scholarly journals Efficacy of Once-Weekly Bortezomib with Daratumumab for Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1958-1958
Author(s):  
Natalia Gut ◽  
Filiz Yucebay ◽  
Jessica Dempsey ◽  
Junan Li ◽  
Don M. Benson
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Hematologic Malignancy ◽  
Small Sample Size ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Small Sample ◽  
Weekly Schedule ◽  
Refractory Multiple Myeloma

Abstract Background Multiple Myeloma (MM) is an essentially incurable hematologic malignancy with the goals of therapy being disease control, improved quality of life, and prolonged survival.1,2 Despite improved survival with proteasome inhibitors and immunomodulatory agents, outcomes for patients with refractory disease, resistant to these classes of therapy, are poor. Daratumumab, an anti-CD38 antibody, is a commonly utilized therapy for relapsed/refractory multiple myeloma (RRMM) as a single agent based on the SIRIUS study which resulted in adequate response and acceptable safety profiles.3,4 Currently, it is approved in various combinations including with bortezomib. The approval of daratumumab in combination with bortezomib days 1, 4, 8, and 11 of a 21-day cycle was based on the CASTOR study which resulted in high response rates and acceptable safety profiles.5With the addition of bortezomib, additional toxicities in this RRMM setting may be a concern.6 Previous studies of bortezomib in RRMM patients have demonstrated that once-weekly bortezomib is equally as efficacious and better tolerated than the standard twice-weekly schedule, with a lower incidence of peripheral neuropathy and myelosuppression.8,9 However, there are currently no published reports of combining once-weekly bortezomib with daratumumab for patients with RRMM. Methods The present study sought to evaluate the progression-free survival (PFS) of daratumumab administered with once-weekly bortezomib for patients with RRMM. Secondary objectives included evaluation of overall survival (OS), overall response rate (ORR), time to response (TTR), and toxicity of once-weekly bortezomib with daratumumab. Eighteen patients were identified in an Institutional Review Board (IRB)-approved retrospective review of our institutional experience with daratumumab and once-weekly bortezomib. The median age of patients was 65 years (range 47 - 76, Table 1). Ten patients (55.6%) had three or more prior lines of therapy. Twelve patients (66.7%) had previous autologous stem cell transplantation. Sixteen patients (88.9%) had prior proteasome inhibitor (PI) therapy. Thirteen patients (72.2%) had disease refractory to their last line of therapy. Results The median PFS was 3.5 months. Median OS was not reached and TTR were undetermined due to the small sample size. The ORR was 33.3%, with 6 out of 18 patients experiencing an objective partial response or better (Table 2). Of those that responded, 4 patients (66.7%) remained on therapy at the time of data collection.The side effect profile was more tolerable, with less thrombocytopenia (27.8% all grade) and peripheral neuropathy (33.3% all grade) than previously reported (Table 3). Conclusions Daratumumab monotherapy was approved in heavily pretreated RRMM based on the SIRIUS trial showing promising efficacy and a favorable safety profile.4 The median PFS was 3.7 months compared to our PFS of 3.5 months. The combination of daratumumab with bortezomib administered twice weekly was approved based results from the CASTOR trial showing superiority of daratumumab in combination with bortezomib and dexamethasone over bortezomib and dexamethasone.5 As depicted in Table 2, our ORR of 33.3% is similar to the ORR of 29.2% in the SIRIUS trial, however differs greatly from 82.9% in the CASTOR trial. While the present work is retrospective and hypothesis-generating, our results suggest that further prospective inquiry is necessary to determine the additional efficacy of adding once-weekly bortezomib to daratumumab. Disclosures Dempsey: Heron Therapeutics: Honoraria; TESARO: Honoraria.

scholarly journals A dose-finding Phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma

