HEM13 MIB slides FINAL

17th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma Meeting in a Box MULTIPLE MYELOMA What Can We Learn From Multiple Myeloma Genomic Analysis? Nikhil Munshi, MD Genomic Analysis Takeaways • Methods of genomic analysis – Established techniques: cytogenetics, FISH – Emerging techniques: RNA- and DNA-based arrays, transcriptprocessing arrays, genomic sequencing, and proteomics • Current goals of genomic analysis in myeloma – Understand the biology of myeloma – Identify risk categories to improve prognostication – Identify and validate novel targets – Develop biologic agents that target the myeloma cell – Ultimately, develop personalized therapy • Currently, gene expression profiling has prognostic value, predicting survival of patients with different genomic signatures, but it cannot yet predict response to therapy High-Risk Smoldering Myeloma – Should We Intervene Early? Ola Landgren, MD, PhD Smoldering Myeloma • Definition of smoldering myeloma1 – Serum monoclonal IgG or IgA ≥ g/dL and/or clonal bone marrow plasma cells ≥ 10% AND – Absence of end-organ damage (ie, hypercalcemia, renal insufficiency, anemia, or bone lesions attributed to plasma cell proliferative disorder) • Overall risk of progression2 – 10% per year in years 0-5 – 3% per year in years 6-10 – 1% per year in years 11-20 • Risk stratification – Mayo Clinic analysis3 stratifies patients according to their 5-yr risk of progression into groups: 25% risk, 51% risk, and 76% risk – PETHEMA Study Group analysis4 stratifies patients according to their 5-yr risk of progression into groups: 4% risk, 46% risk, and 72% Kyle RA, et al Leukemia 2010;24:1121-7 risk Kyle RA, et al N Engl J Med 2007;356:2582-90 Dispenzieri A, et al Blood 2008;111:785-9 Perez-Persona E, et al Blood 2007;110:2586-92 e First Randomized Phase III Trial for Smoldering Myeloma Randomization of high-risk smoldering MM patients: Lenalidomide 25 mg/day, D1-21 Dexamethasone 20 mg D1-D4 and D12-D15 Lenalidomide 10 mg/day, D1-21 every months Induction: Nine 28-day cycles Therapeutic abstention Maintenance: Until progression Therapeutic abstention Primary endpoint: time to progression to symptomatic MM Secondary endpoints: ORR, DOR, PFS, OS, and safety and tolerability Median time to symptomatic progression Len/dex: not yet reached Observation: 21 months HR = 5.67; P < 0001 4-year overall survival Len/dex: 94% Observation: 85% HR = 3.5; P < 01 Mateos MV, et al ASH 2011 Abstract 991 Smoldering Myeloma Takeaways • Current clinical recommendation for smoldering myeloma: no treatment unless part of a clinical trial1 • Better understanding of pathogenesis from MGUS to myeloma needed: – To develop better biological markers – To predict a patient’s risk of progression – To develop early intervention strategies Kyle R, et al Int’l Myeloma Working Group Leukemia Current Trends: Treatment Strategies for Newly Diagnosed Elderly Patients With Myeloma James Berenson, MD Dexamethasone ± Lenalidomide SWOG S0232 Len + Dex (n = 97) Dexamethasone (n = 95) Len: 25 mg/day, D1-28 Placebo: 25 mg/day, D1-28 Dex: 40 mg/day, D1-4, 9-12, 17-20 Dex: 40 mg/day, D1-4, 9-12, 17-20 Three 35-day cycles Three 35-day cycles Disease progression Responding/stable disease Len + Dex Dexamethasone Unblinded Treatment Len: 25 mg/day, D1-21 Placebo: 25 mg/day, D1-21 Len: 25 mg/day, D1-28 Dex: 40 mg/day, D1-4 and 15-18 Dex: 40 mg/day, D1-21 Dex: 40 mg/day, D1-4, 9-12, 17-20 28-day cycles until progression 28-day cycles until progression Three 35-day cycles Objective: to determine the efficacy and