A Phase 1 Trial of Ruxolitinib, Lenalidomide and Methylprednisolone for Relapsed/Refractory Multiple Myeloma Patients

Abstract Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea or intermediate or high-risk myelofibrosis (MF). Preclinical studies from our laboratory have demonstrated that RUX in combination with the immunomodulatory agent lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 is responsible for LEN resistance in MM cells, and RUX blocks its expression in multiple myeloma (MM) cells. Thus, RUX may restore sensitivity to LEN. RUX also downregulates PD-L1 and PD-L2 expression on MM cells and reduces tumor stimulatory M2 macrophage polarization in MM bone marrow. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and the steroid methylprednisolone (MP) for relapsed/refractory (RR) MM patients who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with expansion once a MTD was determined. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, patients received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results Thirty-four patients have been enrolled, and 31 were evaluable for response as of July 13, 2018. The median age was 68 years (range, 49-81), and 20 (59%) were male. Patients received a median of 6 prior treatments including lenalidomide and a PI. No DLTs occurred, and DL+3 was expanded (n=25). Among all 31 evaluable patients, the CBR and ORR were 48% and 39%, respectively (1 CR, 9 PR, 2 VGPR, and 3 MR), and 11 and 5 showed SD and PD, respectively. Notably, all 15 patients achieving ≥ MR were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). The median PFS for all evaluable patients was 7.4 months. Grade 3/4 adverse events included transient thrombocytopenia (11.1%), anemia (8.8%), neutropenia (6.7%), hypoxia (4.4%) and gastrointestinal bleeding (4.4%). Common serious adverse events included abdominal pain (6.7%), gastrointestinal bleeding (6.7%) and hypoxia (6.7 %). Conclusions This phase 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM patients. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients. These promising results are leading to other clinical trials using immunomodulatory agents, steroids and RUX, for treating RRMM patients, and this may represent a new therapeutic approach for these patients. Disclosures Berenson: BMS: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; Takeda: Honoraria, Speakers Bureau; Daiichi: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

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Efficacy and Safety of Ruxolitinib and Steroids for Treating Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2021-151016 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2727-2727

Author(s):

James R. Berenson ◽

Daisy Martinez ◽

Tahmineh Safaie ◽

Noemi Silagan ◽

Jennifer To ◽

...

Keyword(s):

Multiple Myeloma ◽

Drug Combination ◽

Macrophage Polarization ◽

Phase 1 ◽

Janus Kinase ◽

Clinical Activity ◽

M2 Macrophage ◽

Inadequate Response ◽

Phase 1 Trial ◽

Previously Treated

Abstract Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with intermediate or high-risk myelofibrosis and polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Preclinical studies from our laboratory have demonstrated that RUX in combination with dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Specifically, RUX blocks expression of Mucin 1 whose function is linked to lenalidomide (LEN) resistance, downregulates PD-L1 and PD-L2 expression and reduces tumor stimulatory M2 macrophage polarization in multiple myeloma (MM) bone marrow. Recently published results from a Phase 1 trial for 28 heavily previously treated MM patients administered RUX, LEN and methylprednisolone (MP) demonstrated that the therapy was well tolerated and RUX overcame refractoriness to LEN and steroids (Berenson et al., Clin Cancer Res. 2020). The clinical benefit rate (CBR) and overall response rate (ORR) were 46% and 28%, respectively, and all 12 responding patients were refractory to LEN. We evaluated whether the combination of RUX and steroids without LEN was active for treating similar patients through treatment of a cohort within the current trial using this two-drug combination (NCT03110822). Methods MM patients must have failed > 3 prior regimens and have been exposed to a proteasome inhibitor and LEN. Patients were treated orally (PO) with 15 mg RUX twice daily on days 1-28 of a 28-day cycle and 40 mg MP every other day. The treatment of this two-drug combination was continued until disease progression (PD). Once PD was confirmed, LEN at 10 mg PO daily on days 1-21 of a 28-day cycle was added to the regimen. Primary endpoints were safety, ORR and CBR. Results As of July 15, 2021, 27 patients were enrolled. The median age was 64 years (range, 46-85), and 17 (63%) were male. Patients received a median of 4 (range, 3-11) prior treatments including LEN and steroid-containing regimens to which they were all refractory. Twenty-six patients have completed at least 1 full cycle of therapy; and, thus, were evaluable for efficacy. The ORR and CBR were 35% (n=9) and 39% (n=10), respectively. Notably, all 10 responding patients were refractory to LEN (i.e., progressed while on or within 8 weeks of last dosage). The remaining patients showed stable disease (n=12) or PD (n=4). The median follow-up was 13 months. The median progression-free survival was 4 months (range, 1-21). The median duration of response was 11 months (range, 1-20). Of 13 patients who progressed on the two-drug combination and had LEN added to their regimen, 6 patients responded (3 MR and 3 PR). Nine patients experienced SAEs including sepsis (12%), sepsis with neutropenic fever (4%), thrombocytopenia (4%), hyperglycemia (4%), neutropenia (4%), anemia (4%), acute heart failure (4%), rotator cuff tear (4%), osteomyelitis (4%), aspiration pneumonia (4%), pneumonia and pneumothorax (4%), and deep venous thrombosis (4%). Two patients died (one each from pneumonia and PD). Conclusions This ongoing Phase 1 trial is the first study demonstrating clinical activity of the two-drug combination of the JAK inhibitor RUX with steroids for MM patients. The treatment was well tolerated and shows promising efficacy for treating heavily previously treated MM patients. Because of this, additional studies are being conducted with higher doses of RUX in combination with MP for this patient population. Disclosures Vescio: Janssen: Speakers Bureau; Karyopharm: Speakers Bureau; GlaxoSnithKlein: Speakers Bureau; Amgen: Speakers Bureau. OffLabel Disclosure: Ruxolitinib is being investigated off-label to determine if it shows anti-myeloma activity in combination with steroids for relapsed/refractory myeloma patients.

