Newly Diagnosed Myeloma

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Best approach to newly diagnosed myeloma
Elisabet Manasanch, MD

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  • Reeder: Thirty-three newly diagnosed, symptomatic patients with MM
    received bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8
    and 11, cyclophosphamide 300 mg/m2 orally on days 1, 8, 15
    and 22 and dexamethasone 40 mg orally on days 1–4, 9–12 and
    17–20 on a 28-day cycle for four cycles.
    All patients undergoing stem cell harvest

    Richardson:
    Abstract
    This phase 1/2 study is the first prospective evaluation of lenalidomide-bortezomib-dexamethasone in front-line myeloma. Patients (N = 66) received 3-week cycles (n = 8) of bortezomib 1.0 or 1.3 mg/m2 (days 1, 4, 8, 11), lenalidomide 15 to 25 mg (days 1-14), and dexamethasone 40 or 20 mg (days 1, 2, 4, 5, 8, 9, 11, 12). Responding patients proceeded to maintenance or transplantation. Phase 2 dosing was determined to be bortezomib 1.3 mg/m2, lenalidomide 25 mg, and dexamethasone 20 mg. Most common toxicities included sensory neuropathy (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3, respectively. In addition, 32% reported neuropathic pain (11%/3%, grade 2/3). Grade 3/4 hematologic toxicities included lymphopenia (14%), neutropenia (9%), and thrombocytopenia (6%). Thrombosis was rare (6% overall), and no treatment-related mortality was observed. Rate of partial response was 100% in both the phase 2 population and overall, with 74% and 67% each achieving very good partial response or better. Twenty-eight patients (42%) proceeded to undergo transplantation. With median follow-up of 21 months, estimated 18-month progression-free and overall survival for the combination treatment with/without transplantation were 75% and 97%, respectively. Lenalidomide-bortezomib-dexamethasone demonstrates favorable tolerability and is highly effective in the treatment of newly diagnosed myeloma. This study is registered at http://clinicaltrials.gov as NCT00378105.

    had a successful collection. Twenty-three patients underwent
    stem cell transplantation (SCT) and are evaluable through day
    100 with CR/nCR documented in 70% and XVGPR in 74%.

    VRD:
  • Bz 1.3 1,4,8,11
    Dex 40 mg weekly
    Cyclophosphamide 500 mg/m2 days 1 and 8 and 15 in vdc-mod
    Vdcr len 15 mg 1-14
    Vdr len 25 mg 1-14
  • VMP
    Cycles 1–4
    Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32
    Melphalan 9 mg/m2 and prednisone 60 mg/m2:
    d 1–4

    Cycles 5–9
    Bortezomib 1.3 mg/m2 IV: d 1,8,22,29
    Melphalan 9 mg/m2 and prednisone 60 mg/m2:
    d 1–4

    MP
    Cycles 1–9
    Melphalan 9 mg/m2 and prednisone 60 mg/m2:
    d 1–4
  • This ECOG trial is well recognized for determining that dexamethasone dosing of 40 mg/day on a 4-days-on, 4-days-off schedule is too high. This randomized trial of lenalidomide and dexamethasone compared the then-standard dosing of dexamethasone to a once-weekly dosage of 40 mg and found that survival was significantly improved in the low-dose dexamethasone arm -- 1-year OS was 87% with len/high-dose dex vs 96% with len/low-dose dex.
    Objective: to assess if a reduced dose of dex decreases toxicity while maintaining efficacy
    Primary endpoint: ORR after first 4 cycles
    aBased on the superiority of the Rd regimen, the study was stopped at a median follow-up of 12.5 months and patients in the RD arm crossed over to Rd therapy.



  • * Half of the patients start with VMP and half with Rd.
    Treatment duration: 74 weeks
  • Newly Diagnosed Myeloma

