scholarly journals Efficacy of Elotuzumab Based Combinations in Patients with Multiple Myeloma - a Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5548-5548
Author(s):  
Arafat Ali Farooqui ◽  
Ahmad Anjum ◽  
Muhammad Saad Farooqi ◽  
Talha Bin Farooq ◽  
Tanveer Shaukat ◽  
...  
Keyword(s):  
Systematic Review ◽  
Multiple Myeloma ◽  
Partial Response ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Entire Study ◽  
Tract Infections

Introduction Multiple myeloma afflicted cells express signaling lymphocytic activation molecule family member 7 (SLAMF7). Elotuzumab; a monoclonal antibody (mAb), targets SLAMF7 and fights myeloma cells by stimulating phagocytic action of natural killer (NK) cells and via antibody‐dependent cell‐mediated cytotoxicity (ADCC) pathway. This study focuses on the clinical utility and tolerability of elotuzumab based combinations in patients (pts) with multiple myeloma (MM). Methods Literature search of PubMed, Embase, Clinicaltrials.gov, Cochrane and Web of Science was performed from inception to June 12, 2019 for elotuzumab based combinations in MM patients. Total of 06 phase II and phase III clinical trials were selected for systematic review out of 292 studies. Results Elotuzumab (E) based combinations were evaluated in 1075 patients (pts) out of 1115 enrolled pts. 119 were newly diagnosed (ND) and 956 were relapsed/refractory (RR) patients. Newly Diagnosed MM patients: Takezako et al. 2017; in phase II trial, showed overall response rate (ORR) of 88% (complete response [CR] 3% + stringent CR [sCR] 5% + partial response [PR] 43% + very good partial response [VGPR] 38%) with ELd (E-Lenalidomide-dexamethasone) arm vs 74% in Ld arm in 82 ND pts. Progression free survival (PFS) at 1 year (y) was 93% versus (vs) 91%. Grade (G) ≥3 adverse events (AEs) included neutropenia (18%) and leukopenia (15%). Relapsed/Refractory MM patients: E-Bortezomib(B)-d arm in a phase II trial by Jakubowiak et al. (2016) showed 1 y PFS of 39% vs 33% in Bd arm in 152 RR pts (Hazard ratio [HR]: 0.72; p = .09) with 28% decrease in progression or death with EBd vs Bd arm. Objective response rate (ORR) was 66% (4% CR+ 33% VGPR + 30% PR) vs 63%. OS (overall survival) at 1 y was 85% (EBd) and 74% (Bd) (HR: 0.6). G≥3 AEs were infections (21%), thrombocytopenia and peripheral neuropathy (9% each). Mateos et al. (2016) in phase II trial (n=40) evaluated E-T (thalidomide)-d with or without Cy (cyclophosphamide) in heavily pre-treated RR pts. Pts received Cy if they failed to achieve PR by the 5th cycle or because of progressive disease (PD). Responses were better with ETd vs ETdCy. ORR was 38% (95% CI: 23-54) in ETd vs 9% (95% CI: 0-41) in ETdCy. Entire study yielded median PFS (mPFS) of 3.9 months (mo) (95% CI: 2.79%-9.43%) with 1-y PFS of 30% and mOS of 16.3 mo (95% Cl: 8.87%-25.66%) with 1-y survival rate of 63%. G≥3 AEs were lymphopenia (50%), anemia (20%), leucopenia (20%) and respiratory tract infections (RTI) (8%). Dimopoulos et al. 2018 studied E + pomalidomide (P) + d (EPd) for RR pts with ≥2 prior therapies in phase II ELOQUENT-3 trial (n=117). EPd arm yielded mPFS of 10.2 mo vs 4.6 mo in Pd arm [HR: 0.54 (95% CI: 0.34-0.86; p=0.008)], i.e. 46% lower risk of progression or death in EPd vs Pd arm. ORR was 53% (CR 5% + sCR 3% + PR 33% + VGPR 12%) in EPd vs 26% in Pd arm (odds ratio [OR]: 3.25 (1.49-7.11). G≥3 AEs were anemia (10%), neutropenia and infections (13% each). Phase III ELOQUENT-2 trial randomized 646 RR pts. PFS at 4 y was 21% vs 14% (HR: 0.71, 95% CI: 0.59-0.86; p= .0004), favoring ELd with 29% reduction in myeloma progression or death. With VGPR of 30%, ORR was 79% vs 66 % (ELd vs Ld) with HR: 0.77; 95% CI: 0.62-0.95; p = 0.0176. OS at 4 y was 50% vs 43% (HR: 0.78; 95% CI: 0.63-0.96). G≥3 AEs included lymphocytopenia (79%), neutropenia (36%), anemia (20%) and thrombocytopenia (21%). (Dimopoulos et al, 2018). Newly Diagnosed & Relapsed/Refractory MM patients: Phase II trial (n=70) by Berenson et al. (2017) studied G≥3 infusion reactions (IRs) using ELd in ND (n=37) and RR (n=33) pts. ORR was 78% (95% CI: 62%‐90%) for ND and 61% (95% CI: 42%‐77%) for RR pts. Other response rates were CR 6%, VGPR 27% and PR 37% in all patients. G3 AEs included anemia in 10% pts (no G3 IRs were seen). Conclusion: Elotuzumab based combinations showing promising outcomes in terms of ORR, PFS and OS for ND and RR MM patients with tolerable toxicity profile. More clinical studies with elotuzumab in unique and newer combinations need to be tested in prospective trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Three Drug Regimens for Newly Diagnosed Multiple Myeloma Transplant-Ineligible Elderly Patients - a Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5574-5574
Author(s):  
Abdul Aziz Siddiqui ◽  
Kazi Najamus-saqib Khan ◽  
Arafat Ali Farooqui ◽  
Muhammad Saad Farooqi ◽  
Muhammad Junaid Tariq ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Elderly Patients ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Alkylating Agents ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Great Efficacy ◽  
Drug Regimens