safety of Len + Dex as induction therapy in NDMM patients Primary endpoint: PFS Unblinded Len + Dex Len: 25 mg/day, D1-21 Dex: 40 mg/day, D1-4 and 15-18 Zonder JA, et al Blood 2010;116:5838-41 Lenalidomide Monotherapy in CLL • Properties of lenalidomide treatment – Normalization of peripheral blood lymphocytes and T cells1,2 – Improvement in serum Igs2 • Single-agent lenalidomide as salvage therapy: RPCI3 n = 45 MDACC1 n = 44 CLL-014 n = 52 ORR 47% 32% 12% CR 9% 7% 0% SD 18% 25% 58% Response • Lenalidomide monotherapy as frontline therapy for CLL (n = 25):5 – PR = 56% – Tumor flare = 88% – Grade 3/4 neutropenia = 72% Ferrajoli A, et al Blood 2008;111:5291-7 Badoux XC, et al Blood 2011;118:3489-98 Chanan-Khan AA, et al J Clin Oncol 2006;24:5343-9 Wendtner CM, et al Leuk Lymphoma 2012;53:417-23 Chen CI, et al J Clin Oncol 2011;29:1175-81 Lenalidomide Combination Therapy in CLL • Lenalidomide + fludarabine + rituximab in untreated CLL – Phase !/II study: ORR = 56%, but combination too toxic, with myelosuppression and idiosyncratic drug reaction as DLTs.1 – REVLIRIT: Combination followed by lenalidomide and rituximab maintenance therapy Dosages more tolerable; ORR = 87%, 49%, MRDneg = 29%.2 • • CR = Lenalidomide + rituximab in frontline CLL3 – Phase II study of 69 patients, divided by age (65 years) into groups: Group N ORR CR Age < 65 years 40 95% 20% Age ≥ 65 years 29 78% 7% Overall 69 88% 15% Ongoing phase III lenalidomide trials in CLL: – Lenalidomide vs chlorambucil as frontline therapy – Lenalidomide as maintenance (1 after 1st-line and after 2nd-line) Brown JR, et al Leukemia 2010;24:1972-5 Egle A, et al ASH 2011 Abstract 292 James DF, et al ASH 2011 Abstract 291 Lenalidomide Combination Therapy in CLL • Lenalidomide + rituximab in relapsed CLL1 – Phase II study of 59 patients who received prior purine analog therapy – Median prior regimens; 93% prior FCR, PCR, CFAR, or OFAR – No grade 3/4 tumor flare; combination well tolerated Treatment ORR CR Median TTF 3-yr OS Lenalidomide + rituximab 66% 12% 17.4 months 71%  Deletion status did not impact PFS outcomes  Fludarabine-refractory patients had inferior PFS compared with patients not refractory to fludarabine (P = 019) • Lenalidomide + ofatumumab in relapsed CLL2 – Phase II trial of 34 patients who received prior purine analog therapy (100% received FCR) Treatment ORR CR Median PFS 2-yr OS Lenalidomide + ofatumumab 68% 24% 16 months 73% Badoux XC, et al J Clin Oncol 2013;31:584-91 Ferrajoli A, et al ASH 2012 Abstract 720 Management of Patients With MDS Refractory to Hypomethylating Agents David Steensma, MD Hypomethylating Agents for MDS: Response to Treatment • Treatment with hypomethylating agents (HMAs; azacitidine and decitabine): – Improves survival by months in high-risk patients1 – Delays progression to AML by 4-6 months2 – Improves quality of life3 – Has low early treatment-related mortality4 • However, it also: – Produces low CR rate5,6 – Produces hematologic responses in only 30%-60% of patients7,8 – Has variable duration of response9 – Is associated with poor survival – < months – after HMA failure10 Fenaux P, et al Lancet Oncol 2009;10:223-32 Kantarjian H, et al Cancer 2006;106:1794-803 Kornblith AB, et al J Clin Oncol 2002;20:2441-52 Santos FP, et al Expert Rev Anticancer Ther 2010;10:9-22 Itzykson R, et al Blood 2011;117:403-11 Lubbert M, et al J Clin Oncol 2011;29:1987-96 Lee JH, et al Haematologica 2011;96:1441-7 Lyons RM, et al J Clin Oncol 2009;27:1850-6 Steensma DP, et al J Clin Oncol 2009;27:3842-8 10 Prebet T, et al J Clin Oncol 