PP455 Cost-effectiveness Of Ixazomib-Based Regimen Compared With Bortezomib-Based Regimen In Chinese Patients With Relapsed/Refractory Multiple Myeloma: A Retrospective Study

2020 ◽  
Vol 36 (S1) ◽  
pp. 36-37
Author(s):  
Pei Wang ◽  
Jing Li ◽  
Yang Yang ◽  
Peng Liu
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Staging System ◽  
Chinese Patients ◽  
Disease Stage ◽  
Control Group ◽  
Therapeutic Effects ◽  
Lower Grade ◽  
Refractory Multiple Myeloma ◽  
Grade 3

IntroductionThe treatment of relapsed/refractory multiple myeloma (RRMM), a common hematological malignancy, remains a great challenge in China, partially due to the limited accessibility to novel agents and inadequate public health insurance coverage. Ixazomib, a novel oral proteasome inhibitor (PI), was approved by the China Food and Drug Administration (CFDA) for RRMM in 2018. While bortezomib, a traditional PI, is the recommended agent in the clinical guideline for MM. Here, we compared their costs and effectiveness.MethodsRRMM patients who has received an ixazomib-based regimen (at least 2 cycles) were analyzed. Using a propensity score matching method, we generated a control group of RRMM patients who received the bortezomib-based regimen. The criteria included the number of treatment lines, age, and the revised international staging system stage (R-ISS) which representing the disease stage for myeloma, and paired at a ratio of 1:2 (allowing one control to match multiples). The difference in hospitalization stay, grade 3/4 adverse events rates, overall response rate (ORR), mortality during treatment, and treatment costs was then compared.ResultsNineteen patients received ixazomib and twenty-seven that received bortezomib were included. The ixazomib-group demonstrated a shorter hospital stay (9 days versus 27 days, p < 0.001), lower grade 3–4 adverse events rates (42.1% versus 55.6%, p < 0.001), higher ORR (63.2% versus 48.1%, p = 0.228), and lower mortality rate during treatment (0% versus 7.4%, p = 0.169) than that of bortezomib-group. The ixazomib group had lower total costs (127,620CNY versus 156,424CNY [18,033USD versus 22,103USD], p > 0.05), lower drug costs (98,376CNY versus 103,307CNY [13,901USD versus 14,598USD], p > 0.05), and the lower costs of supportive treatment (5,507CNY versus 14,701 CNY [778USD versus 2,077USD], p < 0.001). Only in terms of self-funded costs, the bortezomib-based regimen was significantly lower (37,127CNY versus 11,521CNY [5,246USD versus 1,628USD], p < 0.001).ConclusionsCompared with the bortezomib-based regimen, the ixazomib-based regimen has better therapeutic effects on MM patients while saving costs. Hence, it may be preferable for use in the treatment of RRMM in China.

Bortezomib in Combination with Dexamethasone and Subsequent Thalidomide for Newly-Diagnosed Multiple Myeloma in Chinese Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4827-4827
Author(s):  
Zhen Cai ◽  
Weiyan Zheng ◽  
Guoqing Wei ◽  
Xiujin Ye ◽  
Jingsong He ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Staging System ◽  
Primary Treatment ◽  
Chinese Patients ◽  
Newly Diagnosed ◽  
Overall Response ◽  
International Staging System ◽  
Grade 3

