T1/2 (6.2-11mins) and a large volume of distribution (41-86L) suggesting extensive tissue distribution. Pharmacodynamic analysis demonstrated rapid and robust inhibition of chymotrypsin-like activity in both packed whole blood (PWB) and peripheral blood mononuclear cells (PMBCs), reflecting the irreversible binding nature of MRZ. Evolving inhibition of trypsin-like and caspase-like proteasome activity was also observed in PWB and PBMC with continued dosing. The overall response rate (ORR) and clinical benefit rate (CBR) for the 36 response evaluable patients was 53% (19/36) and 64% (23/36), respectively (Table 1). Subpopulation analysis demonstrated an ORR of 50% (5/10) in high risk cytogenetic patients, 56% (10/18) in LEN/BTZ refractory patients, 71% (5/7) in LEN/BTZ/CFZ refractory patients and 80% (8/10) in CFZ refractory patients. These data compare favorably against POM/Lo-Dex with a near doubling of ORR in both the total patient population and the double refractory patients. Substantial activity in high-risk patients that are triple refractory and in patients that are refractory to CFZ in prior last regimen was observed. MRZ activity in RRMM patients exposed and/or refractory to multiple PIs is likely a consequence of its unique pan proteasome subunit inhibitory actions. In conclusion, MRZ in combination with POM and Lo-DEX was well tolerated and demonstrated promising activity in heavily pretreated, high-risk RRMM patients. Table 1 Table 1. Disclosures Harrison: Janssen-Cilag: Research Funding, Speakers Bureau; Celgene: Honoraria. Zonder:Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Khot:Amgen: Honoraria; Janssen: Consultancy; Pfizer: Speakers Bureau. Anderson:C4 Therapeutics: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; C4 Therapeutics: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Oncoprep: Equity Ownership; Millennuim: 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; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. MacLaren:Triphase Accelerator: Employment, Equity Ownership. Reich:Triphase Accelerator: Consultancy. Trikha:Encycle Therapeutics: Consultancy, Equity Ownership; Triphase Accelerator: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Characterization of Patients with Multiple Myeloma Achieving Complete Response to Bortezomib: An Interim Report From An International Electronic Observational Study.

Blood ◽

10.1182/blood.v114.22.4938.4938 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4938-4938

Author(s):

