scholarly journals Phase I Study of a Novel Bcl-2 Inhibitor, at-101 in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3137-3137
Author(s):  
Sikander Ailawadhi ◽  
Victoria R. Alegria ◽  
Salman Ahmed ◽  
Betsy Laplant ◽  
Alak Manna ◽  
...  

Background: The development of novel treatment strategies has extended the median survival of MM to nearly a decade but the disease remains incurable and relapse is inevitable. The Bcl-2 pathway is highly relevant to MM cell survival and can be mitigated therapeutically. AT-101 is a novel, orally available pan Bcl-2 inhibitor (Bcl-2, Bcl-xl, Mcl-1, and Bcl-w). Preclinical in vitro and in vivo studies showed that AT-101 enhanced cytotoxicity of lenalidomide-dexamethasone (Rd). We conducted a phase I study in RRMM patients to establish the effective dose of AT-101 with Ld as well as record safety and preliminary efficacy of this combination (NCT02697344). Methods: Key eligibility criteria included: RRMM with measurable disease (serum monoclonal protein ≥1.0 g/dL or urine monoclonal protein >200mg/24 hour or serum immunoglobulin free light chain >10mg/dL AND abnormal serum free light chain ratio). Patients must have received 1-3 prior treatment regimens and have an absolute neutrophil count ≥1.0 x 109, platelets 75 x 109, creatinine clearance ≥50 mL/min, and ECOG performance status ≤2. AT-101 dosing was designed to reach a maximum daily target of 20mg (Cohort 1; 10 mg PO QD, Cohort 2; 20 mg PO QD) utilizing a standard 3 +3 dose escalation design in combination with standard doses of Rd. Treatment was given as outpatient for a maximum of 12, 28-day cycles. For pharmacodynamic studies, AT-101 alone was given in cycle 1, with R (25 mg on days 1-21) and d (40 mg weekly) added cycle 2 onwards. Results: Enrolled patients (n=10) included 60% males with median age 68.5 years (range 55-75) and median time since MM diagnosis 4.5 years (range 0.6-8.3). MM ISS stage was II/III in 7 patients and 8/10 had high-risk cytogenetics with 4 each having del17p and 1q+. Only 1 patient had t(11;14).Patients had received median 2 prior lines of therapy (range 1-3), with 7 having had prior autologous stem cell transplant (ASCT) and the initial induction regimen being bortezomib (V), R and dexamethasone (d) (VRd) in 8, Rd in 1 and cyclophosphamide (C) with Vd (VCd) in 1 patient. At the time of study entry, 3 patients were R refractory while 2 were refractory to both, V and daratumumab (Dara). Median duration of treatment was 7.5 cycles (range 2-12) and 3 patients completed all planned 12 cycles of treatment. Among the evaluable patients, dose limiting toxicities (DLTs) at 20 mg daily dose of AT-101 with 25 mg of R and 40 mg weekly included one patient with grade 4 febrile neutropenia and grade 4 neutropenia lasting 9 days and one patient with grade 4 thrombocytopenia lasting 8 days. G3/4 adverse events (AEs) included atrial flutter (n=1), white blood cell count decrease (n=3), neutropenia (n=5), febrile neutropenia (n=1) and thrombocytopenia (n=2), and back pain (n=1) . No G3/4 non-hematological AEs were noted. Any grade non-hematologic AEs seen in at least 20% (n=2) patients included fatigue (n=9), neuropathy (n=6), nausea (n=3), diarrhea (n=5), constipation (n=3), and creatinine increased (n=2). No patients experienced tumor lysis syndrome. Overall response rate (ORR) was 44% (2 each with very good partial response, VGPR and PR) and clinical benefit rate (CBR) was 89% with 2 additional patients showing minor response (MR) and 2 experiencing stable disease (SD) (Fig 1). Patients with high-risk disease had an ORR of 43% and a CBR of 100%. Median progression-free survival (PFS) for all patients was 8.1 months. Correlative analysis from patients who showed an objective response to treatment revealed a significant increase in bone marrow Th-effector cells, NK cells and cytotoxic CD8+ T-cells along with a significant decrease in immunosuppressive T-regulatory and B-regulatory cells was noted after 1 complete cycle of the combination therapy (p<0.05, Fig 2). Conclusions: This is the first reported clinical trial combining a Bcl-2 inhibitor with immunomodulatory drugs (IMiDs) in MM. AT-101-Rd is a clinically active regimen with an ORR of 40% in predominantly high-risk RRMM patients with an acceptable toxicity profile. Additional patients with MM experienced clinical benefit despite refractory status to prior therapy in this early phase clinical trial. These early findings support the further investigation of AT-101 specifically, and Bcl-2 inhibitors in general, with IMiDs in patients with MM. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Chanan-Khan:Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: AT-101 is not currently FDA-approved for treatment of any condition.

