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 Bortezomib-Based First Line Treatment for AL Amyloidosis Patients Who Are Not Candidate for Stem Cell Transplantaion

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3256-3256
Author(s):  
Joon Young Hur ◽  
Kang Kook Lee ◽  
Sang Eun Yoon ◽  
Sehhoon Park ◽  
Jangho Cho ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
The Body ◽  
Autonomic Nerve ◽  
Al Amyloidosis ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
First Line Treatment

Abstract Introduction Systemic AL amyloidosis is characterised by deposition of misfolded immunoglobulin light chains within organs. Treatment for amyloidosis is generally derived from that for multiple myeloma (MM). Combinations of immunomodulatory drugs and proteasome inhibitors are standard frontline MM therapy, but there is little experience with such regimens in AL. For patients not receiving autologous stem cell transplantation (ASCT), bortezomib-based regimens have been first-line treatment in AL amyloidosis over the last few years. The purpose of this study is to investigate the efficacy of bortezomib-based regimens for patients with newly diagnosed AL amyloidosis Methods We performed a retrospective study of all newly diagnosed patients with AL amyloidosis treated at our center between 4/1/11 and 12/31/17. Data pertaining to demographics, diagnosis, treatment and follow-up were extracted from electronic medical records. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. All statistical analyses were performed by using the SPSS 24.0 software. Time to progression (TTP) is defined as time from the date of diagnosis or the start of treatment for a disease until the disease starts to get worse or spread to other parts of the body. The primary endpoint was overall response rate and secondary endpoints were overall survival (OS) and TTP. Results A total 63 patients with newly diagnosed AL amyloidosis who did not receive ASCT were analyzed. Clinical characteristics are shown in Table 1. They included 32 men and 31 women with a median age of 66 years (range, 42-82). Autonomic nerve, Cardiac, peripheral nerve, renal, soft tissue, and liver involvement were found in 46 (73%), 41 (65.1%), 23 (36.5%), 20 (31.7%), 16 (25.4%), 4(6.4%), respectively. The Mayo 2012 stage was: Stage 2 3.8%, Stage 3 30.8% and stage 4 65.4%. Hematological responses were: complete response (CR) 33.3 %, VGPR 19.0%, partial response (PR) 12.6% and no-response (NR) 17.4%. Organ response was 26.9% (n=17). With a median follow-up of 34 months, median OS was 40 months (95% CI 30-50) (Figure 1A) and median TTP was 27 months (95% CI 18-36) (Figure 1B). The rate of early death within 6 months was 28.5% (n=18). Patients were classified according to first-line treatment; bortezomib-based regimens (VMP, n=37; VD (bortezomib and dexamethasone), n=9; VCD, n=8; VMD, n=8; VTD (bortezomib with thalidomide and dexamethasone, n=1). Hematological responses of VMP, VD, VCD, VMD, and VTD were: 75.6%, 55.5%, 50.0%, 50.0%, 100%, respectively. Organ responses of VMP, VD, and VMD were: 35.1%, 22.2%, 25.0%, respectively. Conclusions In this retrospective analysis, bortezomib-based regimens in newly diagnosed AL amyloidosis showed results that appear comparable to those seen at other centers. These findings therefore continue to support the emerging roles for bortezomib-based regimens for the purposes of improving response. Larger scale analyses in multi-center trials would be beneficial to further study these roles. Disclosures Kim: Kyowa-Kirin: Research Funding; Roche: Research Funding; Mundipharma: Research Funding; Novartis: Research Funding; Celltrion: Research Funding; J&J: Research Funding; Takeda: Research Funding.

