scholarly journals Carfilzomib Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5588-5588
Author(s):  
Maimoona Khan ◽  
Asma Waheed ◽  
Rida Ul Jannat ◽  
Arafat Ali Ali Farooqui ◽  
Muhammad Saad Farooqi ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Effect ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Induction Therapy ◽  
Drug Combination ◽  
Alkylating Agents ◽  
Adverse Effect Profile ◽  
Newly Diagnosed ◽  
Grade 3

Background: Carfilzomib (Car), a second-generation proteasome inhibitor (PI), has been approved by the US Food and Drug Administration (FDA) as therapy for relapsed and /or refractory multiple myeloma (RRMM), either as a single agent or in combination with other agents. It has proven to be superior in many ways compared to the the first generation PI, bortezomib, both in terms of superior efficacy and neuropathy related adverse effect profile. Carfilzomib has lower rate of peripheral neuropathy. In this review, we gathered data from trials which studied Carfilzomib for newly diagnosed MM (NDMM). Carfilzomib based two and three drug combination as induction regimens for the management of NDMM is an emerging approach. Through this systematic review, we explore efficacy, adverse effect profile of Car based regimens for NDMM. Methods: Per PRISMA guidelines, a thorough database search was conducted on 06/24/2019 using the following search engines; PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov. We included all published trials that used carfilzomib as an induction agent in NDMM patients and had at least response rates after induction. Results: The total number of articles identified with initial search were 1131, out of which 19 articles met our selection / eligibility criteria (n=2286). The overall response rates (ORR) after induction therapy with carfilzomib based regimens was very impressive (range: 84.3% - 100%). Two drug combination using carfilzomib and dexamethasone (n=72) had an ORR of 90% and a greater than very good partial response rate (>VGPR) of 84%. Three drug combinations used for induction therapy included carfilzomib/dexamethasone with immunomodulators (n=391) and alkylating agents (n=308). The combination of carfilzomib/dexamethasone with lenalidomide (n=189, ORR: 97% - 98%, >VGPR: 69% - 98%) and thalidomide (n=202, ORR: 90% - 94%, >VGPR: 66% - 68%) showed the best response. Alkylating agents used in combination with carfilzomib were melphalan (n=98, ORR: 90% - 93%, >VGPR: 58% - 70%), cyclophosphamide (n=192, ORR: 87% - 95%, >VGPR: 39% - 71%) and bendamustine (n=18, ORR; 100%, >VGPR: 89%). Four drug combinations with carfilzomib used were daratumumab/lenalidomide/dexamethasone (n=22, ORR: 100%, >VGPR: 90%, 12m PFS: 95%) and cyclophosphamide / thalidomide / dexamethasone (n=64, ORR; 91%, >VGPR: 69%, 24m PFS: 76%). One trial directly compared carfilzomib/melphalan/dexamethasone (n=478, ORR: 84%, >VGPR: 61%, PFS: 22.3m) with bortezomib/melphalan/dexamethasone (n=477, ORR: 79%, >VGPR: 49%, PFS: 22.1m). Another trial compared the combination of carfilzomib / dexamethasone with lenalidomide (n=315) or cyclophosphamide (n=159) that showed similar ORR (97% vs 91%) though >VGPR rate was better with lenalidomide (75% vs 60%). Efficacy data including progression free survival (PFS) for carfilzomib based regimens is reported in table 1. Most common >grade 3 hematological adverse effects reported were anemia (2% - 35%), lymphopenia (5% - 76%), thrombocytopenia (4% - 28%) and neutropenia (1% - 38%). Most Common >grade 3 non-hematological adverse events included cardiac events (5% - 10%), respiratory disorders (8% - 16%), infections (2% - 9%), hypertension (6% - 17%), renal events (9% - 10%) and hyperglycemia (6% - 23%). (Table 1) Conclusion: The overall efficacy and favorable adverse effect profile of Carfilzomib-based induction regimens seem very promising for the treatment of NDMM. Car is now approved for weekly dosing which is convenient. Due to cardiovascular toxicity seen in upto 10% cases, Car should be used very judiciously in patients with cardiovascular risk factors and heart failure. Several ongoing phase 3 clinical trials are studying Carfilzomib in various combinations will help to establish foundation for future standard therapy as well as next phase of drug development through clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Safety and Efficacy of Four Drug Versus Three Drug Regimens Among Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Saad Ullah Malik ◽  
Nazma Hanif ◽  
Priyanka Kumari ◽  
Khadija Noor Sami ◽  
Chase Warner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Randomized Clinical Trials ◽  
Standard Of Care ◽  
Drug Regimen ◽  
P Value ◽  
Newly Diagnosed ◽  
Drug Regimens ◽  
Grade 3

