scholarly journals A Phase II Study of Pomalidomide, Daily Low Dose Oral Cyclophosphamide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4520-4520
Author(s):  
Ajai Chari ◽  
Hearn Jay Cho ◽  
Samir Parekh ◽  
Kenneth Lau ◽  
Gillian Morgan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Committees ◽  
Common Grade ◽  
Metronomic Therapy ◽  
Grade 3 ◽  
Study Therapy

Abstract Background A treatment option for patients with relapsed/refractory multiple myeloma (RRMM) is pomalidomide(pom) and dexamethasone (dex), with an overall response rate (ORR) of 33% and median progression free survival (PFS) of 4.2 months. Adding the alkylatingagent cyclophosphamide(Cy) to pom and steroids improves ORR and PFS. Baz et al (Blood, 26 May 2016) combined daily pom with weekly dosing ofCy anddex (PCD), with an ORR of 64.7% and a median PFS of 9.5 months, although grade 3/4 neutropenia increased from 31% to 52%. In our experience, compared to weekly Cy, low dose daily oral Cy is better tolerated with less myelosuppression. Palumbo et al (Blood, 17 Oct 2013) in fact combined pom with alternate day dosing ofCy and prednisone, with an ORR of 51% and a median PFS of 10.4 months and a grade 3/4 neutropenia rate of 42%. However, importantly, granulocyte stimulating factor (G-CSF) and platelet transfusion support wereprohibited, resulting in a lower maximum tolerated dose of pom of 2.5 mg (vs 4 mg in the Baz) and therefore, the rates of neutropenia cannot be compared between the two studies. In the present study, we explored PCD at the doses/schedule shown in table 1 with hematologic support even in patients with baselinecytopenias. This type of metronomic therapy has demonstrated efficacy in refractory B cell malignancies, possibly because the anti-angiogenic effects of metronomic therapy may be synergetic with conventional anti-neoplastic agents. Methods This was an open label, single arm, and single center phase 2study. The primary objective was to evaluate the best ORR. Secondary objectives were to evaluate safety, clinical benefit response (CBR), PFS, and overall survival (OS). Inclusion criteria included lenalidomide refractory, pom naïve RRMM patients with at least 2 prior lines of therapy. Patients were required to have measurable disease, adequate performance status, Cr <3 mg/dL, normal hepatic function, and ANC > 1000/uL and platelets > 50,000/uL if bone marrow plasma cells were < 50%, otherwise >30,000/uL. G-CSF and platelet support were permitted during screening and study treatment if needed. Each drug was administered at the doses and schedule shown in Table 1. Results Overall, 28 evaluable patients with progressive disease (PD) at screening have been enrolled. The median age is 66 (57% > 65 yr) with a median of 3 lines of prior therapy over 5 years since diagnosis. 3 (11%) had ANC<1.5 and 2 (7%) hadplts<50,000/µL at study entry.High-risk molecular findings were present in 13 patients (46%), including 3 with del p53 and 6 with gain of 1q21 by FISH (2 with concurrentt(4;14) and 2 with concurrent del p53). With 8 patients still on study therapy, responses include 3 complete responses (CR), 7 very good partial responses (VGPR), 9 partial responses (PR), 3 minor responses (MR), 5 stable disease (SD), and 1 PD, for an ORR of 67%, CBR (i.e. MR or better) of 78% and a median PFS of approximately 14.5 months. The median OS has not been reached. The most common grade 3/4 toxicity (regardless of drug attribution) was neutropenia with 20 (71%) of subjects experienced grade 3/4 neutropenia. Importantly, there was only 1 episode of febrile neutropenia during study therapy. Grade 3/4 thrombocytopenia was seen in 25% of subjects, and 3/4 anemia seen in 18%. The most common grade 3/4 non-hematologic toxicity was pulmonary disease with Grade 3 lung infections occurring in 21% of subjects (3 viral, 2 bacterial, 1 unknown) and 1 additional grade 3 URI. Of note, all of these admissions occurred at local hospitals and none of these occurred in the setting of neutropenia. One additional pt hadpneumonitisattributed to pom requiring study discontinuation. Grade 3rashwas also observed in 14% of subjects leading to pom dose reductions. Correlative data from peripheral blood and bone marrow aspirates taken at baseline, Cycle 3 Day 15, and at disease progression from all patients will be updated at the time of conference. These include PCD-associated changesin gene expression, clonal evolution and immune microenvironment during therapy and on progression. Conclusions With toxicities similar to those in other studies, the ORR of 67% and PFS of 14 months in our study of PCD compares very favorably to pomdexas well as other triplet regimens containingCy. Disclosures Chari: Takeda: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen Inc.: Honoraria, Research Funding. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Agenus, Inc.: Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Catamero:Celgene: Honoraria, Speakers Bureau. Verina:Celgene: Speakers Bureau. Jagannath:Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