The Efficacy and Safety of RAD (Lenalidomide, Adriamycin and Dexamethasone) In Newly Diagnosed Multiple Myeloma – First Results of a Phase II Trial by the German DSMM Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1945-1945
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars O Muegge ◽  
Albrecht Reichle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Current Phase ◽  
Newly Diagnosed ◽  
First Line ◽  
Peripheral Blood Stem Cells ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 1945 Background Prognosis of patients with multiple myeloma (MM) has significantly improved by the introduction of autologous (auto) stem cell transplantation (SCT). The “novel drugs” which have shown activity in relapsed MM are increasingly used in first-line therapy aiming at maximized response prior to SCT. Whether allogeneic (allo) SCT adds to further disease control remains a matter of debate. Our group has shown the RAD regimen (lenalidomide, adriamycin and dexamethasone) to be highly effective and relatively well tolerated in relapsed and refractory MM. Therefore, we decided to explore RAD in the up-front management. Patients and Methods The current phase-II trial (DSMM XII) was designed to include patients (pts) up to the age of 65 years with newly diagnosed MM requiring treatment. We chose four cycles of RAD (lenalidomide 25 mg d-21; infusional adriamycin 9 mg/m2 per day d1-4; dexamethasone 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks for induction followed by chemomobilization of peripheral blood stem cells. Low molecular weight heparin is mandatory during RAD treatment for thromboprophylaxis. All pts are to undergo one cycle of melphalan 200 mg/m2 followed by auto SCT. A subsequent allo SCT after reduced intensity conditioning (treosulfan/fludarabin) is scheduled for pts featuring at least one previously identified (cytogenetic or serologic) risk factor. Those with very favourable risk are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance (10 mg per day) on a continuous basis. Here, we present results of a planned safety analysis. Results 75 pts with a median age of 57 (range, 35–66) years have been enrolled by 11 German centers between 9/2009 and 7/2010. Currently, 51 pts are evaluable for toxicity during RAD induction: In all, 25 severe adverse events (SAEs) were reported for 16 subjects (31%). 68% of SAEs were assessed to be drug-related. Most frequent events were venous thrombosis (VTE; n=4), pyrexia (n=3) and syncope (n=2). Neutropenia, extravasation, pleural effusion, and allergic dermatitis accounted for one SAE each. 17 patients, 10 of whom (59%) had ISS stage II/III disease, are evaluable for post-induction response. Ten subjects (59%) achieved VGPR or better: 6 pts had VGPR and 2 patients each CR and stringent CR as assessed by the investigator. Conclusions Our preliminary results suggest RAD to be a well tolerated and effective novel induction protocol in up-front treatment of MM. Notably, incidence of severe hematotoxicity observed so far is significantly lower than was in our previous study in relapsed/refractory pts. Incidence of VTE was acceptable while no neurotoxicity occurred. Updated results will be presented. Disclosures: Knop: Celgene Germany: Consultancy, Honoraria. Off Label Use: Lenalidomide in combination with doxorubicin in myeloma first-line therapy. Reichle:Celgene Germany: Research Funding. Einsele:Celgene Germany: Consultancy, Honoraria. Bargou:Celgene Germany: Consultancy, Research Funding.

RAD (Lenalidomide, Adriamycin and Dexamethasone) Is a Novel and Very Effective Induction Regimen in Newly Diagnosed Multiple Myeloma Preceding a Risk-Adjusted Transplant Strategy,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3967-3967
Author(s):  
Stefan Knop ◽  
Christian Langer ◽  
Monika Engelhardt ◽  
Lars O Muegge ◽  
Christoph Röllig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interim Analysis ◽  
Research Funding ◽  
Current Phase ◽  
Induction Treatment ◽  
High Dose ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
First Line Treatment