Abstract Background: Bortezomib-dexamethasone-thalidomide has been reported to be effective in newly-diagnosed multiple myeloma (MM) with an overall response rate of 92% and a CR rate of 18% (Alexanian et al, Hematology12(3):235–239, 2007), but this regimen has not been reported in Chinese patients. We now report our experience with this combination. Objectives: To investigate the efficacy and safety of bortezomib in combination of dexamethasone plus subsequent thalidomide as primary treatment for MM. Patients and Method: Between June 2006 and August 2007, 11 consecutive newly-diagnosed patients with symptomatic MM were treated with bortezomib at 1.3 mg/m2 IV on days 1, 4, 8 and 11, dexamethasone at 20 mg/m2 IV daily on the day of bortezomib and the day after. All patients received daily oral thalidomide that was escalated from 100 mg to 200 mg. Seven of 11 patients were male and 4 were female. Median age was 57 years (range 47–86). Seven of 11 patients were stage 2 according to the International Staging System, 4 out of 11 patients were stage 3. Eleven patients received a median of 2 cycles of therapy (range 1–6). The Blade criteria were used for response evaluation. Toxicities were evaluated according to the NCI Common Toxicity Criteria version 3. Results: Nine out of 11 patients (82%) achieved PR and 2 (18%) achieved CR; therefore the overall response rate was 100%. With a median follow-up duration of 5 months (1– 14 months), no patients died. Grade 3–4 toxicities included fatigue (3/11), thrombocytopenia (3/11), diarrhea (3/11) and orthostatic hypotension (2/11). Grade 2 neuropathy occurred in 3 out of 11 patients, herpes zoster occurred in 3 out of 11 patients. Routine anticoagulation or anti-thrombosis was not used. There was no DVT/PE in 11 patients. Conclusion: Our preliminary experience indicated that bortezomib-dexamethasone-thalidomide is highly effective in newly-diagnosed MM. Grade 3 and 4 toxicities were rare after median 2 cycles of therapy. The relative lower rates of neuropathy and DVT/PE in this report with Chinese MM patients are being cautiously observed.

Bortezomib (Velcade ™) Observational Study in China: Efficacy and Safety of Bortezomib-Based Regimen in 395 Relapsed or Refractory Multiple Myeloma Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5179-5179
Author(s):  
Zhi-Xiang Shen ◽  
Hua Yan ◽  
Linna Wang
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Observational Study ◽  
Response Rate ◽  
Complete Response ◽  
Chinese Patients ◽  
Efficacy And Safety ◽  
Female Ratio ◽  
Bortezomib Treatment ◽  
Grade 3

Abstract Introduction: Multiple myeloma (MM) is a plasma-cell malignancy and overall survival for patients who have relapsed after initial therapy is approximately 2 years. Bortezomib (VELCADE TM) is a first-in-class proteasome inhibitor that has demonstrated significant anti-tumor activity in MM patients. Here we report the results of an observational study of the efficacy and safety of bortezomib-based regimens in Chinese relapsed/refractory MM patients. Methods: This was a multi-center, open-label, phase IV observational study designed to enroll 550 patients with relapsed or refractory MM. From Mar 2006 to May 2008, 500 patients with relapsed or refractory MM were enrolled from 43 medical centers in China and 395 of them were evaluated. Bortezomib (0.7 to 1.6 mg/m2 i.v.) was given on days 1, 4, 8, and 11 in in a 21-day cycle, up to a maximum of 8 cycles, combined with other agents, mainly with the addition of dexamethasone (60.1%). Major endpoint included response rate, safety and time to response. Responses of 62% patients were determined by European Group for Blood and Marrow Transplantation criteria (EBMT). Bortezomib withheld if patients developed neutropenia fever, grade 4 haematologic adverse events (AEs), or grade 3 non-haematologic AEs, and re-administered at 75% of the initial dosage after recovery. Results: In 395 evaluable cases, the median age was 59 years (range 35–82) and the male/female ratio was 1.5:1. 90% of patients were in late stage(stage II/III) and 50% of them were IgG subtype. Patients had received various prior therapies before bortezomib treatment, including VAD (31.3%), VBMCP (M2, 15.1%) and thalidomide-based regimens(14.9%), with best response rate of 10.4% complete response (CR) and 42.3% partial response (PR) from prior therapies. 311 (82%) cases of patients received 1.0–1.4mg/m2 bortezomib-based regimens treatment and 38.5% of them received at least 4 cycles of treatment. 364 patients were evaluable for response, the overall response rate was 287/364 (78.8%), 89 patients (24.5%) achieved a CR, 30(8.24%) had a nearly complete response (nCR), 168 (46.2%) had a PR, 39 (10.7%) had minimal response (MR), 24 (6.6%) had stable disease (SD), and the other 14 (3.9%) had progressive disease (PD). Median time to response was 1 cycle of treatment (range 1–6). Patients who received 4 or more cycles of bortezomib treatment achieved a higher response rate (CR+PR: 81.5%) compared to those who received fewer cycles (partly due to adverse events). And prognosis-related analysis showed that the dosage of bortezomib at 1.0 mg/m2 or more had a significant influence on the time to response and response rate, but no obvious effect on response duration, time to progress or the survival time. Drug related adverse events (AEs) were reported in 50.4% of patients during treatment, including hematologic AEs (mainly thrombocytopenia, 22.5%), gastrointestinal AEs (24.8%), and peripheral neuropathy (22.5%). The rates of grade 3–4 AEs of them were 46.1%, 11.2% and 15.7%, respectively. Serious AEs occurred in 33 (8.4%) cases and 23 (70%) patients recovered finally. Most AEs were predictable and manageable. Conclusion: Bortezomib-based regimen is effective treatment with higher response rate and is well tolerated in most Chinese patients with relapsed and refractory MM patients. Long-term follow-up is continuing.