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1871-1871 ◽  
Author(s):  
Christopher P Venner ◽  
Richard Leblanc ◽  
Irwindeep Sandhu ◽  
Darrell J White ◽  
Andrew Belch ◽  
...  

Background: Carfilzomib is effective in the treatment of relapsed and refractory multiple myeloma (RRMM). Questions remain regarding optimal dosing strategies and combinations. The MCRN-003/MYX.1 single arm phase II clinical trial of high-dose once weekly carfilzomib in combination with dexamethasone and cyclophosphamide (wCCD) in RRMM met its primary endpoint with an overall response rate (ORR) ≥ 80% after 4 treatment cycles [Venner, Blood 2018 132:1984]. This abstract focuses on previously unreported protocol specified secondary and exploratory endpoints including progression free (PFS) and overall survival (OS). Methods: This multi-centre clinical trial is run through the Myeloma Canada Research Network (MCRN) with support from the Canadian Cancer Trials Group (CCTG). Patients who had 1-3 prior lines of therapy and without proteasome inhibitor (PI) refractory disease were eligible. Treatment consists of carfilzomib (20 mg/m2 day 1 of first cycle then escalated to 70 mg/m2 for all subsequent doses) given on days 1, 8, and 15 of a 28-day cycle, plus weekly oral dexamethasone 40 mg and cyclophosphamide 300 mg/m2 capped at 500 mg. Treatment continues until progression or intolerance, except for cyclophosphamide which is discontinued after 12 cycles. Secondary endpoints included toxicity, depth of response, PFS and OS as defined by International Myeloma Working Group Uniform Response Criteria (2016). Exploratory endpoints included the impact of cytogenetics (CG) and prior PI or lenalidomide exposure on efficacy, and the novel endpoint of serum free light chain (sFLC) escape, defined as a > 25% change in the difference of involved to uninvolved light chain with the absolute rise > 100mg/L, in individuals with disease previously measurable by serum or urine protein electrophoresis. This analysis is based on the locked database of 19 June, 2019. Results: Of 76 patients accrued, 75 were included in the analysis. One was ineligible due to prior bortezomib refractoriness. Thirty-nine percent received 1 prior line, 44% two prior lines and 17% three prior lines of therapy. High-risk cytogenetics (t(4;14), t(14;16) and/or del P53, considered positive at any level above local accepted threshold) were identified in 32%. Twenty percent had ISS stage III disease. The majority of participants were previously exposed to PI (87%) and lenalidomide (83%). The median duration of follow-up was 25 months. The ORR at any time was 85% (1 patient achieved a response after 4 cycles) with ≥ VGPR achieved in 68% and ≥ CR in 29%. The presence of high-risk CG conferred a worse ORR (75% vs 97% respectively, p = 0.013). Thirty-one patients have died with a median OS and median PFS of 27 months and 17 months respectively (figure 1). High risk CG conferred a worse median OS (18 months vs NR, p = 0.002) and a trend toward a worse median PFS with high risk CG (14 months vs 22 months, p = 0.06; figure 1). For patients with prior PI exposure the median OS and PFS were 27 and 17 months respectively. For patients with prior lenalidomide exposure median OS and PFS were 26 and 16 months respectively. Free light chain escape events were noted in 11 patients (15%) but was the only progression event in 3 (4%). For the remaining 8 patients the sFLC rise was a harbinger of traditional relapse by electrophoresis. The median PFS when sFLC escape was included as a progression event was 17 months. With updated toxicity data the most common ≥ grade 3 non-hematologic events were infection (40%), cardiac (15%, including 5 dyspnea and 1 pulmonary edema) and vascular (17%, including 7 with hypertension and 3 with thrombotic microangiopathy). To date 57 (76%) patients have discontinued carfilzomib, including 34 due to disease progression and 14 due to toxicity. Conclusion: This phase II trial demonstrates that wCCD remains a safe and effective regimen for RRMM. The survival data presented here is comparable to current phase II and III studies examining the weekly dosing strategy. No new toxicity signals are observed but cardiovascular risks remain an important factor in the use of carfilzomib-based therapies. Using sFLC escape does not negatively affect PFS outcomes but likely better characterizes progression as a harbinger of more traditional events detected by electrophoresis. This regimen will be a useful triplet-based option for RRMM especially in patients refractory to lenalidomide and otherwise ineligible for the carfilzomib-lenalidomide-dexamethasone combination. Disclosures Venner: J&J: Research Funding. Leblanc:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sandhu:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; gilead: Honoraria. White:Celgene: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Reece:Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Chen:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Louzada:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bayer: Honoraria. McCurdy:Janssen: Honoraria; Celgene: Honoraria. Hay:Janssen: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Kite: Research Funding; Takeda: Research Funding; Roche: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; MorphoSys: Research Funding; Gilead: Research Funding. OffLabel Disclosure: While Carfilzomib is approved for use in relapsed and refractory myeloma the combination with cyclophosphamide is not approved.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 747-747
Author(s):  
Shaji Kumar ◽  
Morie A Gertz ◽  
Martha Q. Lacy ◽  
Suzanne R. Hayman ◽  
Francis Buadi ◽  
...  