Introduction: During recent years there has been a boom in the availability of treatments for multiple myeloma (MM). Based on the status of disease (newly diagnosed or relapsed/refractory), several regimens have successfully improved progression free survival (PFS) and overall survival (OS) in these two types of patients. Triple drug regimen is considered the current standard of care for newly diagnosed MM patients. However, with the advent of four drug regimens, some studies demonstrated a significant improvement in PFS and OS compared to standard of care where as others showed marginal to no difference. Also, it remains unclear whether the benefits of using four drug regimen outweigh the risks. Thus, the aim of our meta-analysis was to compare the efficacy and safety of four drug versus three drug regimens among newly diagnosed multiple myeloma patients. Methods: We built a PICO based search strategy using keywords like "multiple myeloma", "randomized clinical trials" and ran literature search on PubMed, Embase, Wiley Cochrane Library, Web of Science and ClinicalTrials.gov ranging from the date of inception till 16th July, 2020. A pre-validated data extraction sheet was used to extract data on PFS, OS and ≥Grade 3 hematologic adverse events at the longest follow-up. We included only randomized clinical trials (RCTs) comparing four versus three drug regimen in newly diagnosed MM patients. We excluded studies other than RCTs, studies conducted on relapsed refractory MM patients or other plasma cell dyscrasias. A generic variance weighted random effects model (DerSimonian and Laird) was used to derive hazard ratio estimates along with their 95% confidence intervals (CIs) for PFS and OS. Risk ratio along with its 95% CIs was estimated for Grade ≥3 hematologic adverse events. Heterogeneity was assessed with Cochrane Q -statistic and was quantified with I2 test (I2 >50% was consistent with a high degree of heterogeneity). A pre-specified sensitivity analysis was also performed for risk of adverse events. Cochrane Collaboration's tool was used to assess the quality of included RCTs and GRADE was used to rate the quality of evidence. Results: Initial search retrieved 7622 titles. After duplicate removal, 4880 articles were left. Following initial screening, 58 articles were considered for full text review. Of these only 3 studies (n=2277) met inclusion criteria. Four drug regimens included daratumumab, bortezomib, melphalan-prednisone (D-VMP), daratumumab, bortezomib, thalidomide-dexamethasone (D-VTd) and bortezomib and melphalan prednisone and thalidomide (VMPT-VT) respectively. Whereas, three drug regimens were bortezomib, melphalan-prednisone (VMP), bortezomib, thalidomide-dexamethasone (VTd) and bortezomib, melphalan and prednisone (VMP) respectively. There was a significant improvement in PFS when 4 vs 3 drug regimens were compared in patients with newly diagnosed MM (HR: 0.53, 95% CI: 0.46-0.62, p-value:<0.001, I2: 0%). Also, OS improved significantly in four drug regimen group (HR: 0.62, 95% CI: 0.51-0.76, p-value:<0.001, I2: 3.5%). There was no statistically significant difference in any grade ≥3 hematologic adverse events when 4 vs 3 drug regimens were compared (RR: 1.26, 95% CI: 0.93-1.73, p-value:0.14, I2: 93%). Sensitivity analysis after removing D-VTd regimen from any grade ≥3 hematologic adverse events revealed similar results (RR: 1.05, 95% CI: 0.97-1.13, p-value:0.23, I2: 23%) confirming the robustness of analysis. When each hematologic adverse event was looked at separately, there was no difference between 4 vs 3 drug regimen in rates of anemia (RR: 0.99, 95% CI: 0.76-1.28, p-value:0.92, I2: 0%), neutropenia (RR: 1.39, 95% CI: 1.00-1.94, p-value:0.05, I2: 85%) and thrombocytopenia (RR: 1.13, 95% CI: 0.92-1.39, p-value:0.24, I2: 33%). There was low risk of bias and strength of evidence was of moderate. Conclusion: Using four drug regimens, compared to three drug regimens, significantly improves PFS and OS among newly diagnosed multiple myeloma patients without any difference in the risk of ≥3 grade hematologic adverse events. Further randomized clinical trials are required to establish four drug regimen as standard of care for patients with newly diagnosed multiple myeloma. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Venous Thromboembolism with Contemporary Lenalidomide-Based Regimens and Adequate Thromboprophylaxis in Newly Diagnosed Multiple Myeloma: A Systemic Review and Meta-Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4835-4835
Author(s):  
Rajshekhar Chakraborty ◽  
Saad Ullah Malik ◽  
Naimisha Marneni ◽  
Alex V. Mejia Garcia ◽  
Faiz Anwer ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Phase I ◽  
Low Dose ◽  
Meta Analysis ◽  
Combination Regimen ◽  
Newly Diagnosed ◽  
Combination Regimens