Effect of Disease Stage and Time Since Diagnosis on Time to Progression for Pegylated Liposomal Doxorubicin + Bortezomib vs Bortezomib Alone in Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2740-2740
Author(s):  
Heather J. Sutherland ◽  
Joan Blade ◽  
Jesus San Miguel ◽  
Arnon Nagler ◽  
Pieter Sonneveld ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Liposomal Doxorubicin ◽  
Pegylated Liposomal Doxorubicin ◽  
Staging System ◽  
Risk Groups ◽  
Phase Iii ◽  
Disease Stage ◽  
Time To Progression ◽  
Total Study Population ◽  
Refractory Multiple Myeloma

Abstract A recent report of a phase III randomized trial with pegylated liposomal doxorubicin (PLD)+bortezomib vs. bortezomib alone in relapsed or refractory multiple myeloma (RRMM) demonstrated improved time to progression (TTP) with PLD+bortezomib (Orlowski, JCO 2007). The present post-hoc analyses evaluated the efficacy of PLD+bortezomib according to International Staging System (ISS) disease stage, and time since initial myeloma diagnosis (TSD). Patients with ≥1 prior therapy were randomized to receive PLD at 30 mg/m2 on day 4 and bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11, or bortezomib alone for up to eight 21-day cycles, or at least 2 cycles beyond CR, or optimal response unless disease progression or unacceptable toxicities occurred. The improved TTP reported previously with PLD+bortezomib over bortezomib alone in the total study population was also observed in the higher risk groups based on disease stage (ISS 2 & 3; Table). TTP was also significantly longer with PLD+bortezomib vs. bortezomib for TSD >2 yrs despite more protracted disease. The therapeutic advantage of prolonged TTP with the PLD+bortezomib combination was maintained consistently across subgroups (heterogeneity tests: ISS 1 vs. 2 vs. 3, p=0.407; TSD ≤2 yrs. vs. >2 yrs., p=0.946). Incidence of grade 3/4 neuropathies was low (<10%) in the two treatment arms in all subgroups. PLD-related hand-foot syndrome was also <10% in all PLD+bortezomib subgroups. Despite high-grade disease or protracted disease history, the PLD+bortezomib combination shows significantly improved TTP as compared to bortezomib alone. Also, the combination therapy was well-tolerated.

scholarly journals Retrospective Analysis of the Efficacy and Safety of Modified Bortezomib-Lenalidomide-Dexamethasonelite (modified RVD-lite) Therapy for Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1961-1961
Author(s):  
Kiyoshi Okazuka ◽  
Tadao Ishida ◽  
Junichiro Nashimoto ◽  
Takao Yogo ◽  
Kanji Miyazaki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Staging System ◽  
Median Number ◽  
Al Amyloidosis ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Grade 3

