Multiple myeloma. November 24, 2017 at Vientiane, Laos

Transcription

1 Multiple myeloma November 24, 2017 at Vientiane, Laos Teeraya Puavilai, M.D. Division of Hematology, Department of Medicine Faculty of Medicine Ramathibodi, Mahidol University, Thailand

2 Multiple myeloma Neoplastic plasma cell disorder Clonal proliferation of malignant plasma cells in the bone marrow microenvironment Monoclonal protein in blood or urine Organ dysfunction 1% of neoplastic diseases 13% of hematologic cancers In western countries, the annual age-adjusted incidence is 5.6 cases per 100,000 persons In recent years, the introduction of autologous stem cell transplantation & the availability of agents such as thalidomide, bortezomib and lenalidomide have changed the management of myeloma and extended overall survival. Patients < 60 years, 10 year survival is approximately 30% N Engl J Med 2011;364:

3 Epidemiology of Thai MM patients Retrospective data collection for 10 years, multicenter study in 2008 Median age = 62 years (20-96) Total case 1,100 cases Gender Male 52.6% Female 47.4%

4 Pathogenesis of Multiple Myeloma The proliferation and survival of multiple myeloma cells within the tumor microenvironment is, therefore, dependent on their interaction with the BMSC and the ECM. Hideshima T, et al. Nature Reviews Cancer 7, (August 2007)

5 Multistep pathogenesis of MM 1. During progression focal amplifications of 1q21.2(43 72%), amplification & translocation of c-myc/bcl2 increasing resistance to anti-mm therapy 2. Increase of coding mutations during therapy(46 ) 3. Acquiring new subclones/changes in the clonal composition under therapy Increasing genetic instability / new genetic alterations during the progression of MM Chesi M and Bergsagel PL et al. ASH education 2011

6 Risk factors for newly diagnosed MM Host Plasma cell genetics Other Advanced age, frailty Deletion (17p) High S phase, high LDH Performance status t(4;14), t(14;16), t(14;20) Circulating PC s Comorbidities (renal failure, low albumin, high β2m) Medical community Deletion (1p); addition (1q) Deletion (13q) by metaphase cytogenetics High serum FLC; high β2m Extramedullary disease Drug discovery/ availability Hypodiploidy Reduced polyclonal BMPC s Rational regimen design High-risk GEP signatures Early relapse; absence of response

7 Clinical presentation of MM Bone marrow failure Bone pain due to osteoporosis or compression fracture of spine Neurological symptoms eg. Polyneuropathy, mononeuropathy multiplex or autonomic neuropathy from paraprotein8 or systemic amyloidosis Paraproteinemia Metabolic : renal failure, hypercalcemia, tumor cachectic syndrome Cardiovascular : high output heart failure, restrictive cardiomyopathy due to cardiac amyloidosis Systemic amyloidosis POEMS syndrome

8 CRAB: end organ damage Hypercalcemia Renal insufficiency Anemia Bony lesions Other associated findings Serum Calcium > 11 mg/dl Serum Creatinine > 1.9 mg/dl Hemoglobin < 10 g/dl Lytic bone lesions, or osteoporosis with compression fractures Symptomatic hyperviscosity, amyloidosis, recurring bacterial infections ( >2 episodes in 12 months)

9 Multiple myeloma (MM) PBS: Rouleaux formation BM smear: immature plasma cell

10 Multiple myeloma (MM) Serum protein electrophoresis Urine protein electrophoresis

11 Multiple myeloma Osteolytic bone lesions

12 Multiple myeloma: CD 138 Am. J. Clin. Pathol. 121 (2):

13 Diagnostic criteria for MM Both criteria must be met: 1. Clonal BM plasma cells 10% or biopsy-proven bony or extramedullary plasmacytoma 2. Any 1 of the following myeloma defining events: Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: 1) Hypercalcemia: serum calcium >0.25 mmol/l (>1 mg/dl) higher than the upper limit of normal or >2.75 mmol/l (>11 mg/dl) 2) Renal insufficiency: CCr <40 ml per minute or serum creatinine >177 lmol/l (>2 mg/dl) 3) Anemia: hemoglobin value of >2 g/dl below the lower limit of normal, or Hb <10 g/dl 4) Bone lesions: 1 osteolytic lesions on skeletal radiography, CT or PET-CT Clonal BM plasma cell 60% Involved: uninvolved serum free light chain (FLC) ratio 100 (involved free light chain level must be 100 mg/l) >1 focal lesions on MRI (at least 5 mm in size) Rajkumar et al., Lancet Oncol, 2014, 15, e538-e548

14 Monoclonal gammopathy of undetermined significance (MGUS) Asymptomatic premalignant stage Rate of progression from MGUS to MM = 0.5%-1% 3%-4% of population of the age > 50 years Lancet Oncol 2014; 15: e538 48