Leukemia ◽  
2020 ◽  
Vol 34 (12) ◽  
pp. 3298-3309 ◽  
Author(s):  
Joseph Mikhael ◽  
Joshua Richter ◽  
Ravi Vij ◽  
Craig Cole ◽  
Jeffrey Zonder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Dose Finding ◽  
Upper Respiratory Tract ◽  
Phase 2 ◽  
Refractory Multiple Myeloma ◽  
Prior Therapy ◽  
Tract Infections

AbstractA Phase 2 dose-finding study evaluated isatuximab, an anti-CD38 monoclonal antibody, in relapsed/refractory multiple myeloma (RRMM; NCT01084252). Patients with ≥3 prior lines or refractory to both immunomodulatory drugs and proteasome inhibitors (dual refractory) were randomized to isatuximab 3 mg/kg every 2 weeks (Q2W), 10 mg/kg Q2W(2 cycles)/Q4W, or 10 mg/kg Q2W. A fourth arm evaluated 20 mg/kg QW(1 cycle)/Q2W. Patients (N = 97) had a median (range) age of 62 years (38–85), 5 (2–14) prior therapy lines, and 85% were double refractory. The overall response rate (ORR) was 4.3, 20.0, 29.2, and 24.0% with isatuximab 3 mg/kg Q2W, 10 mg/kg Q2W/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW/Q2W, respectively. At doses ≥10 mg/kg, median progression-free survival and overall survival were 4.6 and 18.7 months, respectively, and the ORR was 40.9% (9/22) in patients with high-risk cytogenetics. CD38 receptor density was similar in responders and non-responders. The most common non-hematologic adverse events (typically grade ≤2) were nausea (34.0%), fatigue (32.0%), and upper respiratory tract infections (28.9%). Infusion reactions (typically with first infusion and grade ≤2) occurred in 51.5% of patients. In conclusion, isatuximab is active and generally well tolerated in heavily pretreated RRMM, with greatest efficacy at doses ≥10 mg/kg.

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 772-778 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Progression Free Survival ◽  
Prior Treatment ◽  
Once Daily ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Treatment Regimens ◽  
Common Grade ◽  
Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

scholarly journals Quantitative PK/PD Prediction of the Efficacious and Safe Dose Ranges of the LMP7 Inhibitor M3258 for Phase I Application in Relapsed/Refractory Multiple Myeloma Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5582-5582
Author(s):  
Florian Lignet ◽  
Christina Esdar ◽  
Manja Friese-Hamim ◽  
Andreas Becker ◽  
Elise Drouin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research And Development ◽  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Refractory Multiple Myeloma ◽  
Oral Application ◽  
Development Institute ◽  
Safe Dose

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and peripheral nervous systems and cardiac and respiratory organs. Here we describe preclinical PK/PD and PK/efficacy modelling which led to a prediction of the PK profile, and the efficacious and safe dose ranges of M3258 in human which were used to guide the design of the phase I dose-escalation trial of M3258 in >3 line relapsed/refractory multiple myeloma (RRMM) patients. Mouse, rat, dog and monkey PK, plasma protein binding and intrinsic clearance data were used to estimate a half-life of approximately 6 hours for M3258 in human. The human total clearance and volume of distribution for M3258 were predicted to be 0.033 L/h/kg and 0.28 L/kg, respectively, whilst oral bioavailability was estimated to be above 80%. LMP7 proteolytic activity was assessed as a PD readout in human multiple myeloma tumor cells xenografted to mice as well as in dog peripheral blood mononuclear cells (PBMCs). A strong PK/PD relationship was observed for M3258 across both species. LMP7 inhibition by M3258 also correlated strongly with anti-tumor efficacy in multiple myeloma xenografts, with maximal efficacy observed at M3258 exposure delivering sustained inhibition of tumor LMP7 activity. Quantitative PK/PD/efficacy modeling predicted the biologically efficacious dose (BED) of M3258 upon oral application to be between 10 - 90 mg daily in human. By incorporating data from nonclinical safety studies, these data suggest an attractive human PK profile of M3258, enabling oral application, as well as an improved human therapeutic index compared to approved pan-proteasome inhibitors. M3258 is being investigated in a phase I, first-in-man, 2-part, open label clinical study designed to determine the safety, tolerability, PK, PD and early signs of efficacy of M3258 as a single agent (dose-escalation) and co-administered with dexamethasone (dose-expansion) in participants with RRMM whose disease has progressed following > 3 prior lines of therapy and for whom no effective standard therapy exists. Integration of these data will guide the selection of the BED for potential further clinical development of M3258. Disclosures Lignet: Merck Healthcare KGaA: Employment. Esdar:Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Becker:Merck Healthcare KGaA: Employment, Other: Holding shares with a value below 1000-USD. Drouin:EMD Serono Research and Development Institute: Employment. El Bawab:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Gimmi:Merck Healthcare KGaA: Employment. Haselmayer:Merck Healthcare KGaA: Employment. Jährling:Merck Healthcare KGaA: Employment. Sanderson:Merck Healthcare KGaA: Employment. Sloot:Merck Healthcare KGaA: Employment. Stinchi:Merck Healthcare KGaA: Employment. Victor:Merck Healthcare KGaA: Employment. Walter:Merck Healthcare KGaA: Employment. Rohdich:Merck Healthcare KGaA: Employment.