Abstract [Background] Thecombination therapy consisting of bortezomib, lenalidomide and dexamethasone (RVD) for newly diagnosed multiple myeloma has been one of the standard induction therapies in recent years. However, 9-23 % of patients discontinued treatments because of severe adverse events in the previous reports (SWOG S077, IFM2009). Thus, it has not been clarified ifthe dosing schedule of RVD is appropriate. Here, we investigated the efficacy and safety of modified RVD-lite for 45 transplant eligible patients with newly diagnosed multiple myeloma (NDMM). [Patients and methods] We retrospectively analyzed 45 transplant eligible patients with NDMM who received modified RVD-lite for induction therapy between February 2016 and March 2018. The median age was 58 years old (range 36~66), and 6 (13.3%) patients were AL amyloidosisassociated with multiple myeloma. Patients received bortezomib 1.3 mg/m2once weekly subcutaneous (SC) on days 1, 8, 15, 22, lenalidomide 15 mg/day on days 2-7, 9-14, 16-21 and dexamethasone 40mg on days 1, 8, 15, 22. The Revised International Staging System (R-ISS) wereI in 13 (28.9%), II in 30 (66.7%) and III in 2 (4.4%). High-risk cytogenetics, defined as the presence of deletion 17, t(4;14) and t(14;16) by FISH analysis, were identified in 5 (11.1%) patients. After 4 cycles of modifiedVRd-lite, we evaluated the efficacy and adverse events. [Results] The overall response rate (ORR) after four 28-day cycles of modifiedRVD-lite was obtained in 41 (91.1%), including sCR in 6 (13.3%) and CR in 5 (11.1%). SD and PD were observed in 2 patients (4.4%) and 1 patient (2.2%), respectively. One patient was not evaluated efficacy, because a patient changed modifiedRVD-lite to ixazomib, lenalidomideand dexamethasone therapy for grade 3 peripheral neuropathy. Thirty-eight of 45 patients (84.4%) received autologous stem cell transplantation (ASCT) after at least 4 courses of modifiedVRd-lite. The median number of CD34+cells/kg collected was 4.83 x 106(range, 1.1-11.9). All patients received melphalan at doses of 200 mg/m2. In these patients, response after ASCT were sCR in 15(41.7%), CR in 2 (5.6%), VGPR in 8 (22.2%) and PR in 8 (22.2%). Three of seven patients who did not received ASCT will receive ASCT ina few months. Among other 4 patients who did not receive ASCT, 2 patients chose other therapies without ASCT, and 2 patients could not receiveASCT because they showed no improvement in cardiac AL amyloidosis. Grade 3 or higher adverse events (AEs) were observed in 17 (37.8%). Most frequent grade 3 or higher AE was neutropenia (grade 3:17.8%, grade 4:6.7%). Only one patient (2.2 %) discontinued modifiedRVD-lite because of grade 3 peripheral neuropathy. [Conclusions] The ORR after 4 cycles ofmodifiedRVD-lite was high (91.1%). These results might be related to low rate of discontinuation of treatment. Also, the ORR after ASCT was comparable to the results previously published (N Engl J Med .2017 Apr 6:376(14):1311). AEs in modified RVD-lite were feasible and manageable in most patients. Our results suggest that modifiedRVD-lite is very feasible and effective treatment for patients with transplant eligible NDMM. Disclosures Suzuki: Sanofi Aventis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ono: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; SRL.Inc: Employment.

Clinical Efficacy of a Bortezomib, Cyclophosphamide and Dexamethasone Compared with Bortezomib, Cyclophosphamide, Thalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1868-1868
Author(s):  
Jae-Sook Ahn ◽  
Deok-Hwan Yang ◽  
Joon Ho Moon ◽  
Sang Kyun Sohn ◽  
Sung-Hoon Jung ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Herpes Zoster ◽  
Partial Response ◽  
Adverse Events ◽  
Conflicts Of Interest ◽  
Sensory Neuropathy ◽  
Salvage Regimen ◽  
Refractory Multiple Myeloma ◽  
Grade 3 ◽  
Acyclovir Prophylaxis