Introduction: Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for autologous stem cell transplant (ASCT) tend to have comorbidities and/or advanced age that make this subset of patients difficult to manage with current drug regimens. Methods: A comprehensive literature search of PubMed, Embase, Clinicaltrials.gov and Web of Science was performed from inception and completed on 07/17/2019. Studies focusing on efficacy and tolerability of 3-drug regimens in patients with NDMM were included for the review. Results: Out of 3579 studies, a total of 10 (08 phase II and 03 phase III) clinical trials in last ten years (2010-2019) using 3-drug regimens in NDMM elderly pts (893M/807F) ineligible for ASCT (determined by investigators) were selected. A total of 1703/1740 NDMM pts were evaluated. Proteasome inhibitors (PIs) such as carfilzomib (C), bortezomib (V) and ixazomib (I) showed promising results in elderly transplant-ineligible NDMM pts. CLARION trial (phase III, n=955) compared two PIs (C and V) with melphalan (M) and prednisone. There was no statistically significant difference in progression-free survival (PFS) between two groups (median: 22.3 vs 22.1 months; HR: 0.91; 95% CI, 0.75-1.10, p = 0.159) as well as overall survival (OS) (HR: 1.08; 95% CI: 0.82-1.43). Difference in the least square means of the HR-QoL (Health related- quality of life) was 4.99 (p<.0001) favoring C-group. M may not be an ideal drug to combine with carfilzomib in this setting given more AEs.(Facon et al 2019). V as 3-drug regimen in combination with lenalidomide (L) in 242 pts achieved statistically significant prolonged PFS (median 43 mo) and OS (median 75 mo) with great efficacy and acceptable risk-benefit profile. (Durie et al 2017; phase III). Multinational phase II trial (n=70) by Dimopoulos et al (2019) evaluated I, with different fixed doses of cyclophosphamide (Cy). Median duration was 19 cycles, indicating the long-term tolerability of regimen. With favorable toxicity profile and maintained QoL scores, trial concluded that this therapy is tolerable in elderly transplant-ineligible NDMM pts. Tuchman et al (2017) in phase II trial (n=14) investigated (V-Cy-d) and achieved ORR of 64%, with ≥VGPR of 57%. Low dose V showed great efficacy with M yielding ORR of 86% and VGPR or better of 49% in phase II trial (n=101) that also evaluated Cy as 3-drug combination but results were more productive with M with longer PFS and OS which reduced when impact of frailty was examined on outcomes. Since toxicity was higher with M, trial suggested that 2-drug combination should be preferred in elderly frail patients. (Larocca et al 2015). Efficacy was quite promising when Bringhen et al (2014) trialed C with Cy-d; 87% OS and 76% PFS at 1 y in phase II trial (n=58) with much favorable safety profile. Monoclonal antibodies (mAb) such as elotuzumab (E) and pembrolizumab (Pe) are also tested in elderly. First study conducted on NDMM pts using humanized mAb; E, in phase II trial (n=40) by Takezako et al (2017) attained primary endpoint of the study (ORR) of (88%) and VGPR or better of 45% in Japanese pts with tolerable toxicities in elderly. No subjects on this study experienced severe peripheral neuropathy. KEYNOTE-185; a phase III multinational trial by Usmani et al (2019) evaluated Pe with Ld in 151 pts. FDA halted this study due to unfavorable benefit-risk profile; 19 deaths, 6 due to disease progression (PD), and 13 due to treatment-related AEs. Median PFS and median OS were not reached in either group. Immunomodulators such as L achieved one of the longest PFS reported in a trial of transplant ineligible patients (35 mo) by using LVd regimen in phase II multicenter trial (n=50). (O'Donnell et al 2018) Alkylating agents like bendamustine (ben) and M have been tested in different novel regimens. Decreasing intensity and increasing duration of ben resulted in better outcomes in phase II trial (n=59) by Berdeja et al (2016) and can be given as first line treatment. Ben yielded great results with low dose dexa as compared to high dose achieving 92% ORR. Original regimen was effective but relatively more toxic. Incidence of herpes and neuropathy decreased dramatically with the treatment modifications. Conclusion: Three-drug regimens having PIs, mABs, immunomodulators and alkylating agents have shown desirable results in NDMM transplant (ASCT)-ineligible elderly patients and are likely the emerging standard of care for NDMM. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 445-445 ◽  
Author(s):  
Joseph R. Mikhael ◽  
Craig B. Reeder ◽  
Edward N. Libby ◽  
Luciano J. Costa ◽  
P. Leif Bergsagel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Initial Phase ◽  
Stem Cell Transplant ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