scholarly journals Single-agent belantamab mafodotin for relapsed/refractory multiple myeloma: analysis of the lyophilised presentation cohort from the pivotal DREAMM-2 study

2020 ◽  
Vol 10 (10) ◽  
Author(s):  
Paul G. Richardson ◽  
Hans C. Lee ◽  
Al-Ola Abdallah ◽  
Adam D. Cohen ◽  
Prashant Kapoor ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Agent ◽  
Pathological Finding ◽  
Progression Free Survival ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Blurred Vision ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Duration Of Response

Abstract DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.

Outcome of Patients with IgD and IgM Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplants: A Retrospective CIBMTR Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3328-3328
Author(s):  
Donna E. Reece ◽  
David H. Vesole ◽  
Smriti Shrestha ◽  
Angela Dispenzieri ◽  
Gustavo Milone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Small Sample Size ◽  
Conditioning Regimen ◽  
Progression Free Survival ◽  
Marrow Transplant ◽  
Small Sample ◽  
Hematopoietic Stem ◽  
Prior Therapy

Abstract Multiple Myeloma (MM) is the most common indication for autologous hematopoietic stem cell transplantation (auto HCT). However, little information is available regarding the outcome of patients (pts) with the rarer immunoglobulin subtypes IgD and IgM, which represent 2% and 0.5%, respectively, of all MM cases. In addition, IgD MM has been reported previously to have a poorer prognosis, at least after conventional therapy. The CIBMTR conducted a retrospective analysis of MM pts transplanted between 1995–2005 to describe the characteristics and results of auto HCT in IgD (n=36) and IgM (n=11) among 3578 MM patients with auto HCT during this period. Median follow-up of survivors was 41 (range 2–130) months for pts with IgD and 58 (range 5–101) months for those with IgM MM. Among pts with IgD subtype, median age was 52 years (yrs), 67% were male, 36% had a creatinine >2 mg/L, 61% had Durie-Salmon stage III disease at diagnosis and 33% had Kappa Serum Light chain; the corresponding values for IgM pts were 58 yrs, 36%, 73% and 55% respectively. Prior to auto HCT, 75% of IgD pts were chemosensitive and 25% had received >2 lines of chemotherapy, while all IgM pts were chemosensitive and none had received more than 2 lines of prior therapy. Median time from diagnosis to auto HCT was 9 months in both subtypes. The most common conditioning regimen was singleagent melphalan, and all but 1 pt with IgD disease were grafted with blood stem cells. The small sample size precluded multivariate analysis for potential prognostic factors for outcome. Below table summarizes the post-auto HCT results in these pts contrasted with a reference pool of IgG and IgA MM receiving auto HCT in the same time period. Outcomes, probability (95% CI) IgD IgM IgG/IgA (n=36) (n=11) (n=1475) 100-day mortality, % 0 9 ( 0 – 32) 7 (5 – 8) Non MM deaths, % @ 1 yr 0 9 (0 – 32) 5 (4 – 7) @ 3 yrs 3 (0 – 13) 21 (2 – 51) 16 (14 – 18) Relapse/ Progression, % @ 1 yr 21 (9 – 37) 20 (2 – 49) 18 (16 – 20) @ 3 yrs 59 (41 – 76) 32 (8 – 64) 36 (34 – 39) Progression-free survival, % @ 1 yr 79 (63 – 91) 71 (41 – 93) 77 (74 – 79) @ 3 yrs 38 (21 – 56) 47 (17 – 78) 47 (44 – 50) Overall survival, % @ 1 yr 87 (74 – 97) 91 (68 – 100) 79 (77 – 85) @ 3 yrs 69 (51 – 84) 68 (36 – 93) 53 (50 – 57) No striking differences are apparent in the post auto HCT outcomes of patients with IgD and IgM MM. These results are also consistent with published outcomes of pts with IgD/ IgM MM (Wechaleker et al Ann Hematol. 2005 Feb; 84(2):115–7; Maisner et al Bone Marrow Transplant. 2008 Jan; 41(1):51–4).