Abstract Abstract 747 Background: Light chain amyloidosis is a monoclonal plasma cell proliferative disorder characterized by multiorgan deposition of monoclonal light chain derived amyloid fibrils. The diffuse organ infiltration by the amyloid fibrils leads to various AL related clinical features. Therapy of AL has been primarily aimed at elimination or control of the monoclonal plasma cells, thus decreasing the light chain available for amyloid formation. Assessment of response to therapy has been grouped into hematological response demonstrating elimination or reduction of the monoclonal population and organ response demonstrating actual improvement in its structure or function. Given the potentially long delay in observing organ improvement, hematological response has been the surrogate short term marker for long term outcome given the relatively rapid decline seen in the monoclonal protein with effective therapy, as well as studies showing improved long term outcome with a hematological response, especially complete response. However, conventional hematological response criteria give priority to the intact monoclonal protein rather than the light chain, which is the amyloidogenic protein. We hypothesized that a light chain response will correlate better with outcome than changes in the intact monoclonal protein levels. Methods: We identified 348 patients who had undergone stem cell transplant (SCT) for AL from among a large group of patients undergoing different treatments for AL, and in whom serial tests results were available. We identified the lowest value attained following SCT for various hematological response parameters (intact serum M-protein [MP], the difference between involved and uninvolved serum free light chain [FLC-diff], and urine M-protein [UP]) before an alternate therapy was instituted. We first estimated the best cutoff for the degree of change in each parameter that predicted 5-year survival from SCT. Cox proportional hazards model was used for multivariable analysis of factors influencing overall survival (OS). Results: We first examined the relative contribution of the MP and the FLC-diff on the overall survival following transplant. The best cutoff for reduction in FLC-diff to predict OS at 5 years from SCT was 88% if all patients were considered and 90% if only those with a baseline FLC diff > 7.5 mg/dL were considered. The best cutoff for MP reduction was 40% for 5 year survival for all patients and 67% for those with a baseline MP > 1.0 gm/dL. We then looked at the impact of FLC reduction and MP reduction in a multivariable analysis using OS as endpoint. For all patients, FLC reduction, but not MP reduction significantly impacted outcome, and results were similar when considering patients with MP>1.0 gm/dl and FLC-diff > 7.5 mg/dl at baseline. Among those with a baseline FLC-diff >7.5 mg/dL (n=125), the overall survival was 35 mos from SCT for those with less than 90% decrease in FLC-diff (45 pts) compared to not reached for those with at least 90% decrease (80 pts); P < 0.001 (Figure). Conclusions: The current study supports the notion that reductions in the free light chain parameters represent a more useful measure of hematological response that translates into better overall survival and possible better chance at organ improvement. A reduction in the FLC difference of 90% appears to correlate best with prolonged survival. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:celgene: Research Funding.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 603-603 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Steven D. Gore ◽  
Christopher R. Cogle ◽  
Elias J. Jabbour ◽  
M. Renee Ward ◽  
...  

Abstract Abstract 603 Parenteral azacitidine (AZA) is approved for administration on days 1–7 of a 28-day treatment schedule. Based on the short plasma half-life of AZA, S-phase restricted incorporation into DNA, and rapid re-methylation of DNA, it is possible that chronic daily exposure could enhanced its clinical activity. An oral formulation would be convenient and allow evaluation of lower doses administered on extended schedules. The initial phase I study of oral AZA, administered daily on a 7-day schedule demonstrated that it was bioavailable, safe, and clinically active in patients with MDS and AML (Garcia-Manero G, et al. Blood 2009;114:A117). Here, we report the results of a multicenter phase I exploration of extended oral AZA schedules, including dose-limiting