Abstract Abstract 3967 Background Triple combinations utilizing dexamethasone, at least one of the “novel drugs” and either an alkylating agent or an anthracycline are currently considered standard induction regimens in newly diagnosed multiple myeloma (MM). In patients (pts) deemed medically fit, subsequent autologous (auto) stem cell transplantation (SCT) yet is a mainstay of care. Whether allogeneic (allo) SCT in first line treatment of MM further improves prognosis remains, however, a matter of debate. We have shown the RAD regimen to be highly effective and well tolerated in relapsed and refractory MM. Therefore, we decided to integrate this combination as a means of induction into the up-front management. Patients and methods The current phase-II trial (DSMM XII) was designed to include pts up to the age of 65 years with newly diagnosed, symptomatic MM. We chose four cycles of RAD induction (lenalidomide 25 mg/day d 1–21; infusional adriamycin 9 mg/m2 and day d1-4; dex 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks followed by chemomobilization (cyclophosphamide, etoposide) of peripheral blood stem cells. Thromboprophylaxis by low molecular weight heparin is mandatory. All pts are scheduled to receive two transplants, the first of which being an auto SCT following standard high-dose melphalan (200 mg/m2). A subsequent allo SCT after preparation with treosulfan/fludarabin is scheduled for pts featuring at least one cytogenetic or serologic risk factor (RF). Those without any RF (“very favourable risk”) are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance. The primary end point of this trial is response to risk-adapted transplant as assessed after second SCT. This is the first planned efficacy interim analysis after 50 pts having terminated induction treatment. Results 148 pts with a median age of 55.5 (range, 30–66) years have been enrolled by 16 German centers between 9/2009 and 7/2011. In addition to the intended sample size, 2 pts had progressive disease for a total of 52 pts being evaluable for post-induction response according to the IMWG criteria. 32 pts (62%) had ISS stage II and III disease and all except three were evaluable for cytogenetic analysis based on fluorescence in situ hybridization (FISH). Incidences of chromosomal abnormalities were as follows: deletion of 13q, 31%; translocation (4;14), 15%; and deletion of 17p, 12%. Overall response rate was 79% including a 52% rate of at least very good partial response (VGPR). Seven pts (13%) achieved confirmed complete response (CR) and stringent CR. 18/52 pts (35%) experienced severe treatment-emergent adverse events (t-SAEs) with an incidence of hematologic events of 4%. Incidences of infections and venous thromboembolism were 8% and 6%, respectively. Conclusions Results from this interim analysis indicate RAD to be a very effective and well tolerated induction protocol in newly diagnosed MM. High-quality response (VGPR or better) to induction is known to be a major prognosticator for long-term prognosis in a given patient. Thus, combination of RAD with risk-adjusted SCT may contribute to enhanced disease control in a substantial proportion of pts. Disclosures: Knop: Celgene Germany GmbH: Consultancy. Off Label Use: Lenalidomide in combination with dexamethasone and adriamycine in first line treatment of multiple myeloma. Langer:Celgene Germany GmbH: Consultancy. Gramatzki:Novartis, Celgene: Consultancy, Research Funding. Einsele:Celgene Germany GmbH: Consultancy, Honoraria. Bargou:Celgene Germany GmbH: Consultancy, Honoraria, Research Funding.

A phase II trial combining tumor-targeting TP53 gene therapy with gemcitabine/nab-paclitaxel as a second-line treatment for metastatic pancreatic cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4139-4139
Author(s):  
Chris Poki Leung ◽  
Minal A. Barve ◽  
Ming-Shiang Wu ◽  
Kathleen F. Pirollo ◽  
James F. Strauss ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Tp53 Gene ◽  
Phase Iii ◽  
Published Data ◽  
Line Treatment ◽  
Second Line ◽  
First Line

4139 Background: Nearly all stage IV pancreatic adenocarcinoma (PAC) patients progress after first-line treatment, and second-line options are limited. SGT-53 is an investigational product for tumor-targeted TP53 gene therapy that has completed phase Ia/Ib trials [Senser et al (2013), Mol Ther 21:1096; Pirollo et al (2016) Mol Ther 24:1697]. Methods: Here we provide an interim analysis of a Phase II trial (SGT53-02-1; NCT02340117) combining SGT-53 with gemcitabine/nab-paclitaxel (GEM/ABX). Eligible were first-line patients or those who had progressed after FOLFIRINOX (FFX) and/or gemcitabine-based therapy (second-line). In a 7-week treatment cycle, SGT-53 (3.6 mg DNA) was given once or twice weekly with GEM/ABX (1000 mg/m2/wk and 125 mg/m2/wk, respectively, for 3 of 4 weeks). Progression-free survival (PFS) and objective response rate (ORR) are primary endpoints.Overall survival (OS) and PFS are estimated by Kaplan-Meier analysis. Results: Of all evaluable patients (n=20), best response in 7 patients was determined to be partial response (PR) and 13 had stable disease (SD); none had progressive disease. In the second-line patients (n=11) there were 5 PR and 6 SD after 9 had failed FFX treatment, 3 had failed gemcitabine-based treatment and 1 had failed both. For patients with elevated CA19-9, SGT-53 + GEM/ABX resulted in marked reductions in the tumor marker. Published data for patients with PAC after therapy failure [Mita et al (2019) J Clin Med 8: 761; Portal et al (2015) Br J Cancer 113:989; Wang-Gillam et al (2016) Lancet 387:545] are shown for comparison. Notably, mPFS in our second-line patients was 7.4 months versus 3.1 months for the approved second-line therapy [Wang-Gillam et al (2016)]. This improvement in PFS exceeds the benchmark proposed to predict a clinically meaningful Phase III trial [Rahib et al (2016) Lancet Oncol 2:1209]. Conclusions: Our data suggest a clinically meaningful benefit of adding SGT-53 to GEM/ABX particularly for second-line PAC patients, most of whom had failed prior FFX treatment. Clinical trial information: NCT02340117. [Table: see text]

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.

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