Abstract Background: Lenalidomide (Len) and low-dose dexamethasone (dex) in combination with proteasome inhibitor (PI) or cytotoxic agent is an integral part of front-line therapy in multiple myeloma (MM). Use of Lenalidomide (Len) in MM had demonstrated an increased risk of venous thromboembolism (VTE) in initial studies which led to the incorporation of routine thromboprophylaxis with Len-based regimens. Existing estimate of VTE incidence from a prior analysis on Len-based regimens in newly diagnosed MM is 0.8 per 100 patient-cycles [Carrier et al. 2011]. However, there is a gap in literature on the incidence of VTE in patients receiving contemporary Len-based combination regimens along with adequate thromboprophylaxis. Hence, we conducted a systematic review and meta-analysis of clinical trials to assess the incidence of VTE with Len-based regimens in newly diagnosed MM patients. Method: We queried Ovid Medline, Ovid Embase and Cochrane Library databases to obtain relevant studies until March 2018. We included all phase I-III clinical trials testing a Len-based combination regimen for induction +/- consolidation therapy along with protocol-mandated thromboprophylaxis. VTE was defined as deep vein thrombosis or pulmonary embolism (CTCAE Grade 2 or above). Our primary outcome was pooled incidence of VTE events per patient-cycle, which was subsequently converted to VTE events per 100 patient-cycle for ease of comparison with existing literature in MM. We performed meta-analyses with random-effects model using a comprehensive meta-analysis software. Heterogeneity was calculated using I2 statistic and a value <25% was considered negligible, up to 50% moderate, and ≥70% was considered substantial heterogeneity. The protocol for this systematic review is registered with PROSPERO [CRD42018102971]. Results: Initial search generated 1069 citations. After screening, 15 clinical trials with 3381 patients were included. Among 15 trials, 4 were phase I/II, 6 were phase II and 5 were phase III. All but one trial used low-dose dex. The pooled incidence of VTE events was 0.4 per 100 patient-cycles [95% CI. 0.3-0.5; I2: 70%]. Incidence rate of VTE in individual studies are summarized in Table I. The Forest Plot is shown in Figure I. Subsequently, we performed pre-specified subgroup analyses on trials with Len-dex, Len-dex + PI, Len-dex + doxorubicin and Len with Melphalan-Prednisone (MPR). The pooled incidence of VTE per 100-patient cycle with Len-dex was 0.3 [95% CI. 0.1-0.4; I2:92%], Len-dex with PI was 0.9 [95% CI. 0.3-1.6; I2: 69%], Len-dex with doxorubicin was1.5 [95% CI. 0.7-2.2; I2: 0%] and MPR was 0.3 [95% CI. 0.2-0.4; I2: 0%]. Notably, the incidence of VTE was higher with Carfilzomib-Len-dex when compared to Bortezomib-Len-dex regimens. Two trials with Len-dex + Doxorubicin had a higher rate of VTE irrespective of the dex dose. The most common modes of thromboprophylaxis used were ASA (range, 70-325 mg) and low molecular weight heparin. Conclusion: Patients with newly diagnosed MM receiving contemporary Len-based regimens have a significant incidence of VTE despite adequate thromboprophylaxis. However, the incidence rate compares favorably with prior estimate. The rate of VTE was highest with the use of Len-dex + Doxorubicin triplet regimen. In the Len-dex+PI subgroup, the incidence of VTE was higher in trials using Carfilzomib-Len-dex compared to Bortezomib-Len-dex regimen. These findings can be clinically applied at an individual level to choose a Len-based combination regimen based on the risk of thrombosis. New prophylactic agents like direct oral anticoagulants should be tested to further decrease the rate of VTE with Len-based combination regimens. Disclosures Khorana: Janssen: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Bayer: Consultancy. Majhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Atara: Honoraria.