A Phase I Study of Escalated Dose Subcutaneous Alemtuzumab Given Weekly with Rituximab In Relapsed CLL/SLL.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1381-1381
Author(s):  
Jennifer R Brown ◽  
Bradley Messmer ◽  
Lillian Werner ◽  
Evgeny Mikler ◽  
David C. Fisher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Injection Site ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Study Entry ◽  
Ct Scans ◽  
Advisory Committees ◽  
Grade 3 ◽  
Study Therapy

Abstract Abstract 1381 Alemtuzumab is an anti-CD52 antibody originally approved for intravenous administration three times per week to CLL patients refractory to fludarabine and previously exposed to alkylators. Since that time subcutaneous administration three times per week has become widespread because of its reduced infusional toxicity and recently demonstrated equivalent efficacy. In this study we assessed the tolerability, efficacy and pharmacokinetics of administering alemtuzumab subcutaneously weekly at up to 90 mg per dose following an initial 3+3 dose escalation (see table); we further added weekly rituximab in hopes of enhancing activity in lymph nodes. Treatment was administered in up to two eight week blocks with response evaluation between; the second 8 week block continued the dose and schedule used in weeks 5–8. No more than 45 mg was given per subcutaneous injection site. 28 patients were enrolled on this study between 7/2006 and 1/2010. The median age was 62 (range 47–76), and 75% were male. The median time from diagnosis to starting study therapy was 94 mos (14-236 mos). A majority of patients (82%) had Rai stage 3–4 disease and the median number of prior therapies was 4 (1-11). 20/28 patients (71%) had high risk deletions of 17p or 11q. 13/16 (81%) had unmutated IGVH, and 14/19 (74%) were positive for ZAP70. Early study withdrawals occurred due to pre-existing and persistent thrombocytopenia requiring study therapy to be held (n=2), persistent fever attributed to alemtuzumab (n=1), PML in retrospect present prior to study entry (n=1), and a DLT (grade 3 rituximab reaction) which was observed on dose level 2 prior to dose escalation of alemtuzumab. Overall, therapy was well tolerated; injection site reactions were minimal, primarily grade 1 (n=11) with only two grade 2 events. Other toxicities were as expected with alemtuzumab in this patient population, including grade 3–4 neutropenia (54%), grade 3–4 thrombocytopenia (57%), and single cases each of grade 3 rash, AIHA, pulmonary embolism, MRSA bacteremia, diverticular abscess, pulmonary Cryptococcus, EBV lymphoma and metastatic colon cancer. The ORR by NCI-WG criteria at wk 8 was 61% (95% CI 42–76%), with CR rate 11% (95% CI 4–27%). Two of 14 patients who completed a second eight week cycle improved their response (one PR from SD, and one CR from PR). A planned endpoint of this study was to compare lymph node staging by CT to PE, and we found that using CT scans to evaluate nodal response at 8 weeks decreased the ORR rate to 14% (95% CI 6–31%), with no CRs. Bone marrow was completely cleared of disease by 8 weeks in 8 patients and by 16 weeks in an additional 4 patients. The median PFS for the entire population was 13 months with a median follow-up of 9 months in patients who have not progressed. 10 patients have died, 5 of disease, 3 of second malignancies, 1 of PML and 1 of SCT complications. The median OS from study entry is 47 months, with 10 patients having undergone subsequent SCT. Following initiation of therapy we observed a >1,700X decrease in the median CD19+5+ cell count in peripheral blood by the start of week 3. Similar rapid depletion of all T and NK cell subsets was also observed, with first signs of recovery at week 28, and more definite recovery at week 40. Preliminary pharmacokinetic data demonstrated lower maximum levels of rituximab (p=0.06) and alemtuzumab (p=0.05) in patients with >80% bone marrow replacement by CLL but not in those with bulky lymphadenopathy. A trend toward higher alemtuzumab levels was observed in those patients with complete bone marrow clearance (p=0.1) but not in those with objective response. In conclusion, we found that administration of alemtuzumab at 90 mg subcutaneously weekly in combination with rituximab was well-tolerated, convenient and resulted in sustained adequate blood levels of both drugs in most patients. Response rates were high although in this relapsed refractory CLL population, abdominal lymphadenopathy was common, resulting in a decreased response rate when CT scans were included in staging. PFS and OS were favorable for this novel combination regimen and many patients went on to SCT. Disclosures: Brown: Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Calistoga: Consultancy; Genentech: Consultancy. Off Label Use: alternative schedule of alemtuzumab. Kipps:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding; Memgen: Research Funding; Igenica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Research Funding; Abbott Laboratories: Research Funding.