Michel Delforge ◽

Hadewijch De Samblanx ◽

Maria Roussou ◽

Konstantinos Zervas ◽

Eirini Katodritou ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factors ◽

Clinical Practice ◽

Observational Study ◽

Complete Response ◽

Practice Setting ◽

Employment Equity ◽

Clinical Practice Setting ◽

Equity Ownership ◽

Response Groups

Abstract Abstract 4938 Introduction Bortezomib (Velcade®) is effective and well tolerated in patients with multiple myeloma (MM), including those with adverse prognostic factors such as advanced age, more prior lines of therapy, and advanced-stage disease. The international, non-interventional, Electronic Velcade Observational Study (eVOBS) is an ongoing observational study that aims to assess the clinical and health economic outcomes in MM patients treated with bortezomib in the clinical-practice setting. In this study, we characterized patients achieving complete response (CR) with bortezomib in the relapsed/refractory setting, and assessed the effects of adverse prognostic factors on the rate of CR. Methods Adult patients from Belgium, France, Greece, Russia, Spain, Sweden, and Turkey scheduled to receive bortezomib for relapsed MM were eligible for inclusion in eVOBS. All bortezomib doses and concomitant treatments (except investigational therapies) were permitted; dose adjustments and cycle delays were documented. Patients are being followed for up to 3 years to document long-term outcomes; data are collected at baseline and at the end of every bortezomib cycle. Due to the non-interventional nature of the study, no predefined response criteria were mandated; response criteria were defined by the investigator and may have included European Group for Blood and Marrow Transplantation (EBMT), Southwest Oncology Group (SWOG), or M-protein criteria. Patients who had at least 12 weeks data or who had died by the time of data cut-off (June 30, 2009) were included in this exploratory analysis; patients were assessed after completion of four and six cycles. Results A total of 769 patients were included, 129 (16.8%) of whom achieved CR. There were no significant differences in baseline characteristics between patients who did (n=129) vs did not (n=640) achieve CR: 49.8% vs 47.3% were male, median age at baseline was 60.6 vs 62.1 years, median age at diagnosis was 57.9 vs 59.4 years, and median time since diagnosis was 2.3 vs 2.4 years. Patients with adverse prognostic factors were evenly distributed among response groups: of the patients who achieved CR, 7.8%, 55.8%, 23.3%, and 13.2% had 0, 1, 2, and 3 or more prior lines of therapy, vs 3.6%, 56.1%, 23.4%, and 15.8% of those who did not achieve CR. Similar results were seen for patients across disease stages: 14.7%, 31.0%, and 46.5% of CR patients vs 12.3%, 33.1%, and 50.2% of non-CR patients had ISS disease stage I, II, or III, respectively. Similarly, patients with comorbidities such as obesity or diabetes were evenly distributed across response groups: 6.1% and 7.1% of CR patients had obesity or diabetes, respectively, vs 4.4% and 9.6% of non-CR patients. After 4 cycles, the overall response rate (ORR) in patients who had completed 4 cycles (n=518) was 70%, including 12% complete response (CR), 16% near-CR (nCR), and 42% partial response (PR). Improved response rates were seen with prolonged therapy; after 6 cycles, the ORR in patients who had completed 6 cycles (n=321) was 82%, including 16% CR, 20% nCR, and 46% PR. As shown in the Figure, analysis of overall survival by best response at cycle 4 showed that achieving a CR/nCR is associated with significantly improved survival versus PR (p<0.0001). Conclusions Together, these results show that bortezomib, as administered in the clinical-practice setting, is highly active in relapsed/refractory MM patients, with CRs achieved among all patient subgroups. Furthermore, achievement of CR appears associated with prolonged survival and responses to bortezomib appear to improve with prolonged duration of therapy. Disclosures Delforge: Celgene: Honoraria, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria. Hulin:Janssen-Cilag: Honoraria; Celgene: Honoraria. Ganguly:Johnson & Johnson: Employment, Equity Ownership. Diels:Johnson & Johnson: Employment, Equity Ownership. Dhawan:Johnson and Johnson Research Pharmaceuticals: Employment. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho-Biotech: Consultancy, Honoraria.

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Molecular Analysis of RAS-RAF Tyrosine-Kinase Signaling Pathway Alterations in Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2876.2876 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2876-2876

Author(s):

Valentina Artusi ◽

Claudia Haferlach ◽

Alexander Kohlmann ◽

Susanne Schnittger ◽

Wolfgang Kern ◽

...

Keyword(s):