2013;29:3322-7 Hypomethylating Agents for MDS: Outcomes After HMA Failure • Common reasons for azacitidine failure:1 – Primary failure (progression or stable disease): 55% – Secondary failure (initial response, then progression or stable disease): 36% – Intolerance: 9% • Outcomes after HMA failure: HMA Median OS 1-yr OS Azacitidine High risk1 Intermediate-1 risk2 Low risk2 5.6 months 15 months 46 months 29% NR NR Decitabine Intermediate-1 to high risk3 4.3 months 28% Prebet T, et al J Clin Oncol 2013;29:3322-7 Mishra A, et al ASH 2012 Abstract 2815 Jabbour E, et al Cancer 2010;116:3830-4 Hypomethylating Agents for MDS: Treatment Options After HMA Failure Treatment Option After HMA Failure • Median OS, months1 Allogeneic transplant 19.5 Clinical trial with investigational agent 13.2 Intensive cytotoxic chemotherapy 8.9 Low-dose chemotherapy 7.3 Supportive care 4.1 Rigosertib is a multikinase inhibitor that inhibits PI3K/Akt/ERK pathway that is in phase III testing for MDS patients who have progressed after or did not respond to an HMA Randomize 2:1 Rigosertib 1800 mg/24h as 72h continuous infusion days 1, 2, and of a 2-week cycle Best supportive care or low-dose cytarabine Primary endpoint: OS Secondary endpoints: IWG 2006 response, AEs Prebet T, et al J Clin Oncol 2011;29:3322-7 BiTE Antibodies for Treatment of ALL Daniel J DeAngelo, MD, PhD Bispecific T-Cell Engager (BiTE) Antibodies • • BiTE antibodies are bispecific antibodies that harness patient’s immune system by engaging T cells with tumor cells via variable region from a T-cell-specific antibody linked to variable region from tumor-specific antibody Blinatumomab is a BiTE antibody with variable regions of anti-CD3 antibody and anti-CD19 antibody linked together a Blinatumomab for Treatment of ALL in Hematologic CR • Blinatumomab phase II study of 21 patients with ALL in hematologic complete remission with either molecular failure or relapse after ≥ cycles of chemotherapy.1 – Patients received single-agent blinatumomab 15 µg/m2/d continuous infusions wk on/2 wk off Treatment Blinatumomab Molecular CR DFS After Median 15 Months FU 80% 60% – Responses were rapid, occurring within first cycle of treatment – Median DFS not yet reached • E1910: phase III study of blinatumomab in patients with newly diagnosed BCR-ABL-negative ALL Will be followed by consolidation and maintenance chemotherapy for both groups Topp MS, et al J Clin Oncol 2011;29:2493-8 Blinatumomab for Treatment of Relapsed/Refractory ALL • MT103-206 study design: • Cohort 15 µg/m /d Safety evaluation Screening & enrollment Dose-finding run-in phase Cohort 2a 5-15 µg/m2/d N=36 Cohort 2b 5-15-30 µg/m2/d Primary endpoint: CR and CRh* rate within cycles Cohort extension phase 5-15 µg/m2/d Cohort was selected as dosage for extension phase because it had lowest incidence of treatment-emergent AEs Most common AEs were pyrexia, fatigue, headache, tremor, and leukopenia Medically important AEs were cytokine release syndrome (n=3), reversible CNS AEs (n=6), and infection (n=1 death due to fungal encephalitis) Treatment CR Molecular Remission in Pts with CR/CRh* Blinatumomab 69% 88% Median RFS Median OS 7.6 months 9.8 months *CRh = CR with only partial hematologic recovery A Critical Evaluation of the Role of JAK2 Inhibitors for Myeloproliferative Neoplasms Ruben Mesa, MD JAK2 Inhibitors and Myelofibrosis • Ruxolitinib – approved by FDA in 2011 for myelofibrosis – COMFORT I and II – phase III trials of ruxolitinib vs placebo showed ruxolitinib produced dramatic reduction in splenomegaly (both P < 