scholarly journals Efficacy and Safety of Histone Deacetylase Inhibitors in Multiple Myeloma - a Systematic Review of Early Phase Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5629-5629
Author(s):  
Sharoon Samuel ◽  
Muhammad Junaid Tariq ◽  
Muhammad Usman ◽  
Amna Khalid ◽  
Muhammad Asad Fraz ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Phase I ◽  
Hdac Inhibitors ◽  
Complete Response ◽  
Number Of Patients ◽  
Grade 3 ◽  
Early Phase Clinical Trials

Abstract Introduction Recent studies in novel therapies have created opportunities for new treatment regimens to be used in the management of multiple myeloma. Histone deacetylase (HDAC) inhibitors lead to epigenetic manipulation of multiple myeloma (MM) cells by reducing resistance to pro-apoptotic signals. Panobinostat is an FDA approved HDAC inhibitor for multiple myeloma. The aim of this article is to study the safety, efficacy and dose limiting toxicities of HDAC inhibitors in the early phase clinical trials in multiple myeloma. Methods We performed a comprehensive literature search for phase I & I/II trials of HDAC inhibitors during last ten years using following databases: PubMed, Embase, AdisInsight, and Clinicaltrials.gov. Studies involving HDAC inhibitors in multiple myeloma other than panobinostat irrespective of the age, sex or specific eligibility criteria were included. Results Out of 2537 studies, we included 25 trials (23 phase I, 2 phase I/II) of HDAC inhibitors in this systematic review having a total of 518 patients. Of these, 471(90.9%) patients were evaluable for response. Vorinostat (Vor) is the most studied drug used in 13 trials (n=281). Two trials had Vor-only regimen and the remaining 11 had combination regimens mostly with lenalidomide and bortezomib. Vor, in combination with lenalidomide (R), bortezomib (V) and dexamethasone (d) has showed 100% overall response rate (ORR) in 30 newly diagnosed multiple myeloma (NDMM) patients, (Kaufmann et al., 2016), fifty two percent patients achieved very good partial response (VGPR) and 28% patients showed complete response (CR). Another study using Vor + R regimen after autologous stem cell transplant in 16 NDMM patients showed VGPR in 7, stringent complete response (sCR) in 4, partial response (PR) in 2 and CR in 3 patients (Sborov et al.). Grade 3 neutropenia was seen in 1 patient in this study. Richter et al, 2011 showed an ORR of 24% in 29 relapsed refractory multiple myeloma (RRMM) patients with Vor only regimen. Another study (Kaufmann et al., 2012) with Vor only regimen used in 10 RRMM patients showed stable disease (SD) in 9 and minimal response (MR) in 1 patient. ORR of 65% was achieved in 31 RRMM patients receiving Vor in combination with doxorubicin & bortezomib (Vorhees et al, 2017). Thrombocytopenia & neutropenia were reported in 94% and 59% patients respectively. Ricolinostat in combination with Rd and Vd achieved an ORR of 55% and 29% respectively in two studies with 38 and 57 evaluable patients (NCT01583283, NCT01323751). Another ricolinostat regimen with pomalidomide & dexamethasone achieved ≥PR in 6/11 RRMM patients (Madan et al., 2016). Table 1 illustrates the efficacy, number of patients and regimens used in all the studies in this systematic review. Quisinostat in a 2017 study by Moreau P et al. (NCT01464112) showed an ORR of 88% in a combination regimen with Vd in RRMM patients (N=18). Drug related adverse events were seen in 13 patients, thrombocytopenia being most common in 11 patients, 2 patients had grade 3 cardiac disorders and 1 patient had a cardiac arrest. Romidepsin in a phase I/II study (Harrison et al., 2011) combined with Vd was used in 25 RRMM patients. ORR was 60% with VGPR n=7, CR n=2, PR n=6, SD n=5 and PD n=1. Grade ≥3 thrombocytopenia in 16, neutropenia in 9 and peripheral neuropathy in 2 patients was seen. Popat et al used combination of two HDAC inhibitors CHR 3996 and tosedostat in 20 RRMM patients. ORR was 10% and SD was seen in 30% patients. Grade 3/4 toxicities seen were thrombocytopenia (n=12), leukopenia (n=6) and diarrhea (n=5). A phase I study on AR-42 drug in 17 RRMM patients (Sborov et al., 2017) showed SD in 10, PD in 4, MR in 3 patients with progression free survival (PFS) of 8.2 months. Thrombocytopenia, neutropenia and lymphopenia were seen in 11, 10 and 6 patients respectively. A detail of all grade 3 and higher adverse events along with dose limiting toxicity is given in table 2. Three trials (NCT02576496, NCT01947140, NCT03051841) of Edo-S101, romidepsin and CKD-581 are currently recruiting with 84, 93 and 18 planned number of patients. Conclusion Regimens containing vorinostat have shown an ORR up to 100% in NDMM patients. HDAC inhibitors have also shown promising efficacy up to 88% ORR in RRMM population. Majority of the patients developed cytopenias as hematological adverse events. Disclosures No relevant conflicts of interest to declare.