toxicities (DLTs), safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary response data. Patients aged ≥ 18 years with MDS, CMML or AML (not candidates for other therapies) were enrolled in the study. Inclusion criteria were a hemoglobin level of ≤ 9.0 g/dL, and/or platelet count of ≤ 50 × 109/L, and/or be RBC transfusion-dependent; prior azanucleoside therapy was not permitted. Patients received oral AZA daily (QD) or twice daily (BID) on 14- or 21-days schedules, with starting at a dose of 300 mg for QD dosing and 200 mg for BID dosing. Patients were enrolled into cohorts of 6 and evaluated for DLTs at the end of Cycle 1. Patients were monitored continuously for adverse events (AEs) and assessed for disease response at the end of every second cycle. During Cycle 1, on the first and last day of treatment, PK parameters were derived from AZA concentrations in the plasma after the first dose of the day. PD samples were collected during the first 2 cycles and DNA methylation changes were evaluated using a LINE-1 assay. To date, 25 patients (median age 68 years [range 44–87]; 14 male and 11 female) with MDS (n = 13), AML (n = 7 de novo and n = 3 transformed), and CMML (n = 2) have received oral AZA on extended treatment schedules. Two DLTs, grade 3 nausea and grade 3 vomiting, occurred in 1 of 6 DLT-evaluable patients treated at 14-days QD (n = 7). No DLTs were observed on the 21-day QD (n = 6) or 14-day BID (n = 6) schedules; safety evaluation for the 21-day BID schedule is ongoing (n = 6). The maximum tolerated dose has not been reached on these schedules; no patient has received > 300 mg per dose. Overall rates of all grades nausea, vomiting, diarrhea, constipation, and abdominal pain with the extended schedules were similar to those observed with the oral 7-day schedule. The rate of febrile neutropenia (all grades) was higher in the 21-day QD cohort. This was observed in 4 patients with baseline ANC < 500 and/or AML diagnosis. Most common grade 3/4 AEs in the QD schedules were febrile neutropenia (14-day, 1/7; 21-day, 4/6), anemia (14-day, 1/7; 21-day, 0/6), thrombocytopenia (14-day, 1/7; 21-day, 1/6), diarrhea (14-day, 0/7; 21-day, 1/6), nausea (14-day, 1/7; 21-day, 0/6), and vomiting (14-day, 1/7; 21-day, 0/6). Extended BID schedules are under evaluation. PK data have been generated for 19 of 25 patients. For the 300 mg 14-day QD, 300 mg 21-day QD, and 200 mg 14-day BID schedules, using mean AUC (first and last day) results, extrapolated cumulative exposures per cycle were ~28%, 42% and 26%, respectively, compared with historical exposure observed following subcutaneous administration. AZA exposure increased with increasing dose, but was not dose-proportional. Clinical responses were observed for MDS/CMML patients on both extended QD schedules, with assessment ongoing for BID schedules (Table). In summary, extended (14- and 21-day) dosing of oral AZA is generally well tolerated, with no AZA accumulation, and promising clinical responses were observed, including complete remission (CR), marrow CR (mCR), and hematologic improvement (HI). Table. Parameter, n (%) Oral AZA Treatment Schedule MDS/CMML Responders/Evaluable patients, (%) 14-day QD 21-day QD Overall response* (CR, mCR, any HI) 5/6 (83) 3/3 (100) CR 0/6 2/3 (67) mCR 0/6 3/3 (100) HI 5/6 (83) 3/3 (100) HI-erythroid 3/5 (60) 1/1 (100) HI-platelet† 2/5 (40) 3/3 (100) HI-neutrophil 0/1 0/1 Transfusion independence 3/4 (75) 1/2 (50) RBC 1/2 (50) 1/1 (100) Platelet 2/2 (100) 0/1 * International Working Group 2006 criteria, patients only counted once for overall response, but may be counted more than once in individual response categories. † Includes patients achieving partial (≥ 50%) or complete platelet transfusion independence. Disclosures: Gore: Celgene: Consultancy, Equity Ownership, Research Funding. Cogle:Celgene: Research Funding, Speakers Bureau. Ward:Celgene: Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership. Laille:Celgene: Employment. Giordano:Celgene: Employment, Equity Ownership. Kantarjian:Celgene: Research Funding. Skikne:Celgene: Employment.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2823-2823 ◽  
Author(s):  
Catriona HM Jamieson ◽  
Robert P Hasserjian ◽  
Jason Gotlib ◽  
Jorge E. Cortes ◽  
Richard M. Stone ◽  
...  

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2070-2070 ◽  
Author(s):  
Caroline Moreau ◽  
Emmanuel Rouger ◽  
Basile Henriot ◽  
Martine Escoffre ◽  
Martine Sebillot ◽  
...  