Multiple Myeloma ◽

Signaling Pathway ◽

Mutation Rate ◽

Plasma Cell ◽

Deep Sequencing ◽

Response To Therapy ◽

Braf V600e ◽

Employment Equity ◽

Available N ◽

Equity Ownership

Abstract Abstract 2876 Multiple myeloma (MM) is a malignancy of abnormal plasma cells and a correlation with poor outcome has been described for immunoglobulin heavy-chain (IgH) translocations, deletions of 13q or 17p. Thus far, a convincing relationship between specific mutations, disease onset and progression has not been fully established. Aberrant impairment of important signaling pathways can drive oncogenesis and contribute to MM development. We therefore chose to study NRAS, KRAS and BRAF, three members of the RAS-RAF signaling pathway, as well as TP53 and CCND1, two fundamental genes in cell cycle control. We here investigated 41 MM cases to further elucidate molecular mechanisms underlying this disease. Bone marrow (n=35) or, in case of plasma cell leukemia, peripheral blood (n=6) specimens were collected between 12/2006 and 6/2011 and molecular analyses using a deep-sequencing assay (454, Branford, CT) in combination with the 48.48 Access Array technology (Fluidigm, South San Francisco, CA) were performed on mononuclear cells after Ficoll enrichment or magnetic activated plasma cell sorting using anti-CD138 beads (RoboSep, STEMCELL Technologies SARL, France). The cohort included 16 female and 25 male patients at first diagnosis, with a median age of 63 years (range: 33–84 years). Based on fluorescence in situ hybridization (FISH), the cohort was characterized as follows: IgH rearrangements were detected in 54.3% of patients (19/35: n=6 with t(4;14), n=9 with t(11;14), n=3 with t(14;16), n=1 other; data not available: n=5). A deletion 13q14 was present in 64.9% of patients (24/37; data not available: n=4). Trisomy 3 was detected in 48.0% of patients (12/25; data not available: n=16), trisomy 9 was detected in 50.0% of patients (12/24; data not available: n=17), trisomy 11 was detected in 46.4% of patients (13/28; data not available: n=13), and trisomy 15 was detected in 56.2% of patients (9/16; data not available: n=25), respectively. Interestingly, in all cases where FISH data was available (n=36), at least 1 aberration was detectable. Further, we studied the occurrence of somatic mutations in NRAS, KRAS, BRAF, TP53 and CCND1. In our cohort, we detected an overall mutation rate within the RAS pathway of 41.4% (17/41), in line with a recent report (Chapman et al., Nature, 2011). KRAS was the most frequently mutated gene with 21.9% of cases with mutations (9/41 patients), followed by NRAS (19.5%; 8/41 patients). Recently, BRAF V600E mutations have gained clinical interest since they became manageable by targeted treatment in melanoma. Interestingly, Chapman et al. discovered a mutational rate of 4% by sequencing of 161 MM patients (Nature, 2011). Even if BRAF is not a frequently mutated gene in MM, it justifies upfront diagnostic screening since these patients may benefit from new treatments. In our cohort, 2/41 patients harbored BRAF V600E mutations. Moreover, because of their involvement in the same signaling pathway, we also noticed that mutations affecting NRAS, KRAS or BRAF were predominantly mutually exclusive, except for one patient who concomitantly harbored a BRAF and a NRAS mutation. Additionally, we observed an overall molecular TP53 mutation rate of 12.2% (5/41 patients). In these 5 patients, in total 7 mutations (5 missense substitutions; 2 frame-shift mutations) were detected. 1/4 cases concomitantly harbored a deletion of the TP53 gene, as detected by FISH. Finally, we were interested in the analysis of CCND1, which is located on 11q13, a region frequently involved in chromosomal translocations (9/20 IgH translocated cases in our cohort). Here, we were able to detect 2/41 (4.8%) CCND1 mutated cases. Concerning the correlation between IgH rearrangements and molecular aberrations we observed that 21.9% (9/35; n=5 IgH status not available) of patients that were IgH rearranged, concomitantly carried a TP53 or RAS-RAF mutation. In more detail, 2/5 TP53 mutated patients and 50.0% (8/16) RAS-RAF mutated cases concomitantly harbored an IgH rearrangement. Taken together, MM patients are currently stratified in part based on cytogenetic/FISH classification. We demonstrated that deep-sequencing analyses support an additional molecular characterization. In our cohort, all patients carried mutations detected by FISH and 23/41 (56.1%) carried a molecular mutation. Future clinical studies need to confirm the frequencies of these mutations as well as their association with response to therapy and outcome. Disclosures: Artusi: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Grossmann:MLL Munich Leukemia Laboratory: Employment.

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Follow-up of Real Life Treated Multiple Myeloma Patients: Response, Disease Progression and Overall Survival,

Blood ◽

10.1182/blood.v118.21.3937.3937 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3937-3937

Author(s):