    1. 1. Best approach to newly diagnosed multiple myeloma Elisabet Manasanch M.D., M.H.Sc. Assistant Professor, Department of Lymphoma/Myeloma Division of Cancer Medicine
    2. 2. Disclosures Nothing to disclose
    3. 3. Overview Outline Fit patients Unfit patients High risk multiple myeloma
    4. 4. Overview 103,826 new cases 72,453 deaths worldwide Incidence rate 3-5/100,000 Kihyun Kim et al. Clinical profiles of multiple myeloma in Asia – An Asian Myeloma Network Study. 2014. AJH. JH Lee et al. Multiple myeloma in Korea: past, present, and future perspectives. 2010. Int J Hematol. Blacks Age 70 years Incidence rate 0.5-3/100,000 Age 62 years
    5. 5. Overview Plasma cell malignancy – molecular heterogeneity Natural history progression from MGUS/SMM Evidence of end-organ damage GROUPS Associated translocations 7 -> MF t(14;16) and t(14;20) 6 -> CD-2 CCND1/CCND3 t(11;14) and t(6;14) activating Cyclin D 1 and Cyclin D3 5 -> CD-1 CCND1/CCND3 t(11;14) and t(6;14) activating Cyclin D 1 and Cyclin D3 4 -> HY Hyperdiploidy 3 -> MS t(4;14), activation of FGFR3 and MMSET 2 -> LB Low Bone Underexpression of DKK1 1 -> PR PRoliferation Increased proliferation index Zhan et al. The molecular classification of multiple myeloma. Blood. 2006 / Lohr et al. Widespread genetic heterogeneity in multiple myeloma: Implications for targeted therapy. Cancer Cell. 2014.
    6. 6. Treatment History Dex VAD Thal+Dex CTD VD PAD Rd VTD RVD CRd Melphalan/ prednisone High-dose therapy with autologous stem cell HD dexamethasone VAD HD melphalan Autologous BM transplants support Lenalidomide Thalidomide Bortezomib Carfilzomib Pomalidomide Elotuzumab Daratumumab 100 80 60 40 20 0 Sarcolysine 1958 1962 1983-86 1996 1999 2003 2006 2012 Patients with ≥ VGPR (%) S Kumar et al. Cancer Treatment Reviews 2010; Korde et al. ASH 2013.
    7. 7. Overview DIAGNOSTIC APPROACH Blood CBC with differential Complete chemistries LDH Serum quantitative immunoglobulins SPEP/IFE Serum β2-M and albumin Serum free light chain assay Urine 24 hour UPEP/IFE Pathology/Molecular Bone marrow biopsy (core and aspirate – unilateral) Metaphase cytogenetics FISH BM aspirate flow cytometry Gene expression profiling* Imaging Skeletal survey MRI/PETCT RA Kyle and SV Rajkumar. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009. Manasanch et al. Flow cytometric sensitivity and characteristics of plasma cells in patients with multiple myeloma or its precursor disease: influence of biopsy site and anticoagulation method. Leukemia and Lymphoma. 2014. In press.
    8. 8. Overview Outline Fit patients Unfit patients High risk multiple myeloma
    9. 9. Fit patients Absence of comorbidities, even if advanced age IFM 2005/01 GIMEMA HOVON-GMMG PETHEMA/GEM Harousseau VD vs VAD (n= 240 vs 242) JCO 2010 Cavo VTD vs TD (n=241 vs 239) Blood 2012 Sonneveld PAD vs VAD (n=417 vs 416) JCO 2012 Rosinol VTD vs VBCMP/VBAD+V vs TD (n=130 vs 129 vs 127) Blood 2012 Results post-ASCT CR (nCR+sCR) 40% vs 18.4% 73.1% vs 60.9% 31% vs 15% 46% vs 38% vs 24% PFS (months) 36 vs 29.7 (S) NR vs 32 35 vs 28 (S) 56.2 vs 35.5 vs 28.2 (S) OS (months) Not reached (32 months follow up) 90% vs 88% at 3 years Not reached (66 months follow up) 74% vs 70% vs 65% (4 years) (NS) Most patients are treated with ASCT Phase III trials with bortezomib induction regimens
    10. 10. Combinations novel agents Phase II studies with small numbers of patients VRD CyBorD Richardson et al. Lenalidomide, bortezomib and dexamethasone combination therapy in patients with newly diagnosed mutiple myeloma. Blood. 2010. / Reeder et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed Multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009.
    11. 11. Combinations novel agents Randomized phase II study EVOLUTION (140 patients) 8 x 3 week cycles initial therapy followed by 6-week cycles of bortezomib maintenance Small numbers of patients PFS at one year: 86 vs 83 vs 93 vs 100 (%) OS at one year: 94% vs 100% in all other arms S Kumar et al. Randomized, multicenter, phase 2 study(EVOLUTION). Blood. 2012