A Randomized Phase 3 Trial Of Melphalan-Lenalidomide-Prednisone (MPR) Or Cyclophosphamide-Prednisone-Lenalidomide (CPR) Vs Lenalidomide Plus Dexamethsone (Rd) In Elderly Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 536-536 ◽  
Author(s):  
Antonio Palumbo ◽  
Valeria Magarotto ◽  
Sara Bringhen ◽  
Massimo Offidani ◽  
Giuseppe Pietrantuono ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Alkylating Agents ◽  
Second Primary ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Significant Difference ◽  
Grade 3 ◽  
To Receive

Abstract Background Rd and MPR are effective treatments in newly diagnosed multiple myeloma (NDMM) patients (pts). In this study we compared a non-alkylating containing regimen (Rd) vs alkylating-based regimens (MPR/CPR) in elderly transplant ineligible NDMM pts. Methods Patients were randomized (2:1) to receive nine 28-day cycles of MPR/CPR or Rd. MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days; CPR: cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day (eod) in >75 years pts; lenalidomide 25 mg/day for 21 days; prednisone 25 mg every other day. Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years. After induction, patients were randomized to receive maintenance with lenalidomide alone (10 mg/day for 21 days) or with prednisone (25 mg eod on days 1-28), until disease progression. The primary endpoint was progression-free survival (PFS). Results Between October 2009 and October 2012, 659 pts were enrolled ( MPR/CPR:439 and Rd:220), and 641 pts were evaluable (MPR/CPR:430 and Rd:211). Patient characteristics were well balanced in the 2 groups: median age was 73 years in both groups, 38% of pts were older than 75 years, 27% had ISS stage III in both groups, 21% of patients both in the MPR/CPR and in the Rd groups had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. After induction, the response rates were similar in the 2 groups: at least PR rate was 75% versus 79% (p=0.52) and CR rate was 9% versus 7% (p=0.35), in the MPR/CPR and Rd group, respectively. No significant difference in response rate were reported between two alkylating containing regimens. After a median follow-up of 21 months, the 2-year PFS was 55% in MPR/CPR and 49% in Rd (HR=0.86, 95% CI: 0.66-1.12, p=0.26), and 2-year OS was 84% in MPR/CPR and 80% in Rd (HR= 0.93, 95% CI: 0.60-1.41, p=0.71) At least one grade ≥3 hematological adverse event was reported in 51% with MPR/CPR and 29% with Rd (p<0.001), with a significant difference between the two alkylating agents (67% MPR and 31% CPR, p<0.001). At least one grade ≥3 extra-hematologic toxicities were similar in the two groups (31% with MPR/CPR and 28% with Rd, p=0.77). with no difference between two alkylating agents (31% both in MPR and CPR group). Second primary malignancies (SPM) were reported in 5 MPR patients (1 hematologic and 4 solid) in 1 CPR patient (hematologic) and in 2 Rd patients (both solid). Conclusion In a community-based population, triplet alkylating combinations did not lead to different PFS or OS clinical benefits over doublet therapy. Updated results will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Bringhen:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Cavallo:Celgene: Honoraria; Celgene: Membership on an entity’s Board of Directors or advisory committees. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Ixazomib-based frontline therapy in patients with newly diagnosed multiple myeloma in real-life practice showed comparable efficacy and safety profile with those reported in clinical trial: a multi-center study

2020 ◽  
Vol 99 (11) ◽  
pp. 2589-2598
Author(s):  
Jing Li ◽  
Li Bao ◽  
Zhongjun Xia ◽  
Sili Wang ◽  
Xin Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Response Rate ◽  
Real Life ◽  
Comparable Efficacy ◽  
Routine Practice ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Frontline Therapy ◽  
Grade 3

Abstract The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients’ preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1–20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.