Treatment of Newly Diagnosed, Inner-City Multiple Myeloma Patients with Zoledronate, Dexamethasone, and Low-Dose Thalidomide: A Phase II Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5124-5124
Author(s):  
Uwe Klueppelberg ◽  
Eric L.P. Smith ◽  
Marc J. Braunstein ◽  
David Kahn ◽  
Olcay A. Batuman
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Inner City ◽  
Phase Ii ◽  
Low Dose ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Hiv Patients ◽  
Long Term Treatment

Abstract Background: This Phase II trial was designed to assess the long-term effectiveness and safety of low-dose thalidomide with dexamethasone and zoledronate (TDZ) in newly diagnosed multiple myeloma (MM) in an inner-city population in which AIDS is the third-leading cause of death. Although the incidence of MM is increased in HIV+ patients, guidelines for treatment of MM in this population are not yet known. The TDZ regimen was intended to be non-myelotoxic and compatible with HAART. Because zoledronate mitigates tumor growth and angiogenesis as well as bone resorption, it was expected to boost the therapeutic effect of thalidomide and dexamethasone. Method:Of 45 consecutive enrollees, 38 (27F/11M; median age = 60.4 years) were evaluable. All patients had skeletal involvement of varying severity; baseline levels of *2-microglobulin (4.3 mg/dL; SE = 0.68) and serum albumin (3.3 mg/dL; S.E.= 0.38) indicated advanced disease. Eight evaluable patients (21%) were HIV+ (7F/1M; median age = 47 years). Patients with HIV were younger (P &lt; .001), with marginally higher *2-microglobulin levels (P = .076). Seven of the HIV+ patients were on HAART at the time of treatment. The TDZ regimen, given for 24 months or until progression, consisted of: thalidomide, 100 mg daily; dexamethasone, 10–40 mg for 4 days/week for 3 weeks each month for 6 months, then reduced to 4 days each month; zoledronate, 4 mg IV monthly; and ASA, 81 mg daily. Response was stratified by reduction of M protein levels: &gt; 75% (very good partial response [VPR]), &gt; 50–75% (partial response [PR]), or 25–50% (minor response [MR]). Results: Age-adjusted one-year survival was 74.4%, and is identical to NCI SEER data (73.7%). Mean duration of TDZ treatment was 21.4 months (range = 13–24). VPR was achieved in 32% (n = 12), PR in 39% (n = 15), and MR in 18% (n = 7). Three patients had stable disease, and one progressed. Median time to maximum response was 3.0 months. Overall cumulative survival at 24 months was 68% by Kaplan-Meier analysis, and was not affected by HIV status, age, or sex. Baseline creatinine clearance both for HIV+ and HIV− patients was within normal limits, and was not adversely affected by monthly treatment with zoledronate (P &gt; .2 for both). Despite prophylactic ASA, thromboembolism occurred in 6 patients (16%), all of whom were successfully treated with full anticoagulation. Other toxicities ≥ Grade 2, were not observed. Skeletal events occurred in 8% of patients; osteonecrosis of the jaw was not encountered. Death occurred in 10 patients, 9 of whom were evaluable; 6 deaths were due to progression or complications of MM, and 4 were from unrelated causes. Seven patients were dropped from the study (5 moved from the area and 2 patients declined to continue). Conclusion: Thalidomide administered at less than half the standard sage in combination with zoledronate and dexamethasone provided safe and effective long-term treatment of MM both in HIV− and HIV+ patients. The modest frequency of toxicity and skeletal events under this regimen indicates improvement in quality of life as well as survival.