Utility of bortezomib retreatment among patients with refractory multiple myeloma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17549-17549
Author(s):  
J. L. Wolf ◽  
A. L. Leblanc MT ◽  
D. S. Battleman ◽  
B. Davis ◽  
J. R. Lyandres ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Initial Treatment ◽  
Plasma Cells ◽  
Small Sample Size ◽  
Case Series ◽  
Small Sample ◽  
Statistical Testing ◽  
M Protein ◽  
Retrospective Case ◽  
Refractory Multiple Myeloma

17549 Background: Bortezomib (VELCADE; Vc) has emerged as the standard of care for patients with relapsed or refractory multiple myeloma (MM). However, following initial Vc therapy, its utility in recurrent disease is unclear. This retrospective case series provides preliminary evidence of the safety and efficacy of Vc in the retreatment of patients with recurrent MM. Methods: An observational case series was developed based on a medical records review of all patients (N = 10) who completed Vc retreatment following completion of initial Vc therapy. Best response was measured as the greatest mean % reduction in the treatment response measure: serum/urine M-protein or plasma cells. Differences between initial treatment and retreatment efficacy and Vc-related hospitalizations were assessed using descriptive statistics. Results: During initial treatment 44% of patients responded to Vc (≥50% M-protein (3/9) or plasme cell reduction (1/9, 1 pt NA). At retreatment 50% of patients responded (5/10). Following initial Vc therapy, the median treatment-free interval was just over 13 months (56.6 weeks). One patient experienced a dose reduction due to peripheral neuropathy (grade 2) during retreatment, compared to two patients with neuropathy (grade 3) during initial treatment. Termination of therapy due to any unmanageable toxicity was much lower during retreatment (14.3% vs 62.5%). Finally, none of the patients were hospitalized for Vc-related events during retreatment, compared with two patients during initial treatment. Conclusions: Vc retreatment appears to be as effective as initial treatment in terms of response, and may actually yield less toxicity and hospitalizations. Even though this small sample size precluded statistical testing, the observed patterns are instructive and additional prospective trials are currently ongoing. However, based on these preliminary data, prolonged disease control may be achieved with repeated use. [Table: see text]

A Phase I-II Trial of Bortezomib Plus Oral Cyclophosphamide and Prednisone for Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3536-3536 ◽  
Author(s):  
Donna E. Reece ◽  
Giovanni Piza ◽  
Suzanne Trudel ◽  
Mariela Pantoja ◽  
Christine Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Progression Free Survival ◽  
Response Rates ◽  
Median Number ◽  
Weekly Schedule ◽  
Oral Cyclophosphamide ◽  
Refractory Multiple Myeloma ◽  
Dose Levels