Abstract Abstract 1868 Backgrounds & Aims: Salvage therapy such as bortezomib, cyclophosphamide, thalidomide and dexamethasone (Vel-CTD) showed an effective regimen in patients with relapsed or refractory multiple myeloma (MM). However, toxicities of this regimen due to combination bortezomib and thalidomide interrupt the consecutive treatments in a few patients. Therefore, we compared the clinical responses and toxicities between bortezomib, cyclophosphamide and dexamethasone (Vel-CD) and Vel-CTD in patients with relapsed or refractory MM patients, retrospectively. Methods: Eighty-six patients received at least 2 cycles of treatment with Vel-CTD (bortezomib 1.3 mg/m2 i.v. on D1, 4, 8 and 11; cyclophosphamide 150 mg/m2 orally on D1-4; thalidomide 50 mg/day orally every day; and dexamethasone 20 mg/m2 i.v. on D1, 4, 8 and 11 for every 3 weeks) and 67 patients with Vel-CD, which is the same regimen except thalidomide. Vel-CD group was only received low-dose acyclovir for prevention of herpes zoster. Results: 17/67 (25%) and 10/86 (12%) of light chain disease was enrolled in Vel-CD and Vel-CTD group respectively (p=0.027) and there was no statistical difference at baseline demographic and disease characteristics between two groups in the others. The median time from diagnosis to treatment in Vel-CD and Vel-CTD was 15.6 months (range, 2–250 months) and 15.7 months (range, 1–230 months), respectively (p=0.54). The median number of treatment cycles was 6 cycles (range, 2–18) in Vel-CD and 8 cycles (range, 2–24) in Vel CTD group, and the number of cycles delivered was 430 and 678, respectively. The overall response rates (≥PR) of Vel-CD and Vel-CTD group were 88% and 90% ( 49% and 48% of complete response, 9% and 14% of very good partial response, 30% and 28% of partial response), respectively (each, p>0.05). There was no difference in progression free survival (p=0.69) and overall survival (p=0.49). Grade 3 or more hematologic adverse events occurred in the same proportion of patients in the both group. In non hematologic toxicities profiles, Vel-CTD group (14%) showed the higher proportion of grade 3 or more sensory neuropathy compared with Vel-CD group (3%) (p=0.02). Dose adjustment of bortezomib in Vel-CD and Vel-CTD were 40% (27/67) and 41%(35/86), respectively (p=0.96). Two patients (3%) in Vel-CD group received acyclovir prophylaxis developed herpes zoster compared with 17 patients (20%) in Vel-CTD group they were not received acyclovir prophylaxis (p=0.002). Three patients showed thrombotic events (2: pulmonary thromboembolism, 1: acute myocardial infarction) in only Vel-CTD group despite aspirin prophylaxis (p=0.16). Conclusion: Vel-CD combination therapy in patients with relapsed or refractory MM is an effective and more tolerable salvage regimen compared with Vel-CTD in the aspect of comparable response rate, less non-hematologic toxicities especially thalidomide associated adverse events. Disclosures: No relevant conflicts of interest to declare.

A Phase I Study of Ixazomib in Combination with Panobinostat and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4221-4221 ◽  
Author(s):  
Frederic J. Reu ◽  
Jason Valent ◽  
Ehsan Malek ◽  
Ronald M. Sobecks ◽  
Beth M Faiman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Proteasome Inhibitor ◽  
Research Funding ◽  
Response Criteria ◽  
Additional Patient ◽  
Cardiac Events ◽  
Minor Response ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Background: In a pivotal trial addition of panobinostat at 20mg three times a week, two weeks on, one week off, to bortezomib and dexamethasone increased progression-free survival of relapsed or relapsed and refractory multiple myeloma (MM) but clinically significant adverse events, including severe diarrhea and unexpected cardiac events limited enthusiasm. Here we describe safety and preliminary efficacy data for an all-oral regimen that uses ixazomib as proteasome inhibitor and every other week dosing of panobinostat. Methods: Two dose levels (DL) of ixazomib (3mg, 4mg) given on day 1, 8, 15 every 28 days were evaluated in combination with panobinostat 20mg on day 1, 3, 5, 15, 17, 19 and dexamethasone 20mg day 1, 2, 8, 9, 15, 16 using a classical 3 x 3 design. Inclusion criteria included at least two prior regimens, previous therapy with a proteasome inhibitor and IMiD, measurable disease according to uniform response criteria, and adequate organ function with QTcF < 450msec and estimated creatinine clearance of at least 30ml/min. Results: Eleven patients (pts) of median age 65 (range 50-73), all with MM refractory to their last regimen, were enrolled after a median of 5 prior regimens (range 2-10). Their disease was refractory to lennalidomide (n=11), bortezomib (n=10), proteasome inhibititor with IMiD (n=9), carfilzomib (n=7), and alkylating chemotherapy (n=7). The target dose level 2 was reached without dose limiting toxicity (DLT). Median time on therapy as of July 21, 2015 is 54 days (range 21-183) including three pts who remain on study. No serious adverse event was observed and no dose reductions of panobinostat or ixazomib were required. No non-hematologic CTCAE v. 4.03 grade 3/4 toxicities were seen but 3 pts developed grade 3 hematologic toxicities (2 neutropenia, 1 thrombocytopenia). Worst diarrhea was grade 1 (n=6), worst nausea grade 2 (n=1) and 4 additional pts developed transient grade 1 nausea. Other possibly panobinostat or ixazomib related grade 1/2 adverse events included thrombocytopenia (n=5), neutropenia (n=3), fatigue (n=2), anemia (n=2), anorexia (n=1) and arthralgia (n=1). Median QTcF before treatment start was 405 msec (range 378-430) and increased on average by 4.3% (maximally by 13%). One patient developed transient grade 1 QTcF prolongation to 552 msec. No other cardiac adverse events were observed. Best response according to uniform response criteria with adapted EBMT criteria for minor response (MR) was MR in 3 pts, of whom two had disease progressive on proteasome/IMiD combinations at study entry. One MR is ongoing; the other two each lasted 6 months. One additional patient had stable disease for 6 months. Conclusions: Addition of panobinostat at 20mg three times a week every other week to ixazomib at target 4mg weekly, three weeks on, one week off, with dexamethasone 20mg on the day of and after ixazomib was very well tolerated and demonstrated activity in extensively pretreated multiple myeloma patients with progressive disease on proteasome/IMiD combinations. We therefore propose this regimen for phase 2 evaluation. Disclosures Reu: Celgene: Research Funding; Takeda/Millennium: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and Ixazomib combined in myeloma. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faiman:Celgene: Consultancy, Speakers Bureau; Amgen/Onyx: Consultancy; Takeda/Millennium: Consultancy. Hamilton:Takeda/Millennium: Speakers Bureau. Smith:celegene, spectrum, genentech: Honoraria.