scholarly journals The MP0250-CP201 Mirror Study: A Phase 2 Study Update of MP0250 Plus Bortezomib and Dexamethasone in Relapse/Refractory Multiple Myeloma (RRMM) Patients Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1899-1899 ◽  
Author(s):  
Norbert Grząśko ◽  
Stefan Knop ◽  
Hartmut Goldschmidt ◽  
Marc S Raab ◽  
Jan Dürig ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Drugs ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Grade 3

Background Bone marrow neovascularization is a hallmark of multiple myeloma and progression is associated with a substantial increase in pro-angiogenic factors that promote bone marrow angiogenesis, including vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF). At present, anti-angiogenic agents are not part of treatment strategies in multiple myeloma, neither alone nor in combination with approved agents. MP0250 is a first-in-class, tri-specific multi-DARPin® drug candidate neutralizing VEGF-A and HGF as well as binding to human serum albumin to increase plasma half-life. This is a report on early safety and efficacy of MP0250 in combination with bortezomib plus dexamethasone (Vd) in RRMM patients that have previously been exposed to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). Aims To assess the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM (MiRRoR, NCT03136653). Trial Design This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Patients will receive treatment until there is documented disease progression or unacceptable toxicity. Methods The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression-free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, and pharmacokinetics. Exploratory biomarkers for HGF and cMET in bone marrow biopsies are detected by IHC; MM specific markers, circulating HGF and VEGF levels are measured using patient plasma samples. Results As of 01 July 2019, 20 patients (7 ongoing) received a total of 137 doses (1-33 cycles) of MP0250 at the maximum tolerated dose of 8 mg/kg on Day 1 of each 21-day cycle in combination with Vd. Median age was 61 years (46-76), median time since diagnosis was 6.7 years. Median number of prior therapies was 4 (range, 2-9). All 20 patients had prior exposure to IMiDs and PIs and 9 patients received PI-based regimens as their immediate prior line of therapy before start of MP0250 + Vd. Importantly, 6 out of these 9 patients achieved responses ≥ Partial Response (PR). Treatment had been discontinued in 40% of patients due to PD, 15% due to Adverse Event (AE), 5% due to physician's decision and in 1 case at patient's request. The most frequent drug-related grade 3/4 AEs were hypertension in 7/1 patients, thrombocytopenia in 4/1 patients, grade 3 proteinuria in 4 patients and grade 3 anemia in 4 patients. There were no infusion-related reactions. No treatment-related deaths were reported. 20 patients received ≥ 1 dose of MP0250 + Vd and had at least 1 assessment of response and were included in the efficacy analysis. 1 patient (5%) achieved Complete Response, 4 patients achieved Very Good Partial Response (20%) and 3 patients achieved PR (15%) for an ORR of 40%. DOR at cutoff date is 6 months (range, 2-21). Pharmacokinetic data show sustained exposure over multiple cycles with a mean half-life of 11 days (range, 6-17). No indication of ADA-mediated drug clearance was observed. Summary Combining MP250 at 8 mg/kg with standard doses of bortezomib and dexamethasone was generally well tolerated with discontinuation due to AE in only 15% of patients. No unexpected toxicity was observed and AEs consistent with the toxicity profile of the individual agents. Analysis of the preliminary efficacy results showed an encouraging ORR of 40%. Recruitment to this Phase 2 study is ongoing. Disclosures Knop: Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; John-Hopkins University: Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Bringhen:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gamberi:Amgen: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Castellano Acosta:Molecular Partners AG: Employment. Lang:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

scholarly journals A Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2749-2749
Author(s):  
Omar Nadeem ◽  
Robert A. Redd ◽  
Julia Prescott ◽  
Kelsey Tague ◽  
Veronica Romines ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Phase Ii ◽  
Research Funding ◽  
Induction Phase ◽  
Advisory Committees ◽  
Study Therapy