Abstract Bortezomib (btz) has established efficacy in relapsed/refractory multiple myeloma (MM) patients (pts). Combinations of btz and other agents can produce even higher response rates. We have reported that oral cyclophosphamide (CY) + prednisone (P) produced partial remissions (PR) in 41% and a median progression free survival (PFS) of 18.6 mos in MM pts who had progressed after ASCT. We now report a phase I trial adding btz to CY + P in 27 patients with relapsed/refractory MM. CY was given p.o. once weekly on days 1, 8, 15, and 22 of a 28 day cycle while P 100 mg was given every other morning. CY was given before btz on appropriate days. A total of 8 cycles was planned. The median age was 59 yrs (48–74); 16 were male. Ig subtypes were: IgG (19 pts), IgA (4 pts), kappa light chain (4 pts). The median number of prior regimens was 2 (1–6); all had undergone prior ASCT and 59% had received thalidomide and/or lenalidomide. The median pretreatment β2-microglobulin was 228 nm/L (114–875), albumin 38 g/L (30–46) and creatinine 86 nmol/L (58–153). The dose escalation scheme and toxicity with cycle 1 is shown below: Table 1. Dose levels and toxicity Dose Level N CY dose (mg/m2) Btz dose (mg/m2) Gr 3–4 Toxicity (cycle 1) *Community acquired pneumonia without neutropenia; ** protocol amended to exclude G-CSF for 2 weeks before study entry. 1 6 150 0.7 d 1,8,15 2 CAP* 2 3 300 0.7 d 1,8,15 0 3 3 300 1.0 d 1,8,15 1 ↓ PO4 4 6 300 1.0 d 1,4,8,11 1 ↓ANC**; 1 ↑ AST/ALT 5 6 300 1.3 d 1,4,8,11 1 N/V 6 3 300 1.5 d 1,8,15 0 All the above toxicities above were gr 3 except for 1 transient episode of gr 4 hypophosphatemia. Dose limiting toxicity was not seen. The median number of protocol cycles given per pt was 7 (1–8); 1 pt chose to continue therapy and has received 15 cycles. Toxicities in cycles 2–8 were generally mild. Episodes of infection included shingles (5), gr 3 respiratory infection (6) and febrile neutropenia (2). A total of 168 cycles have been administered; the dose of CY was reduced in 5 cycles due to neutropenia (↓ANC) (3), thrombocytopenia (1) or increased AST/ALT (1), while the btz dose was decreased in 4 cycles due to gr 2 peripheral neuropathy (PN) (1) or ↓ANC (3). 12 pts have completed all 8 cycles, 5 are on therapy and 7 have progressed after a median of cycles 3 (1–7). 3 stopped protocol therapy (physician choice in 1 pt with minimal response, gr 2 PN in 2 pts (after 7 cycles at dose levels 2 and 5) including the pt with prior btz dose reduction. 14/15 pts treated at dose levels 4–6 (effective btz doses) were evaluable for response after receiving at least 2 cycles. Best response was CR/nearCR in 6 (43%) and PR in 7 (50%) for an overall response rate of 93%. The median follow-up is 12 mos (1–20). 6 pts have progressed after stopping therapy. The median PFS is 11 mos, while the median overall survival (OS) has not been reached. The actuarial 1 year OS and PFS are 83% (95% CI 61–93%) and 47% (95% CI 24–68%), respectively. 7 of 10 planned additional pts have entered the phase II portion of the trial at dose level 6. 3 have completed at least 2 cycles; 2 are in CR/near CR while one is in PR. We conclude: Btz 1.5 mg/m2 can be given safely on a convenient weekly schedule days 1, 8 and 15 of a 28 day cycle in combination with full dose oral CY + P in relapsed/refractory MM pts; preliminary response rates at this dose level include 4/6 (67%) CR/near CRs and 1/6 (17%) PR.