Hareth Nahi ◽

Johan Liwing ◽

Katarina Uttervall ◽

Johan Andreasson ◽

Astrid Gruber ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Practice ◽

Real Life ◽

M Protein ◽

Novel Agents ◽

Response Distribution ◽

Employment Equity ◽

Study Population ◽

Equity Ownership

Abstract Abstract 3937 Treatment results in clinical practice and in real life can be different from each other. Therefore, evaluating real life outcomes in Multiple Myeloma (MM) patients in order to understand treatment outcome in clinical practice is very important. All patients diagnosed with MM and treated between Jan 2000 and Jul 2010 at Karolinska University Hospital, Huddinge and Södersjukhuset were included. Furthermore, all diagnosed patients between Jan 2005 and Jul 2010 at Karlolinska University Hopital, Solna were included. At diagnosis data regarding age, gender, type of myeloma and skeleton destruction as well as Ca, Hb, β2-microglobelin, albumin and creatinine were collected. For each treatment line, drugs given and specific start and stop dates for each drug were collected. Serum and urine M-protein was collected at baseline and each time the measurement differed from the previous. Near complete response (nCR) was defined as an immeasurable M-protein in the blood and urine by standard electrophoresis but not always confirmed by immunofixation since it was not required in clinical practice. Partial response (PR) was defined as a 50% reduction in M-protein. No response (NR) was defined as less than 50% reduction of M-protein. Progress was considered when M-protein increased with ≥ 25%. Novel agents were defined as bortezomib, lenalidomide and thalidomide. In the total population n=674, 89 (13%) patients were excluded due to non treatment demanding disease or plasmacytoma without MM diagnosis setting the study population to n=585. The median follow up of the study population was 815 days. The median age in the study population was 68 years and 45% were women. High dose treatment (HDT) was given to 214 (37%) patients. The median age in the HDT population was 58 years and 34% were women. The median age in the non-HDT population was 75 years and 51% was women. The median number of given treatment lines was 2. The proportion of patients receiving more treatment lines were declining rapidly with the number of received lines of therapy. The response distribution for the entire population nCR/PR/NR was 27/41/32 in 1st line, 18/34/48 in 2nd line. In the HDT population the same response distribution was 50/38/12 in 1st line and 28/38/34 in 2nd line. In the non-HDT population the response distribution was 14/43/43 in 1st line and 12/33/55 in 2nd line. The depth of the responses was significantly dependent on the line of therapy. Responses were significantly better in the HDT population vs. the non-HDT population in the first two treatment lines. There seems to be a correlation between the responses in 1st and 2nd line in the entire population. Improving the responses in 2nd line compared to 1st line seems not very likely. Statistical analysis shows that the non-HDT patients receiving novel agents in 1st line had a significantly higher probability of achieving nCR, 25% vs 9%.The same statistical difference was seen in the HDT patients with nCR rates of 65% vs 47%. The median TTP/TTNT for the study population was 309/381 days in the 1st line and 182/210 in 2nd line. In the HDT population the TTP/TTNT was 538/639 days in 1st line and 199/257 in 2nd line. In the non-HDT population the TTP/TTNT was 244/295 days in 1st line and 177/193 in 2nd line. In the HDT population both the TTP and the TTNT in the 1st line were significantly better than in the non-HDT population with no difference in the 2nd line. There was a significant trend of increasing TTP/TTNT in 1st line depending on the increased depth of the response. Statistical analysis showed that the use of novel agents in 1st line predicted a longer TTP for the non-HDT population. Median OS was 4.3 years 95% CI [3.9;5.0] with 53% censored. HDT patients had a significant longer median OS 6.3 years 95% CI [5.4;8.5] than the non-HDT patients OS 3.0 years 95% CI [2.2;3.6]. The median OS for non-HDT patients with 1st line best response nCR was 4.9 years, PR 3.3 years and NR 1.5 years. Kaplan-Mayer analysis shows that use of novel agents in the 1st line predicted a longer OS, median 5.1 years vs. 4.1 years. Patients receiving 2nd and 3rd line treatment were declining rapidly. To get a good response in 1st line increases the likelihood of having a good response in 2nd line. Receiving an nCR in 1st line seems to be very important and this study confirms the prognostic impact of achieving at least nCR. The use of novel agents improves the outcome for patients in clinical practice. Disclosures: Liwing: Janssen-Cilag: Employment, Equity Ownership. Näsman:Janssen-CIlag: Consultancy. Aschan:Janssen-Cilag: Employment, Equity Ownership.

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Overall Safety and Treatment Duration in Lenalidomide (LEN)-, Thalidomide (THAL)-, and Bortezomib (BORT)-Treated Patients (Pts) within the European Post-Approval Safety Study (EU PASS) of Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood.v120.21.4068.4068 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4068-4068

Author(s):

Barbara Gamberi ◽

Charalampia Kyriakou ◽

John Ashcroft ◽

Miguel T. Hernandez ◽

Jo Caers ◽

...

Keyword(s):