scholarly journals Treatment Options for Newly Diagnosed Frail and Transplant-Ineligible Patients with Multiple Myeloma: A Systematic Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Syed Maaz Abdullah ◽  
Muhammad Salman Faisal ◽  
Mohammad Ammad Ud Din ◽  
Laeth L George ◽  
Qasim Khurshid ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Adverse Effects ◽  
Frail Elderly ◽  
Drug Combination ◽  
Drug Combinations ◽  
Discontinuation Rate ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Combination Regimens

Introduction: With progressive aging of the worldwide population, the number of newly diagnosed multiple myeloma (NDMM) cases are anticipated to escalate. Disease management for elderly, frail, and transplant-ineligible patients still remains a challenge. With our systematic review, we plan to summarize the available therapeutic options for frail, elderly, and transplant-ineligible NDMM patients. Methods: A comprehensive literature search was performed on May 27, 2020 on PubMed, Cochrane Library, and ClinicalTrials.gov. The search was not limited to any geographical area, date, or language. The keywords used in the search were: newly diagnosed, multiple myeloma, frail, elderly, transplant-ineligible, and treatment outcome. After subsequent screening, following the PRISMA guidelines, 24 ongoing/completed studies (n= 10,095) were included in the review. Results: Two and three drug combination regimens: Among the two and three drug combinations (see tables 1 and 2), lenalidomide (R) and dexamethasone (d) (Rd) combination (n=1445) and bortezomib (V), melphalan (M) and prednisone (P) (VMP) combination (n=1059) have been the most extensively studied combinations thus far. In a phase 2 trial, Takezako et al. (2016) used 9 cycles of VMP followed by bortezomib maintenance exclusively in frail patients, which yielded an ORR of 87%, CR rate of 25%, and PFS of 36 months. The addition of bortezomib (V) to Rd (VRd) was also studied in a phase 3 (SWOG S0777) trial by Durie et al. (2017) (n=471) in transplant-ineligible patients, which showed superior therapeutic response rates (PFS 43 months, OS of 75 months, and ORR of 82%) in the VRd group compared to Rd (PFS of 30 months, OS of 64 months and ORR of 72%) alone. However, the three-drug combination of daratumumab (Dara)+Rd has overall shown the best treatment results (ORR 92.9%, CR 47.6% and VGPR 31.8%) as evidenced by Facon et. al (2019) (n=368). Although, when compared to Rd, Dara-Rd was associated with more neutropenia (50% versus 35.3%); however, Dara-Rd had an overall lower incidence of infections (32.1% versus 73.4%) and hence, lower discontinuation rate (32.4% versus 56.7%) when compared to Rd, respectively. Four or five drug combination regimens: Four and five drug combinations have been studied in two phase II/III trials (n=933) in transplant-ineligible patients. A phase two trial (Mateos, 2015) studying VMPRd in frail patients resulted in an ORR of 68%, CR 20%, and PFS of 25 months after 35 days of VMPRd induction, followed by dose de-escalation to twice monthly bortezomib-only maintenance until disease progression. Dara-VMP was compared with VMP alone in a phase 3 trial (Mateos, 2017) (n=700), in which 9 cycles of Dara-VMP (42 days each) were de-escalated to daratumumab-only maintenance. Thisshowed superior results in Dara-VMP (ORR 90.9% versus 73.9%, CR 42.6% versus 24.4%, and PFS was not reached in Dara-VMP group versus 18.1 months) compared to the VMP group. Moreover, this dose de-escalation also seemed to improve treatment tolerability, as the discontinuation rate due to adverse effects was also lower (4.9%). Currently, various trials are ongoing to explore the connection between frailty status and associated treatment outcomes (table 3). Conclusion: Combination regimens, including agents like daratumumab and bortezomib, have exhibited promising results both in terms of superior efficacy and reduced adverse effects profiles. In addition, dose de-escalated maintenance therapies following induction therapies based on multidrug combinations have exhibited noteworthy success, with comparable efficacy and reduced toxicity rates in frail and transplant-ineligible NDMM patients. However, there remains an opportunity to further tailor the dose and type of drug combinations on a 'frailty-adjusted' basis, with trials designed around this risk stratification providing the highest quality data. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Safety and efficacy of four drug regimens in newly diagnosed multiple myeloma: Systematic review.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19537-e19537
Author(s):  
Udhayvir Singh Grewal ◽  
Rajshekhar Chakraborty ◽  
Fazal I Raziq ◽  
Afia Ashraf ◽  
Ammara Majeed ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Phase I ◽  
Mechanisms Of Action ◽  
Newly Diagnosed ◽  
Safety And Efficacy ◽  
Drug Regimens ◽  
Ongoing Phase