scholarly journals Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma

Blood ◽  
2018 ◽  
Vol 132 (24) ◽  
pp. 2546-2554 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Heather Sutherland ◽  
Darrell White ◽  
Michael Sebag ◽  
Suzanne Lentzsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Low Dose ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Nuclear Retention ◽  
Refractory Multiple Myeloma ◽  
Nuclear Export Protein ◽  
Grade 3 ◽  
Export Protein

Abstract Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once or twice weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy, and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in ≥10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). Incidence (4 patients, 10%) and grade (≤2) of peripheral neuropathy were low. The ORR for the entire population was 63%: 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI nonrefractory, and 6.1 months for PI refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once weekly), bortezomib (1.3 mg/m2 once weekly for 4 weeks), and dexamethasone (40 mg once weekly) per 35-day cycle. This trial was registered at www.clinicaltrials.gov as #NCT02343042.

scholarly journals FDA Analysis: Impact of Body Mass Index (BMI) on Outcomes in Relapsed-Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5505-5505
Author(s):  
Rachel Ershler ◽  
Bindu Kanapuru ◽  
Yutao Gong ◽  
Urvi A Shah ◽  
Sham Mailankody ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Body Weight ◽  
Board Of Directors ◽  
Research Funding ◽  
Small Sample Size ◽  
Univariate Analysis ◽  
Normal Weight ◽  
Small Sample ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma

Background: Obesity has been implicated as a risk factor for the development of certain types of cancers, including multiple myeloma (Wallin 2011). In a report published in NEJM in 2016, the relative risk of multiple myeloma for overweight to class 1 obese individuals was 1.2, versus a relative risk of 1.5 for class 2 to 3 obese individuals (Lauby-Secretan 2016). Recent reports indicate that BMI may impact prognosis in patients with newly diagnosed multiple myeloma (Beason 2013). Minimal information is available on impact of BMI and prognosis in patients with relapsed-refractory multiple myeloma. We analyzed the association between BMI and clinical outcomes in patients with relapsed/refractory multiple myeloma to determine if there is a difference in outcomes based on body weight. Methods: We conducted a retrospective analysis of four clinical trials evaluating novel therapeutics. These trials enrolled patients with relapsed/refractory multiple myeloma who had received one or more prior therapies. Patients were categorized into four groups, underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2) and obese (BMI >30.0 kg/m2). The Kaplan-Meier method was used to estimate progression free survival and overall survival. Results: A total of 2392 subjects were included in this analysis. The median age was 65 years (range 30-91 years). A total of 28 (1.2%) subjects were underweight, 733 (30.6%) were normal weight, 1032 (43.1%) were overweight, and 599 (25.0%) were obese. More of the underweight subjects were female (82.1%), whereas more of the overweight and obese subjects were male (62.9% and 56.6%, respectively). The median PFS and OS K-M curves are displayed below. In this univariate analysis, there were no differences in PFS (p=0.61) or OS (p=0.7) among the four groups. There were some differences in the underweight population; however, the small sample size of this group precludes any meaningful conclusions. Univariate analyses by gender did not reveal any differences in outcomes based on body weight. Conclusion: In patients with relapsed/refractory multiple myeloma, body weight had no impact on outcomes, as measured by PFS and OS. These results are consistent with previous findings on the effect of BMI on survival in subjects with multiple myeloma after autologous stem cell transplant (Kocoglu 2018). Limitations of this analysis include the use of a univariate analysis, the small sample size for patients who were underweight, heterogeneity in the treatment regimens, and immaturity of the OS data. Future studies are needed to evaluate other variables such as the relationship between cytogenetics and body weight, as well as analyses of safety based on body weight in this relapsed/refractory patient population. Figure Disclosures Shah: Physicians' Education Resource: Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Landgren:Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: 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, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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