Clinical Practice ◽

Disease Progression ◽

Treatment Duration ◽

Treatment Discontinuation ◽

Study Entry ◽

Current Clinical Practice ◽

Employment Equity ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 4068 Background: The efficacy and tolerability of LEN in pts with RRMM has been demonstrated in 2 large, randomized, phase 3 studies (MM-009/010). BORT and THAL have also been shown to be effective for RRMM treatment. While many studies have described the safety of antimyeloma drugs in the clinical trial setting, few have addressed the issue of tolerability in current clinical practice. Aims: In this study, we compared the incidence of adverse events (AEs) of special interest, such as neutropenia, thrombocytopenia, venous thromboembolism (VTE), peripheral neuropathy (PN) and second primary malignancies (SPM) in pts treated with LEN versus other antimyeloma therapies for RRMM in current clinical practice. Additionally, duration of treatment was assessed in the context of therapy received just prior to study entry. Methods: In this post-approval, observational, non-interventional, EU PASS study, pts with RRMM were enrolled into either the LEN cohort (LEN-based therapy) or the background cohort (all non-LEN based therapies) at the investigators' discretion. Thromboprophylaxis was per local standard practice. AEs were graded according to NCI-CTCAE v3.0. Assessments for SPM were to be conducted up to 36 months (mos) after treatment discontinuation. Results: As of May 2012, overall median follow-up was 5.7 mos (range 0.02–39.8), (6.4 mos LEN, 5.7 mos THAL, 4.9 mos BORT). There were 3107 pts across 268 institutions in 17 European countries enrolled: 2141 received LEN, 751 received BORT, 110 received THAL, and 105 received other therapies or had incomplete information on the treatment arm. 127 pts from the background cohort crossed over following the physician's decision to initiate LEN treatment as a subsequent therapy. Median age was 70 years (range, 25–95) and 54% were male. Most pts (65%) had good performance status (ECOG score 0–1); 17% had an ECOG score of 2–4. Median overall number of prior therapies was 2 (range, 0–6) and this was consistent across the cohorts: 53% had 2 prior therapies and 21% had ≥3. Baseline characteristics were similar between groups. Overall, 1397 (45.0%) had a grade 3–4 AE. Grade 3–4 neutropenia occurred in 14%, 4%, and 5% of pts in the LEN, BORT, and THAL groups, respectively. Grade 3–4 thrombocytopenia developed in 8%, 9%, and 3% of pts, respectively. In the LEN group, only 7% of pts (1% grade 3–4) reported PN (4% newly occurring) while receiving LEN (despite 36% of pts presenting with PN at baseline) compared with 28% (5% grade 3–4) with BORT (22% PN at baseline) and 16% (2% grade 3–4) with THAL (19% PN at baseline). Grade 3–4 VTE developed in 2.7% of pts in the LEN group, 0.7% in the BORT group, and 1.8% in the THAL group. Overall treatment discontinuation rates (including disease progression) were 70%, 85%, and 86% in the LEN, BORT, and THAL groups, respectively, with nearly identical discontinuation rates due to AEs (17%) in each group, and disease progression rates of 15–20%. SPM incidence was ≤1% overall and invasive SPM incidence rate per 100 patient-years (95% CI) was 1.4 (0.94 –2.09) at a median follow-up of 10 mos and was comparable across the cohorts. Incidence of death during the study was comparable with all treatments (LEN 6%, BORT 4%, and THAL 5%); the incidence of treatment-related AEs leading to death was 1.4%, 1.2% and 0.9%, respectively. The median treatment duration was 4.6 mos in the overall population; 5.4 mos in pts treated with LEN, 3.7 mos in pts treated with BORT, and 4.6 mos in pts treated with THAL. At a 5.7 mos median follow-up, 19.9%, 2.0%, and 14.5% of pts in the LEN, BORT, and THAL arms had a treatment duration of >12 mos; and 2.2%, 0.3%, and 0.9% had a treatment duration of >24 mos, respectively. In an analysis of study treatment by last therapy prior to study entry, patients receiving THAL or BORT followed by LEN had a median on-study treatment duration of 5.7 mos and 5.2 mos, respectively, independent of the line of treatment. In comparison, pts receiving THAL or BORT followed by BORT had lower median study treatment duration of 3.7 mos and 3.8 mos, respectively. Conclusions: Results of this non-interventional, observational study show that AEs were similar with all treatments except for higher rates of neutropenia and lower rates of PN with LEN, compared with BORT or THAL. Despite the current short overall follow-up, treatment duration within the LEN, BORT, or THAL groups appears to be unaffected by prior treatment received but was longer for LEN when compared with BORT or THAL. Disclosures: Küenburg: Celgene Corporation: Employment, Equity Ownership. Rosettani:Celgene Corporation: Employment, Equity Ownership. Ryder-Smith:Celgene Corporation: Employment, Equity Ownership.