Abstract Background: Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit based on previous studies that included treatment with lenalidomide or lenalidomide and dexamethasone (Mateos et al. N Engl J Med 2013; Lonial et al. J Clin Oncol 2020). Combination therapy with triplets has shown higher rates of deep response and improved outcomes in patients with multiple myeloma, including the combination of ixazomib, lenalidomide, and dexamethasone (Moreau et al. N Eng J Med 2016). We present our results of phase II study of ixazomib, lenalidomide and dexamethasone in HR-SMM. Methods: Patients enrolled on the study met eligibility for high-risk SMM based on the defined criteria proposed by Rajkumar et al. (Blood 2014). The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and dexamethasone at days 1, 8, 15, and 22. The induction phase was followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle was defined as 28 consecutive days for a total of 24 months period. Bone marrow samples of all patients were obtained before starting therapy for baseline assessment for minimal residual disease (MRD) testing, whole-exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle for isolating cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Results: Sixty-one patients have been enrolled in this study from February 2017 to 2020. The median age of the patients at enrollment was 64 years (range, 40 to 84), with 33 males (54.1%). The analysis was conducted on patients who have completed at least 2 cycles of therapy (n=55). Thus far, 42 (69%) patients have completed the planned 24 cycles of therapy. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 14 patients out of the 33 evaluable (42.4%) Interphase fluorescence in situ hybridization (iFISH) results. The median number of cycles completed was 24 cycles (range: 2-24). According to the new IMWG risk stratification model (20-2-20), baseline markers showed that 32 patients (58%) were high risk, 18 (33%) were intermediate risk, and 5 (9%) were low risk. The most common grades 3 or greater toxicities were neutropenia (20%), hypophosphatemia (13%), leukopenia (11%), rash (9%), lymphocytopenia (5%), and thrombocytopenia (5%). Stem cells were collected from all eligible patients by the end of the induction phase. No patients discontinued treatment due to toxicity. At the time of data cut off, the overall response rate (partial response or better) in participants who completed at least 2 cycles of treatment was 90.9% (50 of 55), with 12 complete responses (CR, 21.8%), 10 very good partial responses (VGPR, 18.2%), 28 partial responses (50.9%), and 4 minimal responses (MR, 7.3%). ORR in patients who completed the induction phase (≥9 cycles) was 92.3% (n= 48 of 52), with 22 (40%) deep remissions including 12 (23.1%) and 10 (19.2%) having achieved a CR and VGPR, respectively. All patients who had a CR have also achieved a stringent CR. No patients developed progression to overt or active MM while on study therapy. After completion of study therapy, 4 patients progressed to active MM during follow up, 3 additional patients developed biochemical progression and started a new course of therapy but did not meet CRAB criteria and 7 patients confirmed biochemical PD and remain off therapy. Conclusions: The combination of ixazomib, lenalidomide, and dexamethasone is an effective all oral well-tolerated intervention in high-risk smoldering myeloma that demonstrated an ORR of &gt;90% and deep remission in &gt;40% of patients. While no patients progressed to overt MM while on therapy, some developed progression after completion of planned study therapy, indicating the possible need for higher intensification of therapy or maintenance therapy beyond 2 years in this high-risk group of patients. Longer follow-up for disease outcome is ongoing. Disclosures Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Mo: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Sperling: Adaptive: Consultancy. Richardson: AstraZeneca: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene/BMS: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Phase 1/2 Study of Elotuzumab in Combination with Lenalidomide and Low Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma: Interim Results.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 432-432 ◽  
Author(s):  
Sagar Lonial ◽  
Ravi Vij ◽  
Jean-Luc Harousseau ◽  
Thierry Facon ◽  
Jonathan Kaufman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Low Dose ◽  
Phase 1 ◽  
Advisory Board ◽  
Advisory Committees ◽  
Expansion Phase ◽  
Grade 3