e19537 Background: To improve outcomes, multiple agents with varied mechanisms of action targeting different multiple myeloma (MM) clones are needed. Methods: Systematic review of ongoing phase I-III clinical trials in newly diagnosed multiple myeloma (NDMM) was performed, (PRISMA guidelines) using 5 databases. Results: 8 trials n = 1,990 patients included (Table 1). We evaluated the efficacy of following four drug combinations Isatuximab (Isa), bortezomib (V), lenalidomide (R)dexamethasone (d) (Isa-VRd) Daratumumab (Dara) plus V, Melphalan (M) and Prednisone (P) (Dara-VMP) vs VMP Dara-VRd vs VRd Carfilzomib (K), Cyclophosphamide (C), R, Dexamethasone (KCRD) vs an immunomodulatory agent containing triplet (CTD/CRD) Dara with Ixazomib (I), R,d (Dara- IRd) Dara, Cyclophosphamide (Cy), V,d (Dara-CyBord) Elotuzumab (Elo) VRd Dara with K,R,d (Dara- KRd) For transplant-eligible patients, Dara-VRd demonstrated the best treatment response (VGPR = 100%, CR rate = 63% and 15 months PFS = 94%). Dara-VMP (ORR = 90.9%,VGPR+ = 72.9%, mPFS at 27. 8 m = NR) and Isa+VRd (ORR = 93%, VGPR = 71.43%, 7.5 m PFS = 100%) were associated with improvement in OR in transplant ineligible patients. Dara-KRd showed excellent efficacy (ORR = 100%, ≥VGPR = 86%) with 100% 6 m PFS. Conclusions: Four-drug regimens have improved efficacy (higher ORR, deeper response, higher proportion of MRD negativity and higher ≥VGPR responses) compared to three-drug regimens in NDMM, with a comparable incidence of toxicities. Longer follow-up is needed. [Table: see text]

Maintenance Therapy in Newly Diagnosed and Transplant Ineligible Multiple Myeloma Patients: A Meta-Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Abdul Rafae ◽  
Ali Jaan ◽  
Zahoor Ahmed ◽  
Karun Neupane ◽  
Sara Ashraf ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Partial Response ◽  
Adverse Effects ◽  
Maintenance Therapy ◽  
Pooled Analysis ◽  
Newly Diagnosed ◽  
Logit Transformation ◽  
Common Grade ◽  
Grade 3

Introduction: Multiple myeloma (MM) is an incurable plasma cell disorder with more than two-thirds of the newly diagnosed multiple myeloma (NDMM) patients being ≥65 years of age. Recent advancements in the treatment of MM with novel agents and autologous stem cell transplantation (ASCT) have significantly improved survival in those patients. However, the management of NDMM in many elderly patients remains a challenge due to frailty, multiple comorbidities, and their ineligibility for ASCT. Our aim in this study is to review and analyze the safety and efficacy of different maintenance regimes for NDMM patients who are ineligible for ASCT. Methods: A comprehensive literature search was done on four databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). A search was performed without the use of filters and using MeSH terms for multiple myeloma and maintenance therapy (MT). Studies involving transplant-ineligible NDMM patients which reported overall response rate (ORR), complete response (CR), very good partial response (VGPR), or partial response (PR) along with adverse effects were included. A pooled analysis of the extracted data was performed using the "meta" package by Schwarzer et al. in the R programming language (version 4.0.2). The event rates were pooled using the inverse variance method and logit transformation. The between-studies variance was calculated using the DerSimonian-Laird estimator. The random-effects model was used for the analysis. Results: Lenalidomide based MT: Four studies involving 950 transplant-ineligible NDMM patients were included. All patients received lenalidomide (R) based MT following induction therapy. A pooled analysis of these studies showed ORR of 88% (95% confidence interval (CI): 81%-93%, p &lt; 0.01) with 67% of the patients showing ≥VGPR (95% CI: 48%-82%, p &lt;0.01) (Figure 1 A). The most common ≥ grade 3 hematological adverse effects (AE) included neutropenia, anemia, and thrombocytopenia while most common ≥ grade 3 non-hematological AE were infections, diarrhea, and fatigue (Table 1). Bortezomib based MT: Five clinical trials involving 1171 NDMM patients who received bortezomib (V) based MT were included and evaluated in our study (Figure 1 B). Pooled analysis showed ORR of 84% (95% CI: 74%-91%, p &lt;0.01) with 32% patients showing CR (95% CI: 25%-41%, p &lt;0.01). The most common ≥ grade 3 hematological and non-hematological AE's are reported in table 1. Ixazomib based MT: A total of 202 transplant-ineligible NDMM patients were evaluated for a response after receiving ixazomib (I) based MT in 5 clinical trials (Figure 1 C). A pooled analysis of these trials showed an ORR of 86% (95% CI: 69%-94%, p: &lt;0.01) with 60% patients having ≥ VGPR (95% CI: 40%-76%, p &lt;0.01). The most common ≥ grade 3 hematological AE included anemia (9%), neutropenia (15%), and thrombocytopenia (3%). (Table 1) Conclusion: V, R and I based MT has shown promising efficacy with an acceptable safety profile in transplant-ineligible NDMM patients. R based MT has shown superior ORR compared to V or I based MT. However, data from more clinical trials are needed. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Influence of Genetic Polymorphisms in CYP1A2, CYP2C19, CYP3A4, GSTP1, MDR1 and PSMB5 Genes in Toxicity and Response to Induction Therapy in Multiple Myeloma Patients Included in the Trial of the Spanish PETHEMA/GEM 05 for Newly Diagnosed MM Elderly Patients (Age 65 or More)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1412-1412
Author(s):  
Cristina Castilla-Llorente ◽  
Felipe de Arriba ◽  
Virginia Pérez-Andreu ◽  
Maria Victoria Mateos ◽  
Rocio González-Conejero ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Elderly Patients ◽  
Genetic Polymorphisms ◽  
Induction Therapy ◽  
Haematological Toxicity ◽  
Severe Neutropenia ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Original Trial ◽  
Grade 3