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Dreamm-3: A Phase 3, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) Monotherapy Compared with Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Participants with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood-2019-129893 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1900-1900 ◽

Cited By ~ 4

Author(s):

Katja Weisel ◽

Thomas G Hopkins ◽

Doug Fecteau ◽

Weichao Bao ◽

Corinne Quigley ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibody ◽

Research Funding ◽

Standard Of Care ◽

Efficacy And Safety ◽

Open Label ◽

Employment Equity ◽

Phase 3 ◽

Refractory Multiple Myeloma ◽

Equity Ownership

Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study. Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019. Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline. Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa. Disclosures Weisel: Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hopkins:GSK: Employment, Equity Ownership. Fecteau:GSK: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Quigley:GSK: Employment, Equity Ownership. Jewell:GSK: Employment, Equity Ownership. Nichols:GSK: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

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Lenalidomide-Based Treatment for Newly Diagnosed Multiple Myeloma Patients, Ineligible for Transplant: A Healthcare Cost-Impact Analysis in Europe

Blood ◽

10.1182/blood.v126.23.3304.3304 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3304-3304

Author(s):

Stephen A Schey ◽

Casado Montero ◽

Chloe Stengel-Tosetti ◽

Craig Gibson ◽

Sujith Dhanasiri

Keyword(s):

Multiple Myeloma ◽

Treatment Duration ◽

Care Pathway ◽

Newly Diagnosed ◽

Time To Progression ◽

First Line ◽

Employment Equity ◽

Cost Impact ◽

Equity Ownership ◽

Line Setting

Abstract Background: Multiple myeloma remains an incurable and relapsing haematological cancer. The FIRST study showed that lenalidomide, an immunomodulatory agent, plus dexamethasone improved overall survival of newly diagnosed multiple myeloma (ndMM) patients who are not eligible for transplants by 10.4 months when it was used continuously compared with fixed treatment duration (72 weeks) with melphalan, prednisone and thalidomide(Facon et al, EHA 2015). Compared with alternative intravenous agents, lenalidomide as an oral therapy has also been associated with fewer hospital visits(Gualtney et al, J Clin Pharm Ther, 2013; Armoiry et al, J Clin Pharm Ther, 2011; Arikian et al, Curr Med Res Opin, 2015). In an era of increasing cost conscious health systems, additional economic information is playing an important role in access decisions on innovative medicines. This analysis examines the cost impact of lenalidomide when used in the first-line setting for patients with ndMM in the EU5. Methods: A healthcare cost impact model was developed to estimate total costs associated with the treatment of ndMM over 5 years in the EU5 (France, Germany, Italy, Spain and the UK). The model included drug costs and hospitalisation costs of first-line treatment and up to four additional lines of post-progression treatment for lenalidomide-, thalidomide-, bortezomib as well as costs of pomalidomide-based regimens in later lines. The expected rate of lenalidomide uptake in the first-line setting was based on its observed uptake in the US over the last 5 years. Care pathway costs were calculated for the EU5 according to treatment duration and time to progression. Hospitalisation costs from a retrospective medical chart review in Dutch patients with relapse/refractory MM (Gualtney et al, J Clin Pharm Ther, 2013) were adapted to the first-line setting by adjusting for the duration of treatment and the time to progression for each regimen in each line. Results: Baseline yearly costs per patient were €48,032 ($53,066). In year 1, first-line lenalidomide use resulted in a cost increase by 1.9% (€923 [$1,020] per MM patient, on average). In year 5, annual costs were expected to increase by 7.7% (€3,732 [$4,123] per MM patient). The monthly drug cost per patient was greater in lenalidomide treated patients compared with those receiving bortezomib or thalidomide (€6,548 [$7,234] vs. €5,151 [$5,691] and €1,742 [$1,925], respectively). However, lenalidomide use was associated with the lowest monthly hospitalisation cost per patient (€641 [$708]) compared with bortezomib and thalidomide (€925 [$1,022] and €1,209 [$1,336] respectively). Conclusion: Lenalidomide as a treatment option for newly diagnosed patients is a significant development in the management of MM. Use of lenalidomide in this setting is expected to result in an overall MM care pathway cost impact of under 10% over 5 years. Whilst the drug acquisition cost of lenalidomide is relatively higher than currently used options for ndMM, this is partially offset by savings from displaced use of bortezomib and lenalidomide in the first and second lines, respectively. Additionally there are potential savings from lower resource use. Further studies should be undertaken to evaluate full real life healthcare costs. Disclosures Schey: Celgene Corporation: Honoraria. Montero:Celgene Corporation: Honoraria. Stengel-Tosetti:Celgene Corporation: Consultancy. Gibson:Celgene Corporation: Employment, Equity Ownership. Dhanasiri:Celgene Corporation: Employment, Equity Ownership.