Abstract Abstract 432 Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces significant antibody-dependant cytotoxicity (ADCC) against primary myeloma cells in the presence of either autologous or allogeneic peripheral lymphocytes (PBMC), which is significantly enhanced when PBMC effector cells were pretreated with lenalidomide (Tai et al., Blood 112:1329, 2008). The primary objective of the phase 1 portion of the study is to evaluate the maximum tolerated dose (MTD) of elotuzumab in combination with lenalidomide and low dose dexamethasone in patients with relapsed MM. The study is also evaluating safety, pharmacokinetics (PK) and clinical response. Lenalidomide (25 mg PO) is given on Days 1-21 of a 28-day cycle. Elotuzumab in three escalating dose cohorts (5, 10 and 20 mg/kg) is administered by IV infusion on Days 1, 8, 15 and 22 of the 28-day cycle in the first two cycles and then on Days 1 and 15 of each subsequent cycle. Dexamethasone is given weekly at 40 mg PO. Initially, patients received 6 cycles of treatment unless withdrawn earlier due to disease progression or unacceptable. toxicity. The protocol was amended to allow for patients in the 10 and 20 mg/kg cohorts to receive treatment for up to 12 months following enrollment of the last patient. Key entry criteria: age ≥ 18 years; MM with at least one relapse; measurable disease M-protein component in serum and/or in urine; and prior lenalidomide treatment, if any, more than 6 weeks of first dose. To date, 24 patients with a median age of 60 years have been enrolled in the study and 23 patients have received study drug. The median time from initial diagnosis of MM was 5 years and patients had received a median of 3 prior MM treatments. Patients had been previously treated with thalidomide (58%), bortezomib (67%) or lenalidomide (21%) and 42% were refractory to their most recent MM therapy. Patients have been treated in the 3 cohorts; 3 patients each in the first two cohorts (5 and 10 mg/kg elotuzumab) and 17 patients (7 in dose-escalation phase and 10 in the expansion phase) in the third cohort (20 mg/kg). No dose limiting toxicities were identified during the dose-escalation phase of the study and no MTD was established. One patient discontinued in the first cycle due to grade 4 allergic reaction resulting from elotuzumab infusion in the expansion phase of the study. Additional SAEs (1 of each) included grade 2 atrial fibrillation (related to lenalidomide/dexamethasone) and unrelated grade 4 ruptured diverticulum, grade 3 neutropenic fever and grade 3 diarrhea.. Other common grade 3 or 4 AEs included neutropenia (25%) and thrombocytopenia (25%), which were managed by dose withholding or dose reduction of lenalidomide. Approximately 25% of patients experienced grade 1 or 2 chills and/or pyrexia associated with elotuzumab infusion. The best clinical response (IMWG criteria) in the 13 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis of elotuzumab suggests a serum half-life of 10-11 days at 10 and 20 mg/kg. Elotuzumab at all three doses resulted in near complete saturation of CS1 sites on plasma cells and NK cells in bone marrow and NK cells in the peripheral compartment. In conclusion, the combination of elotuzumab with lenalidomide and low-dose dexamethasone has a manageable adverse event profile and compared to historical data for lenalidomide and high-dose dexamethasone, the preliminary efficacy data (≥ PR of 92%) are very encouraging. Additional safety, efficacy and PK/PD data will be presented at the meeting. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Off Label Use: Lenalidomide/dexamethasone in combination with elotuzumab in patients with relapsed/refractory multiple myeloma. Vij:Celgene: Research Funding, Speakers Bureau. Harousseau:Celgene France: Advisory Board; Janssen Cilag France: Advisory Board; Celgene: Honoraria; Janssen Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kaufman:Celgene: Consultancy, Research Funding; Millennium: Consultancy; Genzyme: Consultancy; Merck: Research Funding. Mazumder:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Leleu:Celgene: Research Funding, Speakers Bureau. Fry:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium: Advisory Board; Merck: Advisory Board.

scholarly journals Daratumumab (DARA) Plus Carfilzomib, Pomalidomide, Dexamethasone (KPd) in Lenalidomide Refractory Multiple Myeloma (MM): A Multi-Center MMRC Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-50
Author(s):  
Jagoda Jasielec ◽  
Jeff Zonder ◽  
Benjamin A Derman ◽  
Donna E. Reece ◽  
Craig E. Cole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Second Stage ◽  
Best Response ◽  
Common Grade ◽  
Grade 3