Abstract Background Smoldering multiple myeloma (SMM) is a precursor disease of multiple myeloma (MM). According to 2003 classification, the IMWG (International Myeloma Working Group) recommended only to treat patients with end organ damage - often referred as CRAB criteria (hypercalcemia, renal failure, anemia and radiological bone lesions). The standard of care for SMM was to postpone treatment until progression to symptomatic disease occurred. The average annual risk of progression of SMM to MM was 10%/year. In 2014 IMWG proposed a revised classification including 3 new criteria that enable early diagnosis of MM before organ damage. The new criteria of MM needs the presence of more than 10% clonal bone marrow plasma cells combined with either the presence of end organ damage (CRAB criteria) or one of following new biomarkers of malignancy: bone marrow plasma cells ≥60%, serum free light chains (FLC) ratio ≥100 and ≥2 focal lesions on MRI. The FLC criteria were established with Freelite™ assay (The Binding Site Company) and have not been validated with other available assays. Freelite™ assay which used polyclonal antibodies was available since 2001. More recently N Latex assay (Siemens Healthyneers) using monoclonal antibodies has been commercialized in Europe. It is now well know that there is a good correlation between the 2 assays even though results in absolute values are not numerically identical. In this context, the aim of this study was to evaluate the concordance between the two assays to identify high risk SMM, when considering the biomarker of malignancy FLC ratio ≥100. Methods This is a retrospective study including 185 patients with SMM according to 2003 IMWG criteria. FLC concentration and ratio were evaluated in frozen sera with both assays in a BN Prospec and evolution status was collected. Results The average age was 62.5 (± 10.2) years old. Results revealed poor correlation between the 2 assays with a Slope Passing-Bablok value of 0.63 (0.57-0.67) for the FLC κ and of 0.44 (0.35-0.62) for the κ/ λ ratio ≥ 100, and concordance in determining the level of FLC λ with a Slope Passing-Bablok 1.16 (0.99-1.40). A Freelite™ratio ≥ 100 was found in 27 patients (14.3%), and a N Latex ratio ≥ 100 was found in 10 patients (5.3%). All but one patients with an N Latex ratio ≥ 100 had also a Freelite™ ratio ≥ 100. Mean of follow up was 2.4 years. A progression toward MM was observed in 77 (40.7%) patients. Among the 27 patients with Freelite™ ratio ≥ 100, 14 patients (55.5%) have evolved toward MM (figure 1A). Specificity and sensitivity for a Freelite™ ratio ≥ 100 were respectively 88.7% (95% CI 81.8 to 94.0%) and 20.3% (95% CI 11.8 to 31.2%). With the N Latex Assay, only 10 patients had a FLC ratio ≥ 100, in which 7 patients have evolved towards MM. Specificity and sensitivity for a N-Latex ratio ≥ 100 were respectively be 67.0% (95% CI 57.4 to 75.6%) and 53.2% (95% CI 41.5 to 64.7%). Given the poor predictive performance of a N-Latex ratio ≥ 100 we determined that a N-Latex ratio ≥ 70 have adequate specificity of 95.5% (95% CI 89.9 to 98.5%) and a sensitivity of 13.0% (95% CI 6.4 to 22.6%) (figure 1B). 15 patients (8.1%) patients had a N-Latex ratio ≥ 70. Among these, 10 patients (66.6%) have evolved toward MM. Conclusion Our study shows poor correlation between the two FLC assays in SMM patients. A Freelite™ ratio ≥ 100 had a lesser specificity than previously described (specificity 95% in Larsen study [1]). The 100 cut-off value was not performant enough for N-Latex assay. A new ratio is thus needed and was found to be 70 to have sufficient specificity and sensitivity. This result need to be validated in an independent cohort. However, with a Freelite™ ratio ≥ 100 or an N Latex ratio ≥ 70, a significant number of patients would have been overtreated. Physicians should be aware of the limits of both assays. 1.Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013;27:941-6. Figure 1 probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70) Figure 1. probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70) Disclosures Moreau: The Binding Site: Other: supply of free light chain assays ; SIEMENS: Other: supply of free light chain assays , Research Funding. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4040-4040 ◽  
Author(s):  
Kendra L. Sweet ◽  
Rami S. Komrokji ◽  
Eric Padron ◽  
Christopher L Cubitt ◽  
Leyla Khavarian ◽  
...  

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Tarek H Mouhieddine ◽  
Julia Hieulle ◽  
Erin Moshier ◽  
Josh R. Richter ◽  
Hearn Jay Cho ◽  
...  

Background: The advent of novel therapies has led to tremendous progress in the treatment of multiple myeloma (MM). However, management of patients with high-risk disease who have failed approved agents and have rapidly progressive disease with cytopenias continues to be challenging. While palliative care is an option, many patients hope to qualify for a clinical trial option. Here we report results of a 28-day metronomic therapy (METRO-28) consisting of continuous administration of very low doses of classical chemotherapeutic agents. Sixteen-day cycles of metronomic therapy were previously shown to have a favorable response with acceptable toxicity profiles in MM patients (Papanikolaou et al. Haematologica 2013). Aim: To investigate the efficacy and toxicity in patients with high-risk relapsed refractory MM (RRMM) ineligible for clinical trial options receiving 1 cycle of METRO-28. Method: We retrospectively analyzed the clinical outcomes of 106 