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Discontinuation Patterns in Patients Receiving Novel Oral Agents for Chronic Lymphocytic Leukemia in the Veterans Health Administration

Blood ◽

10.1182/blood-2019-128645 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4309-4309

Author(s):

Hsu-Chih Chien ◽

Vikas Patil ◽

Kelli M Rasmussen ◽

Christina Yong ◽

Juliana M L Biondo ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Real World ◽

Treatment Duration ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Drug Holiday ◽

Median Treatment ◽

Median Treatment Duration ◽

Oral Agents ◽

Equity Ownership

Introduction Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, accounting for 25-30% of all leukemias in the United States. During the past decade, there has been a paradigm shift in CLL treatment, with increasing adoption of novel oral agents (NOAs) such as acalabrutinib (ACALA), duvelisib (DUV), ibrutinib (IBR), idelalisib (IDELA), and venetoclax (VEN) instead of traditional chemoimmunotherapy (CIT). Unlike CIT, most NOAs are given daily for an indefinite period of time and are self-administered at home, raising concerns about adherence and discontinuation. The discontinuation patterns of NOAs in a real-world population of CLL patients is currently unknown. Methods Using the Veterans Administration (VA) Cancer Registry System and electronic healthcare records, we identified patients treated for CLL with NOAs in the VA from November 1, 2013 to November 30, 2018. Patients were followed from the first NOA dispensation until death or the end of the study observation (May 31, 2019). NOAs were selected in accordance with the National Comprehensive Cancer Network (NCCN) guidelinesfor CLL and were extracted using pharmacy dispensation records. Discontinuation was defined as the absence of NOA dispensation within 60 days of estimated exhaustion of patient's NOA supply from the last recorded dispensation. A discontinuation event for each NOA treatment episode in each patient was classified as either 1) a drug holiday, if there was evidence of resumption of the same treatment without any other treatment interventions after the first discontinuation; or 2) permanent discontinuation, in which the treatment ceased without evidence of resumption for 60 days or there was evidence of new treatment initiation after the discontinuation of previous treatment. We report the proportion of discontinuation and exposure-adjusted discontinuation rates (e-AR), which were calculated using the length of NOA duration in person-time. Results We identified 1,196 CLL patients treated with NOAs from November 1, 2013 to November 30, 2018. The mean age at NOA initiation was 70.7 years; 96.7% of patients were male. The median time from diagnosis to NOA initiation was 56.5 months (0-189.5 months). Of the 1,196 patients treated with NOAs, 1,172 received IBR, 53 received IDELA, and 106 received VEN. There were few patients (<10)treated with ACALA and DUV, therefore these patientswere omitted from the final analyses. During a median follow-up of 18.9 months (0-65.3 months), 48.2% NOA treatment courses were followed by a discontinuation event. The proportions of patients who discontinued for IBR, IDELA, and VEN were 47.5%, 77.4%, and 41.5%. The e-AR of IBR, IDELA, and VEN are reported in Table 2. At the end of the study observation (May 2019), 52.6% of IBR, 22.6% of IDELA, and 58.3% of VEN treatment courses were still being administered. In first-line (L1) IBR, the median NOA treatment duration until the first discontinuation was 10.7 months (0.8-55.8 months), 12.6 months (0.5-62.0 months) in second-line (L2) IBR, and 12.2 months (0.78-57.8 months) in third-line or subsequent lines (L3+) IBR. In IDELA treatment courses, the median treatment duration until the first discontinuation was 17.8 months (1.9-41.6 months) in L2 and 4.3 months (1.7-26.2 months) in L3+. In VEN, the median treatment duration until the first discontinuation was 8.4 months (3.1-26.0 months) in L2 and 7.4 months (1.7-18.5 months) in L3+. Of 532 L1 IBR treatment courses with >1 dispensation, 96 (18%) were associated with a drug holiday and 97 (18%) with permanent discontinuation. These numbers were 64 (27%) and 50 (21%) for L2 IBR courses, and 90 (28%) and 76 (24%) for L3+ IBR courses. Similarly, 24 (67%) of L3 IDELA treatment courses with >1 dispensation were associated with permanent discontinuation. Among 63 L3+ VEN courses with >1 dispensation, 6 (10%) were associated with a drug holiday and 14 (22%) with permanent discontinuation. Conclusions To our knowledge, this study is the first to report on the NOA discontinuation in a nationwide VA cohort of CLL patients treated in a real-world setting. Our results suggest there is a substantial proportion of drug holidays and permanent discontinuation among commonly used NOAs. Further efforts will focus on understanding factors leading to discontinuation and the impact of discontinuation/drug holidays on clinical outcomes. Disclosures Biondo: Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Halloran:Roche: Equity Ownership; Genentech, Inc.: Employment. Shapouri:Roche: Equity Ownership; Genentech, Inc.: Employment. Wu:Genentech, Inc.: Employment. Sauer:University of Utah and SLC VA Medical Center: Employment. Halwani:Miragen: Research Funding; Kyowa Hakko Kirin: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Seattle Genetics: Research Funding; Genentech, Inc.: Research Funding; AbbVie: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Immune Design: Research Funding.