Introduction: Lenalidomide (LEN) is a cornerstone in the treatment of newly diagnosed MM both as part of induction and maintenance therapy. As a result, most patients at first or second relapse are LEN exposed/refractory creating a need for effective 2nd line and salvage therapies. While no standard of care regimen has been established in early relapse, several therapies have been evaluated combining second generation immunomodulatory agents, proteasome inhibitors, and daratumumab. We have previously reported the results from the phase I/II trial of KPd demonstrating excellent efficacy in a LEN-refractory patient population. Here, we present the first efficacy and safety results from the cohort in which DARA was added to KPd (D-KPd). Methods: This is a multi-center, open-label, Phase 1b/2 study in subjects with relapsed MM with two sequential treatment cohorts: KPd and D-KPd. Eligibility criteria and KPd doses and schedules were identical for both cohorts. Subjects with measurable disease that progressed after at least 1 prior therapy (LEN refractory disease was required for 2nd-line therapy and LEN refractory/exposed for ≥ 3rd line) were eligible. The KPd cohort has completed enrollment (n=67) and results have been previously reported. The D-KPd cohort received treatment on the following 28-day schedule: Pomalidomide 4 mg daily on days 1-21 for cycles 1-8+, Carfilzomib 20/27 mg/m2 on days 1,2,8,9,15,16 for C1-8, then 1,2,15,16 for C9+ (maintenance), dexamethasone 20 mg days 1,2,8,9,15,16,22,23 for C1-2, then 40 mg days 1,8,15,22 for C3+. DARA was administered as per standard schedule, weekly for the first 2 cycles, then every 2 weeks for cycles 3-6, and monthly thereafter. A Minimax two-stage design was employed for enrollment of subjects on this cohort. Twenty-one patients were required to accrue to the first stage, with at least 4 responders of ≥nCR at 4 cycles necessary to accrue to second stage for a total of 34 pts. Primary endpoint was rate of nCR/CR as per IMWG criteria. Minimal residual disease (MRD) was evaluated by 10-color flow cytometry with limit of detection (LOD) 10-4-10-5 and will also be assessed by next-generation sequencing (LOD 10-5-10-6). Secondary endpoints include overall response rate, depth of response, progression-free survival (PFS), and overall survival. Per study design, a nCR/CR rate of &gt;35% (over the historical 20% rate) would support further study of the D-KPd regimen. Results: As of July 29, 2020, all 22 subjects who were enrolled into the D-KPd cohort were evaluable for safety and the primary endpoint. Median age was 62 (range 37-74) with a median of 1 (range 1-3) prior lines of therapy. 81% of patients were LEN refractory, and high-risk cytogenetics per IMWG criteria were present in 12/19 (68%) evaluable patients. Subjects completed a median of 12.5 cycles (range 2-33) of therapy and 21 (95%) subjects completed at least 4 cycles; 1 subject progressed after cycle 2. In the ITT population (n=22), after 4 cycles, 86% achieved ≥PR and 46% ≥nCR, warranting further enrollment to a second stage. At best response, the ≥PR was 86% with 55% ≥nCR/CR, 45% ≥sCR, and 55% MRD negativity by flow cytometry (n=22). The most common grade 3-4 hematologic adverse events included neutropenia (64%), lymphopenia (36%), and febrile neutropenia (18%). The most common grade 3-4 non-hematologic adverse events included fatigue (27%), respiratory infections (23%), diarrhea (14%), and insomnia (14%). There was one thrombotic event (4.5%) which was grade 2. In comparison to the KPd cohort (67 patients with similar baseline characteristics), there was an improvement in efficacy as demonstrated by an increase in rate of ≥nCR at the end of 4 cycles (from 7% to 46%), as well as the best response (from 20% to 55%). High risk cytogenetics did not significantly affect response (≥nCR 46% at best response [all sCR]). With 20 months of follow-up, median PFS was not reached in the D-KPd cohort and 12-month PFS is 84% vs 63% for KPd. Rates of grade 3/4 cytopenias were higher in the D-KPd cohort. There was no treatment related mortality and 19 of 22 pts are alive. Conclusion: D-KPd demonstrates high efficacy in a population of patients with relapsed/refractory multiple myeloma enriched for high risk cytogenetics. MRD negativity by flow cytometry was achieved in 55% of subjects. The ≥nCR rate of 55% with D-KPd compares favorably to the 20% rate with KPd alone; based on the study design, this warrants further evaluation of D-KPd. Disclosures Zonder: BMS, Celgene: Research Funding; Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy. Reece:Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria; Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Berdeja:Kesios: Research Funding; Karyopharm: Consultancy; Acetylon: Research Funding; Vivolux: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding; Bioclinica: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellularity: Research Funding; Constellation: Research Funding; CURIS: Research Funding; EMD Sorono: Research Funding; Genentech, Inc.: Research Funding; Glenmark: Research Funding; Janssen: Consultancy, Research Funding; Kite Pharma: Consultancy; Legend: Consultancy; Lilly: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Takeda: Consultancy, Research Funding; Teva: Research Funding; Prothena: Consultancy; Servier: Consultancy; Bluebird: Research Funding; CRISPR Therapeutics: Consultancy, Research Funding. Jakubowiak:Adaptive, Juno: Consultancy, Honoraria; AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: Preliminary Outcome from the Open Label Phase II ALLGMM018/AMN003 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1955-1955
Author(s):  
Hang Quach ◽  
Simon J. Harrison ◽  
Slavisa Ninkovic ◽  
Jane Estell ◽  
Noemi Horvath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Abstract Background: Carfilzomib lenalidomide and dexamethasone (KRd) is FDA-approved for the treatment relapsed/refractory multiple myeloma (RRMM) based on data from the ASPIRE study (Stewart K et al. NEJM 2015). Thalidomide, a first generation immunomodulatory drug (IMiD) is less costly than lenalidomide and is synergistic in combination with proteasome inhibitors in the treatment of MM. ALLG MM018/ AMN003 is an open label phase II study of carfilzomib thalidomide and dexamethasone (KTd) for patients with RRMM. The primary end point is progression free survival (PFS). Secondary endpoints include overall response rate (ORR), duration of response (DOR), safety and health related quality of life. Method: Eligible patients were those with RRMM who have had 1-3 prior lines of treatment. The KTd regimen consisted of carfilzomib [20mg/m2 IV C1D1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from C1D8 onwards], thalidomide (100mg po nocte) and dexamethasone [40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, thalidomide was omitted and Kd [carfilzomib 56mg/m2 (36/m2 for patients age ≥75 years) on days 1,2,15,16 and dexamethasone 40mg (20mg for patients age ≥75 years) on days 1,15 every 28 days]was continued for a further 6 cycles. Peripheral blood and bone marrow aspirate and trephine for correlative studies were collected from the first 30 patients, at baseline, after cycle 6 and at confirmed disease progression. The aim of the correlative study was to assess for immunological correlates to clinical outcome. Immunological parameters that will be assessed include NK and T cells subsets on peripheral blood via mass cytometry (CyTOF). On the bone marrow trephine, NK cells, T cells, GRP78 expression within CD38 positive plasma cells, PD1 and PDL1 expression will be assessed at the myeloma site and the surrounding microenvironment using OPAL multiplex immunohistochemistry technology. Results: Between March 2017 to June 2018, 56 patients (median age 66 years, range 56-79; 77% Caucasian and 23% Asian) out of the planned 100 were enrolled, with a median follow up of 4.9 (range, 1.0-13.7) months. Response rates in 39 evaluable patients were ≥MR (97%), ≥PR (89%) and ≥VGPR (66%). Median PFS is not reached, and no patients with ≥MR have relapsed. Grade ≥3/4 AEs occurred in 56% of patients, the most common of which were peripheral sensory neuropathy (13%), dyspnoea (13%) and infections (7%). All grade cardiovascular AEs included dyspnoea (27%), cardiac complications (5%), systemic-hypertension (9%) and pulmonary-hypertension (1.9%), however very few were grade ≥3. Three patients have died on study from disease complications, haemorrhage, and primary cardiac ischaemic event. Thus far, we have not found a significant difference in rates or profile of adverse events between the Caucasian versus Asian subgroups of patients. Conclusion: This preliminary analysis demonstrates that the KTd combination is a tolerable regimen for patients with RRMM with a safety profile in line with previous reports for each of carfilzomib and thalidomide. Initial response rates appear very promising and durable with responses up to 13.7 months thus far in some patients. Patient accrual is ongoing. Disclosures Quach: Janssen Cilag: Consultancy; Sanofi Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Harrison:Janssen-Cilag: Other: Scientific advisory board. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Durie:Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Chng:ASLAN Pharmaceuticals: Research Funding.