RRMM, treated with 1 cycle of 28-day metronomic chemotherapy at the Tisch Cancer Institute - The Mount Sinai Hospital. METRO-28 consists of 6 agents: dexamethasone 8 mg on days 1 through 4, 7 through 10, 13 through 16, 19 through 22 and 25 through 28; bortezomib 1 mg/m2 on days 1, 4, 7, 10, 13, 16, 19, 22, 25, 28; cisplatin 1 mg/m2 daily; doxorubicin 1 mg/m2 daily; thalidomide 100 mg daily; and vincristine flat dose 0.06 mg daily. METRO-28 was administered through a central line in either the inpatient or outpatient setting. Result: Our cohort of 106 RRMM patients has a median age of 65 years (range: 35-85) and at a median of 59 months from time of diagnosis; 42% were females. They had a median of 7 prior lines of therapy (range: 1 - 25); with 73% triple- and 58% penta-refractory cases. Prior autologous transplantation was utilized in 69% of patients including tandem transplants in 30%. Moreover, 78% of patients carried high-risk cytogenetic features, including 1q21 duplication/amplification (89%), 17p deletion (49%), t(4;14) (17%), t(14;16) (17%) or t(14;20) (3%). At the time of METRO-28 initiation, patients were cytopenic with grade 3 and 4 anemia (21%), neutropenia (8%) and thrombocytopenia (23%). Profound cytopenias in some patients led to early discontinuation of treatment; forty-three patients (41%) received the full 28-day course of METRO-28, while 11%, 17%, 20% and 11% were treated for &lt;1 week, &lt;2 weeks, &lt;3 weeks or &lt;4 weeks, respectively. Grade 3-4 cytopenia increased: anemia 66%, leucopenia 61%, neutropenia 55% and thrombocytopenia 76%. On an intent to treat basis (106 patients), the deepest response included 2% stringent complete response (sCR), 7% near complete response (nCR), 7% very good partial response (VGPR), 28% partial response (PR), 11% minimal response (MR) and 12% stable disease (SD). Only 43 patients (41%) completed all 4 weeks of METRO-28 and had a 72% overall response rate (ORR) and 88% clinical benefit rate (CBR). Seventy-four percent of these patients were able to move on to new therapies, including novel agents and clinical trials. Their overall survival (OS) was 11.8 months (range: 6.1-NE) as opposed to an OS of 4.2 months (range: 3.4-7.2) for patients with &lt;4 weeks of METRO-28. Sixty-three patients had their treatment interrupted: 34 due to disease progression or absence of response, 18 due to bacterial or viral infections and 11 due to hematologic toxicity. Conclusion: Giving 1 cycle of METRO-28 is better tolerated in patients with good hematologic reserve and offers an opportunity for a clinical benefit and a bridge to a subsequent treatment option for these advanced refractory myeloma patients. Disclosures Richter: Takeda: Consultancy; Janssen: Speakers Bureau; Sanofi: Consultancy; AstraZeneca: Consultancy; X4 Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy, Speakers Bureau; Oncopeptides: Consultancy; Secura Bio: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Speakers Bureau. Parekh:Foundation Medicine: Consultancy; Celgene: Research Funding; Karyopharm: Research Funding. Chari:Adaptive Biotechnology: Honoraria; The Binding Site: Honoraria; Array BioPharma: Honoraria; Novartis: Honoraria; Secura Bio: Consultancy; Glaxo Smith Kline: Consultancy; Antengene: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy; Seattle Genetics: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Jagannath:Legend Biotech: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Madduri:Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Legend: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Kinevant: Consultancy; Foundation Medicine: Consultancy.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3321-3321 ◽  
Author(s):  
Rakesh Popat ◽  
Sarah R Brown ◽  
Avie-Lee Tillotson ◽  
Fiona Collinson ◽  
Louise M Flanagan ◽  
...  

Abstract Introduction: Histone deacetylase inhibitors (HDACis) have demonstrated clinical efficacy in multiple myeloma, particularly in combination with proteasome inhibitors. CHR-3996 is a class 1 selective HDACi with potent anti-myeloma activity in vitro. Aminopeptidase inhibitors act downstream of the proteasome and prevent breakdown of proteasome generated peptides into amino acids. Synergistic cytotoxicity was observed in vitro when CHR-3996 was combined with the aminopeptidase inhibitor, tosedostat through rapid activation of NFkB followed by increased expression of the repressors IκBα, A20, CYLD, BIRC3. The MUK-three study was designed to translate these pre-clinical findings into a phase 1 clinical trial. This dose escalation study aimed to determine the maximum tolerated dose, safety and preliminary activity of CHR-3996 administered in combination with Tosedostat for patients with relapsed, refractory MM. Here we present the final study results. Methods: MUK-three was an open label multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had failed conventional treatments. Patients were permitted to meet the haematological entry criteria using growth factor and/or blood product support. During dose escalation subjects received CHR-3996 (20-40mg days1-28) and Tosedostat (0-60mg days 1-28) (Table 1) every 28 day cycle until disease progression or withdrawal. Dose limiting toxicities (DLTs) were evaluated during cycle 1 and dose escalation followed the 3+3 design. Responses were assessed using modified IMWG uniform response criteria, with the primary endpoint for the expansion phase of stable disease (SD) rate after 4 cycles of therapy. Toxicity was graded by CTCAE V4.0. Results: The trial was open to recruitment from July 2012 to December 2015. 