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A US Budget Impact Model for Selinexor in Combination with Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood-2019-125997 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5824-5824

Author(s):

Ian Gould ◽

Jan Bassali ◽

Jyotsna Mehta ◽

Jatin Shah ◽

Dee Dee Mladsi

Keyword(s):

Multiple Myeloma ◽

Health Plan ◽

Budget Impact ◽

Employment Equity ◽

Cancer Society ◽

Refractory Multiple Myeloma ◽

Number Of Patients ◽

Equity Ownership ◽

Budget Impact Model ◽

The Cost

BACKGROUND: Multiple myeloma is a relatively uncommon hematological cancer that occurs when the bone marrow produces malignant plasma cells that enter the blood stream. In the United States, the lifetime risk of getting multiple myeloma is 1 in 132 (0.76%). American Cancer Society estimates that about 32,110 new cases will be diagnosed and about 12,960 deaths are expected to occur among multiple myeloma patients. (American Cancer Society. Cancer Facts and Figures 2019). An increasing number of treatments are available for multiple myeloma, however, due to the highly refractory nature of the disease surviving patients must eventually resort to best supportive care (BSC). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) for the treatment of relapsed or refractory multiple myeloma (RRMM). OBJECTIVE: To estimate the budget impact of Selinexor in combination with dexamethasone (Sel-dex) for the treatment of patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody in US. METHOD: An interactive budget impact model was developed to evaluate the addition of Selinexor for treatment of RRMM using a hypothetical health plan of 25 million lives over a time horizon of 3-years (2019-2021) after the introduction of Selinexor. The model compares the formulary without Selinexor to a formulary with Selinexor and considers direct cost only. The model was developed following guidelines from the International Society for Pharmacoeconomics and Outcomes Research. The key assumptions in the model are that there is no reasonable alternative to Selinexor besides BSC, the use of Selinexor will not meaningfully reduce the cost of BSC, and the number of patients eligible to receive Selinexor is expected to remain the same for each of the 3 years evaluated in the model. The assumed uptake rates for Selinexor were included. The average per-person drug cost for each year of treatment is calculated by accounting for the cost of the drug including dosage, frequency, and duration of treatment. The costs of treatment-emergent adverse events occurring at grade 3 or higher occurring in at least 5% of patients in the STORM trial (NCT02336815) were included. As Sel-dex is taken orally, wastage was not considered for this model. Total annual treatment costs included drug costs, AE costs, and BSC costs, and were calculated for each scenario to estimate the budget impact of making Selinexor available as a treatment for eligible patients. One-way sensitivity analysis was conducted to test the robustness of the model results and the sensitivity of the results to uncertainty in key model input parameters including time on treatment with Selinexor (weeks), uptake of Selinexor in year 1 after market entry and the drug cost of Selinexor. Results were calculated in terms of total plan, per-member-per-month (PMPM), and per-treated-member-per-month costs. RESULTS: In the hypothetical health plan of 25 million lives, the annual number of patients eligible for Selinexor was estimated to be 182. After the adoption of Selinexor, the base case results showed minimal budget impact with $0.01 per member per month incremental cost for year 1 and $0.02 for both year 2 and year 3. For Commercial and Medicare patients, the incremental cost was < $0.02 per member per month for all three years. CONCLUSION: The results indicated that with limited treatment options in the later lines, Sel-dex for the treatment of multiple myeloma will have a minimal budget impact for a US health plan. Disclosures Gould: RTI International: Employment. Bassali:Karyopharm Therapeutics: Employment, Equity Ownership. Mehta:Karyopharm Therapeutics: Employment, Equity Ownership; Sanofi: Equity Ownership; Alkermes: Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Mladsi:RTI International: Employment.

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