scholarly journals Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 804-804 ◽  
Author(s):  
Mark Bustoros ◽  
Chia-jen Liu ◽  
Kaitlen Reyes ◽  
Kalvis Hornburg ◽  
Kathleen Guimond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Rna Sequencing ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

scholarly journals 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 ◽  
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.

A Phase I Study of Bendamustine Combined with Lenalidomide and Dexamethasone in Patients with Refractory or Relapsed Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1856-1856 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Amy O’Sullivan ◽  
Silvana Lalo ◽  
Carrie Kruppa ◽  
Diane Gardner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Dose Level ◽  
Research Funding ◽  
Advisory Board ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 1856 Poster Board I-882 Background: Lenalidomide is an analog of thalidomide that has shown significant clinical activity in patients with relapsed or refractory multiple myeloma (MM), both as a single agent and in combination with dexamethasone. Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma that has progressed during or relapsed within 6 months following a rituximab-containing regimen. Bendamustine combined with lenalidomide may be an effective treatment option for MM patients, particularly those with preexisting or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: Patients aged ≥18 years with confirmed, measurable stage 2 or 3 MM that was refractory to or progressed after 1 or more prior therapies, including lenalidomide, received bendamustine by intravenous infusion on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle. Treatment was continued until a plateau of best response, as determined by the IBMTR/ABMTR, was reached. Study drug doses were escalated through 4 levels (Table), with 3–6 patients enrolled at each level depending on the rate of dose-limiting toxicity (DLT). After determining the MTD, up to an additional 12 patients will be enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: To date, 11 patients have been enrolled, with a median age of 63 years (range, 38–75 years). The MTD of bendamustine and lenalidomide has not been identified at this point; currently, patients are enrolling on dose level 3 with 100 mg/m2 bendamustine and 10 mg lenalidomide. Thus far, DLT included 1 grade 4 neutropenia at dose level 2. Nine of 11 patients are currently eligible for response assessment. A partial response was observed in 67% of patients, including 1 very good partial response and 5 partial responses (PR). Two patients experienced stable disease and 1 exhibited progressive disease. Grade 3/4 adverse events included grade 3 neutropenia, thrombocytopenia, anemia, hyperglycemia, and prolonged QTC, and 1 grade 4 neutropenia. Conclusions: Bendamustine, lenalidomide, and dexamethasone form a well-tolerated and highly active regimen even in heavily pretreated MM patients, with a PR rate of 67%. Additional updates on response and MTD will be available at the time of presentation. Disclosures: Lentzsch: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bendamustine is not FDA approved for the treatment of multiple myeloma in the USA. Burt:Millennium: Honoraria; Celgene: Honoraria. Mapara:Resolvyx: Consultancy, Research Funding; Genzyme: Membership on an entity's Board of Directors or advisory committees; Gentium: Equity Ownership; Celgene: Spouse is consultant , has received research funding, and participates on advisory board; Cephalon: Spouse has received funding for clinical trial and participates on advisory board. Redner:Biogen: Equity Ownership; Wyeth: Equity Ownership; Glaxo-Smith-Kline: Equity Ownership; Pfizer: Equity Ownership; Genzyme: Membership on an entity's Board of Directors or advisory committees. Roodman:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Acceleron: Consultancy. Zonder:Amgen: Consultancy; Pfizer: Consultancy; Cephalon: Consultancy; Millennium: Consultancy, Speaking (CME only); no promotional talks.