Lenalidomide, Adriamycin and Dexamethasone (RAD) As An Induction Regimen In Newly Diagnosed Multiple Myeloma – Interim Results From a German Multicenter Phase II Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1987-1987 ◽  
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars O Muegge ◽  
Wolf Roesler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Phase Iii ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
First Line Treatment

Abstract Background Induction triplets utilizing at least one of the “novel drugs” and steroids with or without chemotherapy are considered current standard of care in newly diagnosed, symptomatic multiple myeloma (MM). Medically fit patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while use of allogeneic (allo) SCT remains a matter of debate. As we had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory MM, we evaluated this combination in first-line treatment. Methods The current phase II trial (DSMM XII) was designed to include a total of 190 pts up to 65 years of age with symptomatic MM. Four 4-week cycles of RAD (lenalidomide 25 mg/day, d 1-21; adriamycin 9 mg/m² as 24-hour infusion, d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) preceded stem cell chemomobilization. Low-molecular weight heparin for prophylaxis of venous thromboembolic events (VTE) was mandatory. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel200) or auto followed by allo SCT. Allo SCT (preparative regimen: treosulfan/fludarabine) was reserved for pts featuring at least one cytogenetic or serologic risk factor who had a matched sibling or unrelated donor available. Lenalidomide maintenance was administered for one year following both tandem auto and auto/allo SCT. This is the second pre-planned interim safety and efficacy analysis. Results Eighty-nine pts with a median age of 54 (range, 30-65) years, who were recruited between August 2009 and October 2010, are evaluable. Fifty pts (56.2%) had ISS stage II/III disease and in all except three, molecular cytogenetic analysis was performed. Incidences of chromosomal abnormalities were as follows: deletion of (del) 13q, 24.7%; translocation t(4;14), 12.4%; t(14;16), 3.4%; and del 17p, 5.6%. Treatment-related mortality with RAD induction was 0% while 61.8% of pts had treatment-emergent SAEs. Seventeen pts (19%) experienced neutropenia of grades 1 to 4. Incidences of severe (grades 3/4) and febrile neutropenia were 5.6 and 1%, respectively. Seven pts each (8%) had pneumonia and VTE, respectively. Post-RAD-induction CR/sCR and at least VGPR rates were 9% and 47.2%, respectively. All 78 pts with at least stable disease successfully mobilized stem cells. Overall response rate (at least partial response, PR) following first SCT on an intention-to-treat basis was 83%. Twelve pts each (13.5%) achieved centrally confirmed complete response (CR) or stringent (s)CR, respectively, and 54 pts (60.7%) had at least very good PR (VGPR). Conclusions This interim analysis shows RAD to be very well tolerated and effective in first line treatment of symptomatic MM. Mel200 further increased rates of deep response (at least VGPR) achieved by RAD induction. We are currently comparing this regimen to bortezomib, lenalidomide and dexamethasone (VRd) in a phase III trial. Disclosures: Knop: Celgene GmbH: Honoraria. Off Label Use: Lenalidomide and doxorubicin in newly diagnosed multiple myeloma. Engelhardt:MSD, Janssen-Cilag: Research Funding. Einsele:Celgene GmbH: Consultancy, Honoraria, Research Funding. Bargou:Celgene GmbH: Research Funding.

scholarly journals Antibody Based Three-Drug Regimens for Multiple Myeloma - a Systematic Review of Phase II and Phase III Clinical Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5546-5546
Author(s):  
Arafat Ali Farooqui ◽  
Humaira Sarfraz ◽  
Zunairah Shah ◽  
Muhammad Saad Farooqi ◽  
Maimoona Khan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Partial Response ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Residual Disease ◽  
Drug Regimen ◽  
Drug Combinations ◽  
Phase Iii ◽  
Myeloma Cells