scholarly journals Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone As Salvage Therapy in Relapsed/Refractory Multiple Myeloma: Results of a Safety Run-in Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3117-3117 ◽  
Author(s):  
Caitlin L. Costello ◽  
Michelle Padilla ◽  
Edward D. Ball ◽  
Carolyn Mulroney
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Residual Disease ◽  
Refractory Multiple Myeloma ◽  
Overall Response ◽  
Grade 3 ◽  
Observation Period

Background: Triplet combination strategies have widely been accepted as the standard of care for the management of multiple myeloma due to improved outcomes as compared to doublets. The combination of daratumumab, pomalidomide and dexamethasone (DPd) has previously demonstrated deep and durable responses, including high rates of MRD negativity, in a heavily pretreated patient population. Quadruplet regimens offer an opportunity to further improve upon these results. We report preliminary findings from an ongoing phase 2 multicenter trial of the addition of ixazomib to the combination of DPd in patients with relapsed/refractory multiple myeloma. The primary objective is to determine overall response rate and the safety and tolerability of this novel regimen. Key secondary endpoints include PFS, OS and MRD negativity rates. Methods: Eligible patients may have received ≥1 and ≤3 prior lines of therapy, have had no prior exposure to daratumumab or ixazomib, and may have not progressed on prior pomalidomide. Patients receive daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg PO days 1-21/28, ixazomib 4mg PO days 1,8,15 every 28 days, and dexamethasone 40mg PO weekly. Patients continue on therapy until disease progression, intolerability or preference. Dose-limiting toxicities (DLT) were defined as grade 3-4 hematologic adverse events (AE) or any AE that required a dose modification of pomalidomide or ixazomib at the lowest dose levels on a dose de-escalation plan. An interim safety review was performed after the first 6 patients were enrolled and completed the DLT observation period, which is the first cycle (28 days) since the start of a new dose level of pomalidomide and/or ixazomib. Results: At the time of this analysis, six patients have been enrolled and treated, and completed the DLT observation period. Patients had a median age of 62 (range 52-65) and median number of 2 prior lines of therapy (range 1-2). All patients were refractory to lenalidomide and pomalidomide-naïve. Common adverse events (AEs) included neutropenia, thrombocytopenia, GI upset, and upper respiratory infection. Grade 3-4 AEs were predominantly hematologic including neutropenia and thrombocytopenia, but also included grade 3 hypertension in 1 patient, and grade 3 hypophosphatemia, grade 4 hypokalemia, and grade 3 small bowel infection in 1 patient. No IRR > grade 2 occurred with daratumumab administration. No DLTs occurred in the first six patients in the safety run-in. The overall response rate of the cohort is 100% with 3 patients achieving a stringent complete response (CR), and 3 patients achieving a very good partial response (VGPR) after a median of 7 cycles of treatment. One patient discontinued therapy due to influenza A, the other five remain on therapy. Minimal residual disease assessments are being performed by EuroFlow for patients in VGPR or better due to concern for daratumumab interference. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Conclusion: The quadruplet regimen DIPd in patients with relapsed/refractory myeloma is a well-tolerated combination and has shown early safety in an initial safety run-in analysis. Enrollment continues in an expansion cohort to assess efficacy at multiple sites with the University of California Hematologic Malignancies Consortium. Figure Disclosures Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