Phase 1/2 Study of Elotuzumab in Combination with Bortezomib in Patients with Multiple Myeloma with One to Three Prior Therapies: Interim Results.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3876-3876 ◽  
Author(s):  
Andrzej J Jakubowiak ◽  
William Bensinger ◽  
David Siegel ◽  
Todd M. Zimmerman ◽  
Jan M. Van Tornout ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Surface Glycoprotein ◽  
Advisory Committees ◽  
Cell Surface Glycoprotein

Abstract Abstract 3876 Poster Board III-812 Background Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma (MM). In mouse xenograft models of MM, elotuzumab demonstrated significantly enhanced anti-tumor activity when combined with bortezomib compared to bortezomib alone (Van Rhee et al., Mol. Cancer Ther., in press, 2009). This phase 1/2 trial will determine the maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK) and clinical response of elotuzumab in combination with bortezomib in patients with relapsed MM following 1-3 prior therapies. Methods The study consists of 4 escalating cohorts of elotuzumab (2.5 mg/kg to 20 mg/kg) administered on Days 1 and 11 and bortezomib (1.3 mg/m2) administered on Days 1, 4, 8 and 11 of a 21-day cycle. Patients with progressive disease at the end of Cycle 2 or 3 also receive oral dexamethasone (20 mg) on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each subsequent cycle. Patients with stable disease or better at the end of 4 cycles will continue treatment for 6 or more cycles unless withdrawn earlier due to unexpected toxicity or disease progression. Key entry criteria: age ≥ 18 years; confirmed diagnosis of MM and documentation of 1 to 3 prior therapies; measurable disease M-protein component in serum and/or in urine; and no prior bortezomib treatment within 2 weeks of first dose. Results To date, a total of 16 MM patients with a median age of 64 years have been enrolled in the study. The median time from initial diagnosis of MM was 3.5 years and patients had received a median of 2 prior MM treatments. Patients have been treated in four cohorts; 3 each in 2.5, 5 and 10 mg/kg elotuzumab cohorts, and 7 in the 20 mg/kg elotuzumab cohort. No dose limiting toxicity (DLT) was observed during the first cycle of the study and the MTD was not established. Five SAEs have been reported in four patients in later treatment cycles; two events, chest pain and gastroenteritis, occurring in one patient, were considered elotuzumab-related. Other SAEs include grade 3 sepsis, vomiting, pneumonia and grade 2 dehydration. The most common AEs reported include Grade 1-3 diarrhea, constipation, nausea, fatigue, thrombocytopenia, neutropenia, anemia and peripheral neuropathy. The best clinical response (EBMT criteria) for the 16 patients who have received at least two cycles of treatment is shown in the table below. Preliminary PK analysis suggests a serum half-life of 10-11 days at higher doses (10 and 20 mg/kg). Preliminary analysis of peripheral blood mononuclear cells and bone marrow of patients on study indicates that objective responses in the study correlate well with complete saturation of CS1 sites by elotuzumab on bone marrow plasma and NK cells. Conclusions The combination of elotuzumab with bortezomib has a manageable adverse event profile and shows promising preliminary efficacy with ≥PR in 44% and ≥MR in 75% of all enrolled patients. Accrual is ongoing in the expanded 20 mg/kg cohort. Updated safety, efficacy, and PK data will be presented at the meeting. Disclosures: Jakubowiak: Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor Ortho Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Bortezomib in combination with elotuzumab for the treatment of relapsed/refractory multiple myeloma. Bensinger:Millennium: Membership on an entity's Board of Directors or advisory committees. Siegel:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Zimmerman:Millennium: Speakers Bureau; Centecor: Speakers Bureau. Van Tornout:BMS: Employment. Zhao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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