001), reduced overall and individual symptoms (P < 001), and improved OS (HR = 0.50 and 0.58; P ≤ 04).1,2 • SAR302503 – in phase III testing (JAKARTA) – Phase II data from 31 patients showed mean spleen volume reduction of 42% in patients receiving the highest dose (500 mg daily) Also evidence of symptom improvement in majority of patients.3 • Pacritinib – in phase III testing – In a phase II study of 34 patients, pacritinib reduced splenomegaly by ≥ 25% in one-third of patients.4 • CYT387 – in phase II testing – Phase II study of 166 patients demonstrated rapid and sustained reductions in splenomegaly, marked improvement to complete resolution of constitutional symptoms by majority of patients, and increased transfusion independence.5 Verstovsek S, et al N Engl J Med 2012;366:799-807 Harrison C, et al N Engl J Med 2012;366:787-98 Talpaz M, et al ASH 2012 Abstract 2837 Komrokji RS, et al ASH 2011 Abstract 282 Pardanani A, et al ASH 2012 Abstract 178 Ruxolitinib for Polycythemia Vera and Essential Thrombocythemia • Polycythemia vera (PV) – Hydroxyurea and IFN are frontline therapies Ongoing trial will determine standard of care for PV – Ruxolitinib examined in open-label phase II study of patients with PV refractory or intolerant to hydroxyurea • Nearly three-quarters of patients remained on-study and phlebotomy-free for ≥ 144 weeks.1 • Clinically meaningful improvements in pruritus, night sweats, and bone pain sustained through week 1441 • In phase III testing (RESPONSE and RELIEF) • Essential thrombocythemia – Of 39 patients, 79% achieved ≥ 50% reduction in platelets during ruxolitinib use.2 – Ruxolitinib in phase III testing (RELIEF) Verstovsek S, et al ASH 2012 Abstract 804 Verstovsek S, et al ASH 2010 Abstract 313 Leukemia and MPN Takeaways • Ongoing debate regarding best TKI for frontline treatment of CML-CP: imatinib or 2nd-generation agents dasatinib and nilotinib Imatinib has excellent longterm safety, but 2nd-generation TKIs produce more early cytogenetic and molecular responses • A number of novel regimens being tested in elderly patients with CLL, including rituximab + GM-CSF, GA101 + chlorambucil, and lenalidomide • Ibrutinib and idelalisib have shown promising efficacy and safety in CLL and are currently in late-stage development for treatment of this disease Lenalidomide, alone or in combination with other agents (primarily anti-CD20 antibodies), is currently under investigation for several CLL indications • Treatment options limited for MDS after failure of hypomethylating agents Rigosertib is a targeted agent in phase III testing for this indication • Blinatumomab is a BiTE antibody that has demonstrated encouraging efficacy and safety for treatment of ALL and is undergoing phase III evaluation • JAK2 inhibitor ruxolitinib approved for treatment of myelofibrosis and under investigation in polycythemia vera and essential thrombocythemia Several other JAK2 inhibitors in development for myelofibrosis ... cyclophosphamide + bortezomib + dex 93% 39% DVD2 bortezomib + pegylated liposomal doxorubicin + dex 86% 20% VRD3 bortezomib + lenalidomide + dex 100% 37% BAM4 bortezomib + ascorbic acid + melphalan... melphalan → maintenance bortezomib 74% 13% BiRD5,6 clarithromycin + lenalidomide + high-dose dex 90% 39% CRd7 carfilzomib 27 mg/m2 + lenalidomide + dex 100% 85% CYCLONE8 carfilzomib + cyclophosphamide... Carfilzomib: 003-A1 003-A0 MM: Progressive disease > prior therapy lines including bortezomib, thalidomide or lenalidomide, an alkylating agent, and anthracycline alone or in combination Carfilzomib