    12. 12. CRd in newly diagnosed MM Jakubowiak et al (Phase I/II, n = 53) Korde et al (Phase II, n = 45) Combination therapy CRd (Phase II Cfz 20/36 mg/m2) 8 cycles CRd (Cfz 20/36 mg/m2) 8 cycles Extended dosing CRd (Cfz every other week) 16 cycles, off-protocol Ln at last tolerated dose d1-21 after 16 cycles Ln 10 mg d1-21, 24 cycles Transplant ≥PR stem cell collection, HDM optional Stem cell collection Jakubowiak et al (Phase I/II, n = 53) Korde et al (Phase II, n = 45) ORR 62% nCR/CR, 81% VGPR, 98% PR after 12 cycles 51% CR/nCR, all MRD negative (without ASCT) PFS 92% (at 24 months) 97% (at 12 months) A Jakubowiak et al. A phase ½ study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 / N Korde et al. Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Extended Dosing (CRD-R) Induces High Rates of MRD Negativity in Newly Diagnosed Multiple Myeloma (MM) Patients. ASH abstract 538. 2013.
    13. 13. New agents in NDMM RANDOMIZED PHASE 3 STUDIES 1.- IFM/DFCI: RVD with upfront or delayed autologous stem cell transplant 2.- RVD vs CRd EARLY PHASE TRIALS 1.- Carfilzomib, cyclophosphamide, dexamethasone 2.- Carfilzomib, bendamustine, dexamethasone 3.- Ixazomib, lenalidomide, dexamethasone 4.- Ixazomib, cyclophosphamide, dexamethasone 5.- RVD+ panabinostat 6.- Cyclophosphamide, lenalidomide, dexamethasone
    14. 14. Overview Outline Fit patients Unfit patients High risk multiple myeloma
    15. 15. Velcade as initial treatment in newly diagnosed myeloma not eligible for transplant Randomized, international, phase III trial of VMP vs MP in 682 previously untreated patients with symptomatic MM who were not candidates for HDT-ASCT due to age (≥65 yrs) or co-morbid conditions VMP Cycles 1–4 Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32 Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4 Cycles 5–9 Bortezomib 1.3 mg/m2 IV: d 1,8,22,29 Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4 MP Cycles 1–9 Melphalan 9 mg/m2 and prednisone 60 mg/m2: d 1–4 R A N D O M I Z E 9 x 6-week cycles (54 weeks) in both arms • Primary end point: TTP • Secondary end points: CR rate, ORR, time to response J San Miguel et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM. 2008
    16. 16. VISTA trial Time to progression Overall survival VMP: 24.0 months MP: 16.6 months P < .000001 100 80 60 40 20 0 VMP MP Time (months) Median follow-up: 25.9 months 3-year OS: VMP: 72% MP: 59% P = .0032 VMP MP Time (months) 0 3 6 9 12 15 18 21 24 27 100 80 60 40 20 0 0 4 8 12 16 20 24 28 32 36 40 682 patients RR: 71% VMP versus 35% MP Rate of CR: 30% VMP versus 4% MP J San Miguel et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM. 2008
    17. 17. HD vs LD lenalidomide. ECOG E4A03 Four 28-day cycles 1-yr OS 2-yr OS HD/lenalidomide 87% 75% LD/lenallidomide 96% 87% Transplant-eligible patients can proceed to SCT Continue therapy until disease progression Lenalidomide + High-Dose Dexamethasone (RD)a Len: 25 mg/day, days 1-21 Dex: 40 mg/day, days 1-4, 9-12, 17-20 (n = 223) Lenalidomide + Low-Dose Dexamethasone (Rd) Len: 25 mg/day, days 1-21 Dex: 40 mg/day, days 1, 8, 15, 22 (n = 222) Rajkumar et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010.
    18. 18. Mateos MV et al. Proc ASH 2013;Abstract 403.
    19. 19. FIRST trial Progression Free Survival Overall Survival T. Facon et al. ASH 2013. Abstract 2.
    20. 20. Overview Outline Fit patients Unfit patients High risk multiple myeloma
    21. 21. High risk MM Genomic abnormalities FISH - del 17p - t(14:16) - t(14:20) GEP - High risk signature Laboratory abnormalities Renal failure Circulating plasma cells Increased LDH or B2M Moreau et al. Combination of International Scoring System 3, High Lactate Dehydrogenase, and t(4;14) and/or del(17p) Identifies Patients With Multiple Myeloma (MM) Treated With Front-Line Autologous Stem-Cell Transplantation at High Risk of Early MM Progression–Related Death. JCO. 2014
    22. 22. High risk MM * Bortezomib containing regimens as initial treatment * Use of bortezomib consolidation/maintenance * Use of ASCT as consolidation * Explore tandem ASCT * Enroll in clinical trials if this is a possibility AK Nooka et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014.
    23. 23. Conclusions * Fit patients: *3 drug combination as initial therapy. *Stem cell collection and evaluation for ASCT. * Unfit patients: *VMP (other MPR, MPT) *Rd continuous treatment * High risk patients: *Refer for clinical trials *Use bortezomib (proteasome inhibitors) in consolidation/maintenance *Evaluate for ASCT/tandem ASCT
    24. 24. MDACC Myeloma Center Dr. Robert Orlowski Dr. Jatin Shah Dr. Donna Weber Dr. Sheeba Thomas Dr. Michael Wang Dr. Parmar Dr. Qazilbash Dr. Shah Dr. Bashir Stem Cell Transplant Department Support staff, nurses, coordinators Patients

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