15 Smouldering multiple myeloma (SMM) Intermediate stage between MGUS and MM Progression rate to MM in first 5 years after diagnosis = 10% per year 14% of all plasma cell dyscrasias 2 subsets Patients with biologically premalignancy Patients with CRAB negative malignancy Need study for prognostic factor identification Lancet Oncol 2014; 15: e538 48

16 Multiple myeloma (MM) 80% originate from non-igm MGUS : IgA, IgD, IgE, IgG 20% originate from light chain MGUS : kappa, lambda IgM MGUS usually evolves Waldenstorm macroglobulinemia Rare for progression from IgM MGUS to MM Lancet Oncol 2014; 15: e538 48

17 Comparison of Clinical Features MM, SMM, or MGUS Characteristics MM SMM MGUS Marrow plasma cells 10% 10% < 10% Serum M-spike 3 g/dl 3 g/dl < 3 g/dl Bence-Jones protein 1 g/24 hrs < 1 g/24 hrs < 1 g/24 hrs Anemia Usually present May be present absent Hypercalcemia, renal insufficiency May be present absent absent Lytic bone lesions Usually present absent absent

18 Revised IMWG criteria MGUS SMM MM <10% BMPC and <3 gm/dl protein and No MDE 10-60% BMPC or 3 gm/dl S. M protein or 500 mg/24hr Ur. M protein and No MDE PCPD, and 1 or more MDE CRAB 60% BMPC 100 PLC ratio >1 MRI focal lesion Rajkumar SV, Dimopoulos M, Palumbo A, et al. Lancet Oncol. 2014;15(12):e538-e548

19 International Staging System Gripp PR et al. JCO 2005;23:

20 Cytogenetic risk groups (by FISH) for MM Risk group Cytogenetic findings Disease characteristics Median survival Good risk hyperdiploidy t(11;14) by FISH t(6;14) by FISH Intermediate risk Most often Express IgG kappa Lytic bone lesions t(4;14) by FISH Often IgA lambda Less bone disease High risk del 17p by FISH t(14;16) by FISH cytogenetic del 13 hypodiploidy 1q gain plasma cell leukemia Often express IgA lambda Skeletal-related complications (less often) 8-10 years 5 years < 2 years

21 Cytogenetic risk groups (by FISH) for MM Risk group Cytogenetic findings Disease characteristics Median survival Good risk hyperdiploidy t(11;14) by FISH t(6;14) by FISH Intermediate risk t(4;14) by FISH cytogenetic del 13 High risk del 17p by FISH t(14;16) by FISH cytogenetic del 13 hypodiploidy 1q gain plasma cell leukemia Most often Express IgG kappa Lytic bone lesions Often IgA lambda Less bone disease Often express IgA lambda Skeletal-related complications (less often) 8-10 years 5 years < 2 years

22 ISS and Revised-ISS for MM Stage International Staging System (ISS) Revised-ISS (R-ISS) I Serum β2 microglobulin < 3.5 mg/l or Serum albumin 3.5 mg/l ISS stage I and standard risk chromosome abnosmalities by FISH and Serum LDH < the upper limit of normal II Not ISS stage I or III Not R-ISS stage I or III III Serum β2 microglobulin 5.5 mg/l ISS stage III and either high risk chromosome abnosmalities by FISH or Serum LDH > the upper limit of normal

23 Revised International Staging System for Myeloma R-ISS for MM 5 year survival rate (%)* Stage I All of the following: 82 Serum albumin 3.5 gm/dl Serum beta-2-microglobulin <3.5 mg/l No high-risk cytogenetics Normal serum LDH Stage II Not fitting Stage I or III 62 Stage III Both of the following: 40 Serum beta-2-microglobulin >5.5 mg/l High-risk cytogenetics [t(4;14), t(14;16), or del(17p)] or Elevated serum LDH

24 Revised International Staging System (R-ISS) Palumbo et al. JCO 2015;33:2863-9

25 Goals of initial therapy High response rate: rapid response Depth of response Improve performance status and QOL PBSC mobilization (for younger patients)

26 Treatment paradigm for NMM Transplant eligible patients Transplant ineligible patients Induction therapy Autologous stem cell transplantation Initial therapy/ maintenance Consolidation Maintenance Treatment of relapsed disease Supportive care

27 Medications for MM in Thailand Chemotherapy : VAD, Cy-dex, MP, DCEP, DVD, Melphalan IV for ASCT Target therapy Immunomodulatory drug: Thalidomide, Lenalidomide, Pomalidomide Proteosome inhibitor: Bortezomib IV & SC, Carfilzomib Anti-CD 38: Daratumomab Clinical trial drug: Ixazomib (oral PI) Bisphophonate: Pamidronate, Zolindronic acid, Alendronate Mobilization for ASCT G-CSF Cyclophosphamide high dose + G-CSF Plerixafor (CXCR4 antagonist) + G-CSF