Bortezomib (Velcade™) Observational Study in China - Efficacy and Safety of Bortezomib Based Regimen in 223 Relapsed or Refractory Multiple Myeloma Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4833-4833
Author(s):  
Zhi-xiang Shen
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Observational Study ◽  
Initial Dosage ◽  
Complete Response ◽  
Chemotherapeutic Agents ◽  
High Response Rate ◽  
Chinese Patients ◽  
Open Label ◽  
Grade 3

Abstract Introduction: Multiple myeloma (MM) is a plasma-cell malignancy with approximately three years’ median survival. Patients usually relapse or become refractory to existing treatments. Clinical studies have confirmed that bortezomib is an effective agent for relapsed MM patients and has potent synergy with other chemotherapeutic agents, which provides a new clinical regimen that may improve response. In this observational study, we intend to observe the safety/tolerability and efficacy of bortezomib-based regimens in Chinese patients with relapsed/refractory MM. Methods: This was a multicenter, open-label, phase IV observational study for patients with relapsed or refractory MM. Bortezomib (0.7 to 1.6 mg/m2 i.v.) was given on days 1, 4, 8, and 11 of a 21-day cycle, for a maximum of 8 cycles, combined with other agents, mainly of dexamethasone addition. If pyretic neutropenia, grade 4 hematologic adverse events (AEs), or grade ≥3 non-hematologic AEs developed, bortezomib treatment was temporarily discontinued and re-administered at 75% of the initial dosage after remittance of the AEs. Responses were classified mainly by European Group for Blood and Marrow Transplantation criteria (EBMT). Results: Between Mar 2006 and May 2007, 223 patients with MM were enrolled at 31 medical centers. Median age was 58 years (range 35–82), 96% of patients were in stage II/III, and the most common subtype was IgG (46%). Patients had received various prior therapies such as VAD (29% of patients), VBMCP (M2) (16%), and thalidomide combinations (15%). There were 198 patients evaluable for response, of whom 54 (27%) achieved a complete response (CR), 99 (50%) achieved a partial response (PR), 20 (10%) had minimal response (MR), 16 (8%) had stable disease (SD), and the other 9 (5%) had progressive disease (PD). Patients who received 4 or more cycles of bortezomib achieved a higher CR rate (56%) compared with patients who received fewer cycles (partly due to adverse event). Rapid responses were seen with the median time to response being 1 cycle (range 1–5). Common predictive factors including age, isotype, number of previous therapies, concentration of C-reactive protein, or beta2-microglobulin had no significant influence on treatment response. The incidence of adverse events (AEs) was 54%, including 18% of patients with hematologic AEs (33% of them grade 3–4), 27% with gastrointestinal AEs (50% of them grade 3–4), and 20% with peripheral neuropathy (40% of them grade 3–4). Serious AEs occurred in 25 (11%) patients. Most AEs were predictable and manageable. Conclusions: These data demonstrate that a bortezomib-based regimen is a promising regimen with high response rate and is well tolerated in most relapsed and refractory MM patients. Additional clinical trials and long-term follow-up on Chinese patients are warranted.

scholarly journals Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14)

2021 ◽  
pp. JCO.21.00443
Author(s):  
Nizar J. Bahlis ◽  
Rachid Baz ◽  
Simon J. Harrison ◽  
Hang Quach ◽  
Shir-Jing Ho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Phase I ◽  
Phase I Study ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Grade 3

PURPOSE Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab. METHODS This phase I study ( NCT03314181 ) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity. RESULTS Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd. CONCLUSION VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

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