Introduction Elotuzumab is monoclonal antibody (mAb) that specifically targets signaling lymphocytic activation molecule family member 7 (SLAMF7) that is present on myeloma cells. It fights myeloma cells by stimulating phagocytic action of NK cells and via ADCC (antibody‐dependent cell‐mediated cytotoxicity) pathway. Daratumumab is an anti-CD38 mAb with dual mechanisms of action i.e. tumoricidal and immunomodulation. The aim of this study is to review the efficacy and toxicity of elotuzumab and daratumumab based 3-drug combinations in patients (pts) with multiple myeloma (MM). Methods A systematic search of PubMed, Embase, Clinicaltrials.gov, Cochrane and Web of Science was performed for elotuzumab and daratumumab based regimen in MM patients from inception to June 12, 2019. Out of 604 studies, 08 phase II and III clinical trials based on 3-drug regimen were finalized. Results Total 2809 patients (pts) were evaluated out of 2879 enrolled pts. 856 were newly diagnosed (ND) and 1953 were relapsed/refractory (R/R). Elotuzumab (E) based 3-drug regimen were evaluated in 560 whereas daratumumab (D) based 3-drug regimen were analyzed in 889 pts. ELOQUENT-3 trial (n=117) in phase II used E + pomalidomide (P) and dexamethasone (d) (EPd) for R/R pts with ≥2 prior therapies. Median (m) progression free survival (PFS) was 10.2 months (mo) in EPd versus (vs) 4.6 mo in Pd arm [Hazard ratio (HR) 0.54 (95% CI: 0.34-0.86; p=0.008)], i.e. 46% lower risk of progression or death in EPd vs Pd arm. ORR (overall response rate) was 53% (complete response [CR] 5% + stringent CR [sCR] 3% + partial response [PR] 33% + very good partial response [VGPR] 12%) in EPd vs 26% in Pd arm (odds ratio [OR]: 3.25 (1.49-7.11). Grade (G) ≥3 adverse events (AEs) were anemia (10%), neutropenia and infections (13% each). (Dimopoulos et al. 2018). Phase II trial by Jakubowiak et al. (2016) observed 1 year (y) PFS of 39% in E-Bortezomib(B)-d vs 33% in Bd arm in 152 R/R pts (HR: 0.72; p = .09) with 28% decrease in progression or death with EBd vs Bd. ORR was 66% (4% CR+ 33% VGPR + 30% PR) vs 63%. OS (overall survival) at 1 y was 85% (EBd) and 74% (Bd) (HR:0.6). G≥3 AEs were infections (21%), thrombocytopenia and peripheral neuropathy (9% each). In phase II trial, ELd (E-Lenalidomide-d) arm yielded ORR of 88% (CR 3% + sCR 5% + PR 43% + VGPR 38%) vs 74% in Ld arm in 82 ND pts. PFS at 1 yr was 93% vs 91%. G≥3 AEs included neutropenia (18%) and leukopenia (15%). (Takezako et al. 2017). Berenson et al. (2017) in phase II trial (n=70) studied G≥3 infusion reactions (IRs) using ELd in ND and R/R pts. ORR was 70% (CR 6% + VGPR 27% + PR 37%). G3 AEs included anemia in 10% pts (no G3 IRs). ELOQUENT-2 trial randomized 646 R/R pts in phase III. PFS at 4 y is 21% vs 14% (HR: 0.71, 0.59-0.86; p= .0004), favoring ELd with 29% reduction in myeloma progression or death. With VGPR of 30%, ORR was 79% vs 66 % (ELd vs Ld) with HR: 0.77; 0.62-0.95; p = 0.0176. OS at 4 y was 50% vs 43% (HR: 0.78; 0.63-0.96). G≥3 AEs included lymphocytopenia (79%), neutropenia (36%), anemia (20%) and thrombocytopenia (21%). (Dimopoulos et al, 2018). POLLUX trial used daratumumab (D)-Ld regimen in 569 R/R patients in phase III. PFS at 3 y was 55% vs 27% (DLd vs Ld) in pts with 1-3 prior therapies. With 56% CR and 80% VGPR; ORR was 93% vs 76%. DLd arm achieved 30% minimal residual disease (MRD)-negative status compared to 5% in Ld arm (p<0.001). OS at 3-yr was 34% vs 42%. G≥3 AEs were neutropenia (55%), anemia (18%), thrombocytopenia (15%) and pneumonia (14%). (Bahlis et al. 2018). CASTOR trial in phase III (n=498) showed 18-mo PFS of 48% vs 7.9% in DBd vs Bd arm in R/R pts (HR: 0.31 (0.24-0.39); p<0.0001). ORR was 83.8% (CR 28.8%+ sCR 8.8% + VGPR 62.1%) vs 63.2% (p<0.001). DBd-treatment led to 11.6% MRD-negative status vs 2.4% in Bd-treated pts (p=0.000034). Thrombocytopenia (45.7%), anemia (15.2%) and neutropenia (13.6%) were G≥3 AEs. (Spencer et al. 2018). A Phase III trial (n=737) observed 30 mo PFS of (66 vs 52) % in ≥75 y old pts [HR 0.63 (0.44-0.92)] with DLd vs Ld arms in ND transplant ineligible pts with ORR of (90 vs 81) % (≥CR 41% + ≥VGPR 77%). MRD- negative rate was (19 vs 8) % in DLd vs Ld arms respectively. G≥3 AEs were neutropenia (60%), lymphopenia (19%), anemia (16%), pneumonia (15%) and leukopenia (12%). <75 y old showed ORR of (95 vs 82) % with 30 mo PFS of (75 vs 58) % in both arms. (Usmani et al 2019). Conclusion: Elotuzumab and daratumumab based 3-drug combinations showing great improvements in ORR, PFS and OS of ND and RR MM patients with favorable toxicity profile. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Phase III Study of the Value of Thalidomide Added to Melphalan Plus Prednisone in Elderly Patients With Newly Diagnosed Multiple Myeloma: The HOVON 49 Study