Abstract Abstract 1412 Over the last decade, numerous new drugs have been incorporated in the treatment armamentarium of multiple myeloma (MM). However, there is not much information on the role of single nucleotide polymorphisms (SNPs) regarding toxicity and efficacy of the new myeloma therapies. Aims: to analyze the influence of genetic polymorphisms on toxicity and outcome of induction therapy on patients included in the trial of the Spanish PETHEMA/GEM 05 for newly diagnosed MM elderly patients (age 65 or more, “GEM05mas65”). (Lancet Oncol 2010; 11: 934). Patients and Methods: Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of botezomib plus melphalan and prednisone VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy. Genetic studies were performed in blood samples from 169 patients among the 260 included in the original trial (VMP: 84 patients; VTP: 85 patients). Toxicity and outcome parameters were analyzed and related to the genotype of polymorphisms in genes involved in bortezomib (CYP1A2 *1C, CYP1A2 *1F, CYP3A4), thalidomide (CYP2C19 *2, CYP2C19 *17) and melphalan metabolism (GSTP1 I105V) as well as bortezomib transport (MDR1 −3435C>T) and drug target (PSMB5 1042G>A). Results: Clinical results in our cohort reproduced those of the 260 patients of the original trial already published. The most frequent non haematological toxicity was peripheral neuropathy, similar in both arms. Among the 169 patients included in our study CYP2C19 *17 T carriers had worse overall response (p=0.033). Likewise, MRD1 −3435TT carriers presented less incidence of grade 3–4 neutropenia (p=0.041) meanwhile patients AA for CYP2C19 *2 genotype presented more grade 3–4 thrombopenia (p=0.009). The impact of the different genotypes among the two arms and inside each one was also analyzed. Wild type patients for MRD1 −3435T SNP displayed higher rate of severe neutropenia only in the VMP arm and in a genetic load depending manner (CC=71%, CT=38%, TT=22%; p= 0.012). Conclusions: Our results suggest that polymorphisms in genes involved in the metabolism of thalidomide, (CYP2C19 *17 y *2) or bortezomib transport (MDR1 −3435C>T) may result in a thalidomide modified metabolism rate or in a lower efficacy in the bortezomib transport, suggesting a potential influence in the haematological toxicity (neutropenia and thrombopenia) and overall response rates in MM patients treated with VMP or VTP. These results together with the relative elevated frequency of these SNPs in this population (>20%) justifies the interest of studying the genetic profile since it can become a step forward on the individualized management of MM patients. Disclosures: Mateos: Celgene: Honoraria; Janssen: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

Sign in / Sign up

Export Citation Format

Share Document