20 patients were treated during dose escalation, including 8 at the recommended dose (RD) and 12 at dose levels (DL) 1-3. Only 1 DLT was observed at DL3 (grade 4 thrombocytopenia); however, this DL was deemed not tolerable due to the high incidence of low grade gastrointestinal toxicities. Hence the RD was determined as DL3b, CHR-3996 20mg and Tosedostat 60mg. A further 2 patients were treated at RD during dose expansion to make the required 10 patients for the protocol defined initial analysis at which point the trial closed. At the RD (n=10) median age was 63 years (range 47-73). 80% of patients had received at least 4 prior lines of therapy (median 4, range 2-9); 50% were ISS II, 30% ISS III; 4/6 patients with evaluable FISH data had 1q gain. The median time from diagnosis to treatment for the overall population was 85.3 months (27.5-198.8). The median number of cycles received was 2.5 (range 2-8) and 2 patients remain on treatment with 8 stopped due to disease progression. The 2 patients ongoing (received 5 & 9 prior lines) had their schedule adjusted to a 5 day a week dosing to further improve tolerability. Both had a clinical response (1MR, 1PR) and remained progression free at 6 months. 3/10 patients had SD after 4 cycles, the overall response rate (≥PR) was 1/10(10%) and the clinical benefit rate (≥MR) 2/10 (20%). Overall outcomes were: PR 10%, MR 10%, and SD 30%. Median time to maximum response was 1.84 months (95% CI [1.09, 8.65]). Toxicities at the RD were manageable, 30% of patients required a dose reduction. 22 serious adverse events were reported in 16 patients across all doses, mainly infections (10/22, 45.5%). The commonest grade 3-4 toxicities reported for all 22 patients were: platelet count decrease (12, 54.5%), white blood cell decreased (6, 27.2%), diarrhoea (5, 22.7%). The most frequent grade 1-2 toxicities were fatigue (15, 68.2%), nausea (14, 63.3 %), anorexia (14, 63.6%), anaemia (13, 59.1%). 1 patient withdrew due to toxicity, and there were no treatment related deaths. Conclusions: This study demonstrated that the novel combination of CHR-3996 and tosedostat was safe and tolerable in multiply relapsed, refractory myeloma patients many of which had poor bone marrow function. The recommended dose of the combination was 20mg and 60mg, respectively. Following further adjustment to an intermittent 5 day/ week dosing schedule, treatment was well tolerated and clinical benefit observed. This suggests that further evaluation of this novel combination is warranted. Acknowledgments: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 24989786. Disclosures Williams: Novartis: Honoraria; Janssen: Honoraria, Other: Travel support, Speakers Bureau; Celgene: Honoraria, Other: Travel support, Speakers Bureau; Takeda: Honoraria, Other: Travel support, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Cook:Takeda Oncology: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Glycomimetics: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau. Jenner:Amgen: Consultancy, Honoraria, Other: Travel support; Takeda: Consultancy, Honoraria, Other: Travel support; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Davies:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3830-3830
Author(s):  
Laura Agresta ◽  
Maureen M O'Brien ◽  
Kana Mizuno ◽  
Robin Norris ◽  
Erin H. Breese ◽  
...  

Despite significant advances in AML therapy over the past decades, 30-40% of all young patients with AML will suffer a relapse, after which achieving long-term disease-free survival remains challenging. In pediatric and young adult patients with AML, curative-intent treatment at relapse involves intensive induction therapy to achieve CR followed by consolidation with HSCT. Historically, initial response rates to salvage therapy were limited. Recently, Children's Oncology Group presented results from a Phase II study of CPX-351 (liposomal cytarabine:daunorubicin at a synergistic ratio) in pediatric patients with AML in first relapse demonstrating an impressive CR/CRp/CRi rate of 81.3%. Separately, we presented data from our first-in-pediatrics CPX-351 Phase I trial showing 48% M1 marrow response in a population consisting of children with multiply relapsed and refractory (R/R) AML patients. We also obtained single cell RNA sequencing on study patients' peripheral blasts before, during, and after CPX-351 treatment (i.e.: Days 0, 1 and 5). Preliminary data showed that CPX-351 differentially impacts p53 targets within leukemic blast clusters over time, with an enrichment for genes regulating apoptosis (e.g.: FAS, BAX) in most clusters. This suggests that these blasts may be primed for apoptosis following CPX-351 treatment. Anti-apoptosis signaling in leukemias is an established mechanism of chemoresistance. Venetoclax is an orally available, small molecule inhibitor of anti-apoptotic protein BCL-2, which is frequently overexpressed in leukemias. Based on published preclinical data and single cell RNA sequencing data from our CPX-351 trial, we developed a Phase I study to investigate the combination of CPX-351 and venetoclax in the treatment of young patients with R/R acute leukemias. The V2 trial is a single-institution Phase I pilot study (NCT03826992) designed to test the safety and tolerability of combining venetoclax with CPX-351 in patients ages 1-39 years for the treatment of R/R acute leukemias. Inclusion diagnoses are based on preclinical sensitivities and include AML, MPAL, or AUL in first or