2010 ◽  
Vol 28 (19) ◽  
pp. 3160-3166 ◽  
Author(s):  
Pierre Wijermans ◽  
Martijn Schaafsma ◽  
Fabian Termorshuizen ◽  
Rianne Ammerlaan ◽  
Shulamiet Wittebol ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Elderly Patients ◽  
Response Rate ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Intent To Treat

Purpose For several decades, the treatment of elderly patients with multiple myeloma (MM) has consisted of melphalan and prednisone (MP). The Dutch-Belgium Hemato-Oncology Cooperative Group (HOVON) investigated the efficacy of thalidomide added to MP (MP-T) in a randomized phase III trial. The objective of this study was to investigate the efficacy, toxicity, and effects on quality of life of MP-T. Patients and Methods A randomized phase III trial compared standard MP with MP-T (thalidomide 200 mg/d) in newly diagnosed patients with multiple myeloma older than age 65 years. Maintenance therapy with thalidomide 50 mg/d was administered to patients after MP-T until relapse. The primary end point was event-free survival (EFS); response rate, overall survival (OS), and progression-free survival (PFS) were secondary end points. Results An intent-to-treat analysis of 333 evaluable patients showed significantly higher response rates in MP-T–treated patients compared with MP-treated patients a response (≥ partial response: 66% v 45%, respectively; P < .001; and ≥ very good partial response [VGPR]: 27% v 10%, respectively; P < .001). EFS was 13 months with MP-T versus 9 months with MP (P < .001). OS was 40 months with MP-T versus 31 months with MP (P = .05). Conclusion This study demonstrates that thalidomide improves the response rate and VGPR in elderly patients with newly diagnosed MM. MP-T also results in a better EFS, PFS, and OS.

scholarly journals A Phase II Multi-Center Study of Lenalidomide, Subcutaneous Bortezomib and Dexamethasone (RsqVD) in Newly Diagnosed Multiple Myeloma - Ctrial-IE (ICORG) 13-17 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2117-2117
Author(s):  
Peter O'Gorman ◽  
Michael E O'Dwyer ◽  
Oonagh Gilligan ◽  
John Quinn ◽  
Mark Coyne ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Partial Response ◽  
Phase Ii ◽  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Newly Diagnosed ◽  
Cell Mobilization