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A Phase 1 Trial of Ruxolitinib, Lenalidomide and Methylprednisolone for Patients with Relapsed/Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2019-131370 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1903-1903 ◽

Cited By ~ 1

Author(s):

James R. Berenson ◽

Jennifer To ◽

Tanya M. Spektor ◽

Daisy Martinez ◽

Armando J. Sanchez ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Research Funding ◽

Phase 1 ◽

Janus Kinase ◽

M2 Macrophage ◽

Inadequate Response ◽

Phase 1 Trial ◽

Refractory Multiple Myeloma ◽

Equity Ownership

Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea or intermediate or high-risk myelofibrosis (MF). Preclinical studies from our laboratory have demonstrated that RUX in combination with the immunomodulatory agent lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 (Mucin 1) is responsible for LEN resistance in MM cells, and RUX blocks its expression in multiple myeloma (MM) cells. Thus, RUX may restore sensitivity to LEN. RUX also downregulates PD-L1 and PD-L2 expression on MM cells and reduces tumor stimulatory M2 macrophage polarization in MM bone marrow. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and the steroid methylprednisolone (MP) for relapsed/refractory (RR) MM patients who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 49 patients. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, patients received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results As of March 1, 2019, 43 patients were enrolled, and 40 were evaluable for efficacy. The median age was 65 years (range, 46-81), and 25 (58%) were male. Patients received a median of 6 prior treatments including LEN and steroids to which they were all refractory. No DLTs occurred, and DL+3 was expanded. Among all 40 evaluable patients, the CBR and ORR were 47% and 37%, respectively (1 CR, 4 VGPR, 10 PR and 4 MR), and 16 and 5 patients showed SD and PD. Notably, all 19 patients achieving > MR were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). The median PFS for all evaluable patients was 4 months. G3/4 AEs included anemia (16%), sepsis (14%), lymphocytopenia (14%), pneumonia (12%), neutropenia (12%) and hypokalaemia (12%). Most common SAEs included sepsis (14%) and pneumonia (12%). Conclusions This phase 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM patients. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients. These promising results are leading to expansion of the current clinical trial to 78 patients, and represent a potential novel therapeutic approach for treating MM. Disclosures Berenson: Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Sanofi: Consultancy; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy; OncoTracker: Equity Ownership, Other: Officer; OncoTracker: Equity Ownership, Other: Officer; Takeda: Consultancy, Speakers Bureau; Incyte Corporation.: Consultancy, Research Funding; Incyte Corporation.: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Eades:Celgene: Other: Stock. Boccia:Genentech: Speakers Bureau; DSI: Speakers Bureau; AMAG: Consultancy; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. OffLabel Disclosure: The goal of this clinical trial is to establish ruxolitinib in combination with lenalidomide and methylprednisolone as the therapy for relapse/refractory multiple myeloma patients.