greater relapse, or ETP-ALL, MLL-rearranged ALL, or T-ALL in second or greater relapse. Patients must have measurable disease. Exclusion criteria include CNS status 3, bone marrow failure syndromes, and prior anthracycline and mediastinal radiation exposures above acceptable cardiotoxicity risk thresholds. Subjects receive a single course of study therapy consisting of daily venetoclax and CPX-351 at the FDA approved dose for adults on Days 1, 3, and 5 (Fig. 1) with the goal of CRMRD- to allow for off-study HSCT. The venetoclax dose exploration phase begins with a starting dose of 400 mg (or the allometrically-scaled equivalent) for 21 days with a 3-day ramp to target dose. The dose exploration phase proceeds on a rolling 6 design and will require 4-12 patients to determine RP2D. Provided a tolerable RP2D is found, a dose expansion phase will open. Primary endpoints are determination of RP2D and description of the safety profile including time to hematologic recovery. Secondary endpoints are estimations of CR/CRp/CRi +/- MRD- within the context of a phase I study, and evaluation of cancer therapy-related cardiac dysfunction (CTRCD) rates. Correlative studies include evaluation of venetoclax PK with concomitant CPX-351 using modeling & simulation with a combined limited sampling and pediatric opportunistic PK sampling (POPS) strategy, and exploration of the correlations between BCL-2 family expression and pediatric tumor genetics with treatment response. Figure 1 Disclosures O'Brien: BTG: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; BMS: Research Funding. Phillips:Novartis: Membership on an entity's Board of Directors or advisory committees. Vinks:Myriad Genetics: Consultancy, Patents & Royalties. Perentesis:Kurome Therapeutics: Consultancy. Absalon:Jazz Pharmaceuticals: Other: CPX-351 for clinical trial . OffLabel Disclosure: This clinical trial involves the off-label use of CPX-351 and venetoclax for relapsed/refractory pediatric and young adult leukemias.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4428-4428 ◽  
Author(s):  
Helene Caillon ◽  
Michel Attal ◽  
Herve Avet-Loiseau ◽  
Cyrille Touzeau ◽  
Philippe Moreau ◽  
...  

Abstract Background : Free Light Chain (FLC) escape has been described for the first time in 1971 by Hobbs, who reported biochemical relapses of multiple myeloma (MM) with only Bence Jones proteinuria, in patients followed for an intact monoclonal immunoglobulin (Ig) MM. Indeed, FLC escape is defined as an increase of FLC without corresponding increase of the intact monoclonal Ig. In the era of novel-agent based therapy and autologous stem cell transplantation (ASCT), the patterns of disease progression may change, including a potential increased rate of FLC escape. Brioli and al (Blood 2014;123(22):3414-9) reported that 10% of the cases at relapse presented with FLC escape, and that FLC evaluation at relapse could represent an interesting marker of impact from intraclonal heterogeneity on myeloma outcome. We analysed the relapse patterns of patients treated according to the IFM 2009 clinical trial. Methods: Patients treated according to the IFM 2009 clinical trial (Lenalidomide bortezomib dexamethasone RVD + / - ASCT, Attal and al, ASH 2015) were analyzed. In patients presenting with an intact monoclonal Ig at diagnosis, serum and urine electrophoresis + FLC were compared in a central lab at the time of diagnosis and at the time of progression, in order to identify FLC escape. Results: 700 patients with symptomatic de novo MM were enrolled in the IFM DFCI 2009 clinical trial. Among them, 318 had a progressive disease, assessed with a centralized biochemistry analysis and 267 patients of them with an intact monoclonal Ig were included in this study. A vast majority (250 patients, 94%) showed an increase of the initial serum monoclonal component up to 5 g/L or up to 25% from the NADIR (IMWG criteria for progressive disease). 8 patients progressed with new bone lesions or plasmocytoma (3%) without any biological markers of progressive disease... Finally, 9 patients (3%) were identified as FLC escape as they did not exhibit an increased intact monoclonal Ig but they had an increased serum FLC and/or an increased Bence Jones proteinuria. Three of them had a serum and urinary measurable disease on diagnosis and they relapsed with both an increase of FLC and an increase of Bence Jones proteinuria. The six other patients presented at diagnosis only with an urinary measurable disease: 3 of them relapsed with an increase of FLC, without any Bence Jones proteinuria, the three others relapsed both on FLC and urines. Isotype of monoclonal component was IgG (6 patients), IgA (2) or IgD (1); light chain was Kappa for 6 patients and Lambda for the three others. Four patients were treated with RVD alone, and 5 patients with RVD + ASCT. The relapse occurred in a median of 2 years after diagnosis (5 months - 3.5 years). Conclusion: Based on a very large study of patients treated into a phase 3 clinical trial with centralized assessment of response and relapse, we are showing that FLC escape in a very rare phenomenom, observed in 3% of the cases. The low frequency of FLC escape does not lead to a systematic monitoring of intact Ig MM by FLC. Disclosures Attal: amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy. Avet-Loiseau:sanofi: Consultancy; janssen: Consultancy; amgen: Consultancy; celgene: Consultancy. Moreau:Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria.


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