Abstract Introduction: Lenalidomide, bortezomib and dexamethasone (RVD) is considered a new standard of care regimen for patients with newly diagnosed multiple myeloma. A previous phase I/II study of RVD in front-line myeloma enrolled 66 patients and achieved a partial response rate or better of 100%, overall and a CR/nCR rate of 52% in the phase 2 portion of the study with encouraging tolerability, but high rates of peripheral neuropathy (PN), albeit mainly mild to moderate grade (Richardson et al, Blood 2010). Subcutaneous (SQ) administration of single agent bortezomib has been shown to be non-inferior to IV bortezomib and led to lower rates of PN, a common treatment-related toxicity (Moreau et al, Lancet Oncol 2011). Herein we present preliminary results of the RsqVD Study, a multi-center, open-label single arm phase II trial, incorporating SQ bortezomib with lenalidomide and dexamethasone and including patients who were considered either transplant eligible or ineligible. All patients subsequently received maintenance therapy with lenalidomide until progression, plus the addition of subcutaneous bortezomib twice monthly in high risk patients (ISS stage II or III and/or high risk cytogenetics features, t(4;14, t(14;16) and del17p). The primary endpoint was overall response rate (ORR) after 4 cycles of induction therapy (PR or better). Secondary endpoints include: rate and severity of PN, safety, time to progression, progression-free survival, duration of response and overall survival. Methods: Planned treatment was 4 cycles of lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m2as SQ injection on days 1, 4, 8 and 11 of a 21-day cycle. Thromboprophylaxis with aspirin 75 mg/day or higher was mandatory and HSV prophylaxis was as per institutional standard. Following 4 cycles, patients were planned to proceed with stem cell mobilization and autologous stem cell transplant (ASCT) or further induction therapy up to a total of 8 cycles. Following completion of ASCT or induction therapy, all patients were scheduled to receive lenalidomide maintenance in 28 - day cycle until progression, unacceptable toxicity or withdrawal of consent. Patients with high-risk features received SQ bortezomib on days 1 and 15 during maintenance phase. Response was investigator-assessed as per IMWG criteria. Sample size (n=42) was determined to provide 80% power to test an acceptable ORR of >70% versus an unacceptable ORR of <50% (1-sided alpha=0.05) including an estimated drop-out rate of 10%. Results: Between November 2014 and February 2016, 42 patients were enrolled across 8 sites in Ireland. Baseline demographic factors include: 64% males, 36% females; median age of 64 years (45-79 years); 41% ISS stage I, 59% ISS stage II/III. FISH analysis detected t(4;14) in 18% of patients (7/40), t(14;16) in 3% of patients (1/36) and del17p in 10% of patients (4/40). 64% (27/42) patients proceeded to stem cell mobilization and 60% (25/42) to ASCT. The median number of induction cycles completed was 4 (1 to 8 cycles). 40 of a total of 42 patients were considered evaluable for the primary endpoint of ORR. A preliminary analysis of ORR following 4 cycles of induction therapy indicates that 98% (39/40) of patients achieved partial response or better. PN of any grade has been reported by sites in 43% (18/42) of patients to date. Conclusion: RsqVD is a highly effective regimen in newly diagnosed multiple myeloma producing a very high ORR following initial induction therapy, with a lower overall rate of PN described by sites than expected. Full analyses of response and safety data for induction treatment and follow up will be presented, as well as preliminary evaluation of response to subsequent therapy. Disclosures O'Gorman: Janssen Cilag: Research Funding; Celgene: Research Funding. O'Dwyer:Celgene: Consultancy, Honoraria, Research Funding; Glycomimetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Quinn:Celgene: Honoraria; Janssen Cilag: Honoraria. Murphy:Celgene: Honoraria; Janssen Cilag: Honoraria. Crotty:BMS, Takeda, Novartis, Janssen, Roche: Honoraria. Hayden:Celgene: Honoraria; Janssen Cilag: Honoraria; Amgen: Honoraria. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Efficacy of Bortezomib plus dexamethasone as a first line treatment in newly diagnosed cases of Multiple Myeloma: A Single Centre Study in a Tertiary Care Hospital

2020 ◽  
Vol 28 (1) ◽  
pp. 34-41
Author(s):  
Mahbuba Sharmin ◽  
Mohammad Manirul Islam ◽  
Abdul Aziz ◽  
Salauddin Shah ◽  
Md Jalilur Rahman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Intracranial Haemorrhage ◽  
Response Rate ◽  
Malignant Tumors ◽  
Tertiary Care ◽  
Care Hospital ◽  
Newly Diagnosed ◽  
Overall Response ◽  
Highly Effective

Background: Multiple Myeloma (MM) accounts for 1% of malignant tumors and 10%–15% of hematopoietic neoplasms. Bortezomib, a first in class proteasome inhibitor, induces apoptosis and growth arrest and reverse chemoresistence in Myeloma cell and has demonstrated no irreversible adverse effect on haemopoietic stem cell. Dexamethasone increases the response rate. Thus, Bortezomib plus dexamethasone represent highly effective regimen for previously untreated Multiple Myeloma cases and significantly higher response rates approximately 70%– 90% have been observed.This combination thus may serve the basis of future strands of care in Multiple Myeloma patients. Objective: The aim of the study was to assess the efficacy , safety and tolerability of Bortezomib in newly diagnosed cases of Multiple Myeloma patients in Bangladesh. Materials & Methods: This prospective observational study was carried out in the Haematology department of BSMMU from June 2017 to December 2018. Patients received inj. Bortezomib (1.3mg/m2 ) 4 cycles as an intravenous bolus on days 1,4,8,11 in a three week cycle (twice weekly administration) in indoor and same patients as day care basis in outpatients department. Dexamethasone at 40 mg was given intravenously or orally on the day of and day after inj Bortezomib.A self administered questionnaire containing different set of questions regarding Multiple Myeloma were used for data collection. Results: Among the study population, 93% of patients had anaemia followed by bone pain (86%) and renal impairment (39%). Out of 25 patients,complete response achieved in 13 patients (52%), where 4 patients(16%) showed partial response,6 (24%) showed very good partial response and 2 (8%) patients showed no response. The overall response rate was 92% belonged to partial,very goofd partial and no respone respectively. Death occurred in 3 cases (12%). 5 patients (20%) developed Bortezomib induced peripheral neuropathy.Life threatening intracranial haemorrhage occurred in two patients (8%). Death occurred in 3 cases (12%),2 patients due to intracranial haemorrhage and another from cardiac arrest. In this study,S. creatinine, â2 microglobulin and bony lesion variables showed significant association with treatment response. Conclusion: Bortezomib plus dexamethasone is a highly effective and safe regimen for previously untreated multiple myeloma patients. This novel therapy in myeloma represent a new trearment paradigm targeting both tumor and microenvironment which has markedly improve overall response(OR), long progression free survival (PFS) and overall survival (OS)across in all risk groups. Moreover,it can be administered safely in the outpatient setting provided by clinicians. J Dhaka Medical College, Vol. 28, No.1, April, 2019, Page 34-41