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Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽

10.1182/blood.v122.21.287.287 ◽

2013 ◽

Vol 122 (21) ◽

pp. 287-287 ◽

Cited By ~ 2

Author(s):

Inger S. Nijhof ◽

Sonja Zweegman ◽

Mark-David Levin ◽

Harry R. Koene ◽

Aart Beeker ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Dose Level ◽

Research Funding ◽

Phase 1 ◽

Oral Cyclophosphamide ◽

Phase 2 ◽

Efficacy And Safety ◽

Grade 3 ◽

Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

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A Phase 1/2, Open-Label, Prospective, Multicenter Study to Evaluate the Efficacy and Safety of the Lower Dose of Bortezomib Plus Busulfan and Melphalan As a Conditioning Regimen in Patients with Multiple Myeloma Undergoing Autologous Peripheral Blood Stem Cell Transplantation: Result of Phase 1 Trial

Blood ◽

10.1182/blood.v120.21.1937.1937 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1937-1937

Author(s):

Jin Seok Kim ◽

Chang Ki Min ◽

Sung-Soo Yoon ◽

Jae Hoon Lee

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Oral Mucositis ◽

Phase 1 ◽

Conditioning Regimen ◽

Phase 1 Trial ◽

Conditioning Regimens ◽

Grade 3

Abstract Abstract 1937 Background: Despite the advantages of autologous stem cell transplantation (ASCT) over conventional chemotherapy, the results of ASCT in multiple myeloma (MM) are still unsatisfactory. Intravenous (iv) melphalan at a dose of 200 mg/m2 is the most commonly used conditioning regimen for ASCT. However, better conditioning regimens are still needed, and more intensive conditioning regimens have been investigated. We evaluated the role of bortezomib-containing regimen (escalated dose of bortezomib + iv busulfan and iv melphalan) in the MM patients who had a sensitive response to bortezomib during the induction chemotherapy. In the phase 1 trial, we assessed the MTD (maximum tolerated dose) of bortezomib. The trial is registered on National Cancer Institute website, number NCT01255527. Methods: Nine MM patients who were candidate for ASCT enrolled in this study. M:F=5:4 and median age were 59 (34–62). They were treated with escalating doses of bortezomib as a conditioning regimen (N=3/group; 0.7, 1.0, and 1.3 mg/m2 on D-6, D-3 & D+1) and a fixed dose of busulfan (3.2 mg/kg from D-5 to D-3) and melphalan (140 mg/m2 on D-2). Dose limiting toxicities (DLT) were defined as any toxicity of grade 3 or greater, with the following exceptions: vomiting, fatigue, alopecia, libido, amenorrhea, nausea, febrile neutropenia, infection, anorexia, depression, anxiety, and cytopenias. Grade 3/4 hematological toxicity was acceptable. Grade 4 of mucositis, °Ã Grade 3 diarrhea and °Ã Grade 3 cardiac toxicity were regarded as DLT. Only one patients had grade 3 oral mucositis and there were no other non hematologic toxicities of grade 3 or greater. DLT refers only to toxic events (symptomatic grade °Ã 3 toxicity) that occur until day +28 after ASCT and are attributed as possibly, probably, or definitely due to treatment. Results: Four patients had grade 3 oral mucositis (2 in 0.7 mg/m2 group, 1 in 1.0 mg/m2 group and 1 in 1.3 mg/m2 group), but no grade 4 (considered as DLT) oral mucositis. No other non hematologic toxicities of grade 3 or greater. Therefore, there were no dose limiting toxicities in this phase 1 trial and MTD of bortezomib was 1.3 mg/m2. Median times to ANC > 0.5 · 106/L and platelet > 20 · 106/L were 12 and 10 days, respectively, with no graft failures. All patients achieved at least very good partial response. Six patients (67%) achieved complete remission(CR) after ASCT. Conclusion: In the phase 1 trial, MTD of bortezomib was 1.3 mg/m2. Addition of bortezomib to busulfan and melphalan conditioning regimen shows to be safe, well-tolerated and worthy of phase 2 trial. Disclosures: No relevant conflicts of interest to declare.

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Ongoing Phase 1a/1b Dose-Finding Study of CWP232291 (CWP291) in Relapsed or Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v128.22.4501.4501 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4501-4501 ◽

Cited By ~ 3

Author(s):

Sung-Soo Yoon ◽

Chang-Ki Min ◽

Jin Seok Kim ◽

Elisabet E. Manasanch ◽

Robert Hauptschein ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Adverse Events ◽