28 Should we tailor therapy? By genetic risk category Proteosome inhibitors improve but not overcome poor prognosis of high risk genetics By age with comorbidities Dose modification and intensity modulation For severe renal impairment Choose Bortezomib, Thalidomide, Pomalidomide, Cyclophosphamide, Dexamethasone

29 Thailand Newly diagnosed transplant candidate MM Age 65 Induction therapy 4-6 cycles Response VGPR Response < VGPR Autologous stem cell transplantation Salvage therapy until response VGPR Consider consolidation/maintenance

30 Thai guideline 2017 Primary therapy for transplant candidates Thalidomide-based therapy Cyclophosphamide/thalidomide/dexa methasone (ก๒/+) Thalidomide/doxorubicin/dexamethas one (ก๒/+) Thalidomide/dexamethasone (ข๒/+) Bortezomib-based therapy Bortezomib/dexamethasone (ก๒/+) Bortezomib/doxorubicin/dexamethas one + bortezomib maintenance (ก๒/+ & ก๒/++ for high risk) Bortezomib/thalidomide/dexamethas one (ก๒/+) Cyclophosphamide/bortezomib/dexa methasone (ข๒/++)

31 Thai guideline Primary therapy for transplant candidates Lenalidomide-based therapy Lenalidomide/dexamethasone (ข๒/+/-) Bortezomib/lenalidomide/dexameth asone (ข๒/-) Chemotherapy therapy Cyclophosphamide /dexamethasone VAD DCEP DVD

32 Thai guideline Primary therapy for transplant candidates MM + Peripheral neuropathy caution if use thalidomide or bortezomib (ข๒/++) MM + Hx or risk of thromboembolism avoid thalidomide and lenalidomide (ข๒/++) MM + Severe renal abnormality avoid lenalidomide (ข๒/++) MM + high risk + renal abnormality early use bortezomib (ข๒/++)

33 Thai guideline Primary therapy for transplant candidates MM with age 65 years & good performance status & good end organ function upfront ASCT (ก๒/++) Tandem ASCT : Response rate but TRM (ก๒/-) Allogeneic SCT only research (ก๒/+)

34 Phase 3 trials evaluating novel agent-based maintenance therapy after ASCT Study Regimen Comparator Increased PFS? Increased OS? Lenalidomide Attal et al McCarthy et al Palumbo et al Thalidomide Attal et al Barlogie et al Spencer et al Lokhorst et al Morgan et al Stewart et al Bortezomib Sonneveld et al Rosinol et al LEN LEN LEN THAL + PAM THAL + IFNa + DEX THAL + pred THAL THAL THAL + pred PAD BORT BORT + THAL Placebo Placebo No maintenance PAM or no maintenance IFNa + DEX Pred IFNa No maintenance No maintenance VAD THAL THAL or IFNa Yes Yes (TTP and EFS) Yes Yes (EFS) Yes (EFS) Yes Yes (EFS) Yes Yes Yes Yes No Yes No No Yes Yes No No No No No Facon T. Hematology 2015;279-85

35 Treatment paradigm for NMM Transplant eligible patients Transplant ineligible patients Induction therapy Autologous stem cell transplantation Initial therapy/ maintenance Consolidation Maintenance Treatment of relapsed disease Supportive care

36 NCCN version Non-Transplant candidate for MM

37 Transplantation ineligible Transplant Ineligible High Risk Standard Risk MPT 12 cycles or consider bortezomib containing regimen to max response MPT 12 cycles If not in CR consider Thal-Pred to max response if no prior thalidomide Observation

38 Selected nontransplant trials for NMM Phase Trial Arm N PFS* HR ORR VGPR CR 3 FIRST MPT Rd 18 Rd cont. 3 SWOG S0777 VRd Rd # % 73% 75% % 71.5% 28% 43% 44% 43.5% 31.8% 2 RVD lite RVd 50 90%@ 60% 25% 3B UPFRONT Vd VTd VMP 3 GEM2005 VMP VTP 3 MAIA Rd-dara Rd 3 TOURMALINE- MM2 IRd Rd * Median PFS in months # HR of Rd continuous vs Response rates are after 4 cycles of treatment in 40 patients % 80% 70% 80% 81% Ongoing Closed to accrual 37% 51% 41% 9% 14% 15% 15.7% 8.4% 3% 4% 4% 20% 28%

39 Effect of patient fitness on myeloma treatment outcomes Palumbo A et al. Blood 2015;125:

40 CR correlate with long term survival in elderly patients treated with novel agents Gay F et al. Blood 2011;117:

41 M protein (g/dl) Cure: Use aggressive multidrug strategy targeting CR Control: Sequential disease control approach that emphasizes QOL as well as OS 10 Asymptomatic Symptomatic Active myeloma 5 2 MGUS or smouldering myeloma Plateau remission Relapse Refractory relapse Time Durie BGM Concise review of the disease and treatment options. Multiple myeloma. North Hollywood, CA: International Myeloma Foundation. Available from: Accessed November 2012.

42 Thank you for your attention