Phase II Trial of 4′-Epi-Doxorubicin in Locally Advanced or Metastatic Gastric Cancer

1988 ◽  
Vol 74 (3) ◽  
pp. 313-315 ◽  
Author(s):  
Eduardo Cazap ◽  
Roberto Estevez ◽  
Mario Bruno ◽  
Daniel Levy ◽  
Carlos Algamiz ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Adenocarcinoma ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Phase Iii ◽  
Future Studies ◽  
Phase Iii Trials

Patients with locally advanced or metastatic gastric adenocarcinoma received an i.v. bolus of 4′-epi-doxorubicin, 75/mg/m2/cycle, every 21 days. Partial responses were observed in 5 of 23 evaluable patients (21.7%). Treatment was generally well tolerated and toxicity was mild. The response rate to epirubicin appears to be very similar to that reported for doxorubicin. Larger doses of epirubicin could be safely used in future studies, and further evaluation of epirubicin in phase III trials is indicated.

A Phase II Study of PS-341 for Patients with High Risk, Newly Diagnosed Multiple Myeloma: A Trial of the Eastern Cooperative Oncology Group (E2A02).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2546-2546 ◽  
Author(s):  
Angela Dispenzieri ◽  
Emily Blood ◽  
David Vesole ◽  
Rafael Fonseca ◽  
Natalie Callander ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Peripheral Neuropathy ◽  
High Risk ◽  
Partial Response ◽  
Progressive Disease ◽  
Response Rate ◽  
Cell Labeling ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Background: Multiple myeloma (MM) is an incurable disease with a anticipated overall survival (OS) ranging from months to decades. Modest improvements in OS have been made with high-dose chemotherapy with peripheral blood stem cell transplant (PBSCT), but to date prognostic factors have a greater impact on OS than do individual therapies. Patients with adverse risk factors such as elevated beta-2 microglobulin (B2M), plasma cell labeling index, deletions of the long arm of chromosome 13 by metaphase cytogenetics (del 13q) require innovative new treatment strategies. Bortezomib has significant activity in patients with both newly diagnosed and relapsed/refractory MM, but its specific role in patients with adverse features has not yet been defined. Methods: Patients with newly diagnosed “high-risk” myeloma (B2M ≥ 5.5., PCLI ≥ 1, or del 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule were to have the full induction schedule resumed. Responses were by the EBMT criteria but a very good partial response category was included. The primary end-point was the response rate in these high-risk patients (90% power to detect a response rate of 50% or higher). The study decision rule requires that 16 or more responses, among 39 eligible patients, are seen in order to declare this treatment effective. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 43 eligible patients, median age was 63; 51% were male. All patients had high risk disease: del 13q (6/41); plasma cell labeling index ≥1% (16/34); and B2M≥5.5 (34/43). Preliminary response data are available for 18 of the 44 cases enrolled, of which 7 had partial response, 1 had minimal response, 1 had no response, 2 had progressive disease, and 5 were unevaluable. Among those patients completing induction therapy and with response information, the median number of cycles of therapy administered is 5, range (0,8). The most common non-hematologic adverse events (AEs) of grade 3 or higher included hyponatremia (9 patients) and diarrhea (6 patients). Mild sensory peripheral neuropathy was common: grade 1, 16 patients; grade 2, 2 patients. Only 1 patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses bortezomib due to heart block and asystole. Two patients had a grade 4, 25 patients had grade 3, and 13 had grade 1 or 2 as the worst grade non-hematologic adverse event. Based on data received by August 1, 2005, 18 patients have gone off study: AEs (2); death (1); progressive disease (9); and other reasons (6). Updated results on the full study population along with FISH data for IgH translocations and deletions of 13q and 17p will be presented at the meeting. Conclusions: Preliminary results suggest that upfront bortezomib has activity in patients with high-risk MM, but further follow-up is required.

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