Target Genes ◽

Phase 1 ◽

Dose Range ◽

Single Agent ◽

Serious Adverse Events ◽

Pharmaceutical Corporation ◽

Grade 3

Abstract Background: CWP291, a novel peptidomimetic small molecule, has potent and selective inhibitory activity on a Wnt gene reporter and decreases expression of the β-catenin target genes, cyclin D1 and survivin. It has broad anti-cancer efficacy in vitro, outperforming lenalidomide and bortezomib in multiple myeloma murine xenografts and demonstrating improved survival when used in combination with lenalidomide in bone marrow engraftment models. Methods: Subjects with relapsed or refractory MM were infused CWP291 iv over at least 30 minutes twice weekly for 3 weeks out of a 4-week cycle in a 3+3 dose-escalation, Phase 1 design. Results: Results as of July 15, 2016 over a dose range of 198 - 446 mg/m2 in 9 subjects are reported. Median duration of treatment was 3 cycles (range 1.3 - 6.5 cycles) with 3 subjects ongoing. The most common (>20% of subjects) drug-related adverse events (AEs) were due to GI toxicities, including diarrhea (77.8%), nausea (55.6%) and constipation (33.3%). Toxicity was mostly ≤grade 2, however grade 3/4 events were frequently related to myelosuppression, including neutropenia (33.3%), and anemia and thrombocytopenia (22.2% each). Serious adverse events were recorded for 5 subjects with 8 separate events: 6 events in 4 subjects considered unrelated were hospitalizations for pneumonia, and 2 events in 1 subject each considered possibly related were a urinary tract infection and grade 3 hypoxia. Dose-limiting toxicities occurred in 2 patients at 446 mg/m2, which were hypoxia (grade 3) and thrombocytopenia (grade 4). Accrual at 335 mg/m2 has now been initiated. Stable disease (≥3 months on therapy with no increase in M protein as per the IMWG) was seen in 4 subjects. There was also documentation of a 34.6% decrease in bone marrow plasma cells in one subject for whom a bone marrow aspirate was available. PK in the first 3 subjectsreceiving198 mg/m2showed plasma levels of the active metabolite had very little inter-patient variability, which were comparable to patients with AML receiving this same dose in another study. There was less than 4% excreted in the urine, and there was no evidence of accumulation from Day 1 to Day 18. Changes in targeted genes in blood and BM, as well as additional PK, will be provided from expanded and escalated dosing cohorts. Furthermore, preliminary observations in the Phase 1b part of this study, which combines the administration of CWP291 with lenalidomide and dexamethasone, will be reported. Conclusions: CWP291, a novel and first in class molecule with significant preclinical activity, shows single agent safety as well as early evidence of efficacy in subjects with MM. Accrual is ongoing to establish the optimal dose level for both single agent and combination therapy. Disclosures Hauptschein: JW Theriac Pharmaceutical: Employment. Choi:JW Pharmaceutical Corporation: Employment. Lee:JW Pharmaceutical Corporation: Employment.

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

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462320001798 ◽

2020 ◽

Vol 36 (S1) ◽

pp. 36-37

Author(s):

Pei Wang ◽

Jing Li ◽

Yang Yang ◽

Peng Liu

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Staging System ◽

Chinese Patients ◽

Disease Stage ◽

Control Group ◽

Therapeutic Effects ◽

Lower Grade ◽

Refractory Multiple Myeloma ◽

Grade 3

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

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Bortezomib, lenalidomide, and dexamethasone with panobinostat for front-line treatment of patients with multiple myeloma who are eligible for transplantation: a phase 1 trial

The Lancet Haematology ◽

10.1016/s2352-3026(18)30174-1 ◽

2018 ◽

Vol 5 (12) ◽

pp. e628-e640 ◽

Cited By ~ 5

Author(s):

Elisabet E Manasanch ◽

Jatin J Shah ◽

Hans C Lee ◽

Donna M Weber ◽

Sheeba K Thomas ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase 1 ◽

Line Treatment ◽

Front Line ◽

Phase 1 Trial

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A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.4774.4774 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4774-4774

Author(s):

James R. Berenson ◽

Laura V. Stampleman ◽

Alberto Bessudo ◽

Peter J. Rosen ◽

Leonard M Klein ◽

...

Keyword(s):

Multiple Myeloma ◽

Progressive Disease ◽

Liposomal Doxorubicin ◽

Phase 1 ◽

Single Agent ◽

Pegylated Liposomal Doxorubicin ◽

Great Promise ◽

Phase 2 ◽

Grade 3

Abstract Background Immunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM. Methods The phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11. Results As of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22). During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled. Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months. ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose. Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis. Conclusions This phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. Disclosures Berenson: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

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

Blood ◽

10.1182/blood-2020-143379 ◽

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.

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Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽

10.1182/blood-2020-139174 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Hang Quach ◽

Simon J Harrison ◽

Je-Jung Lee ◽

Nichloas Murphy ◽

Jae Hoon Lee ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Board Of Directors ◽

Phase Ii ◽

Primary Endpoint ◽

Research Funding ◽

Open Label ◽

Advisory Committees ◽

Open Label Phase ◽

Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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