Multiple Myeloma F1 蘇勇誠 /MA 林棟樑

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1 Multiple Myeloma F1 蘇勇誠 /MA 林棟樑

2 Plasma Cell Disorders Multiple Myeloma Other Disorders Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Solitary Plasmacytoma» Bone» Extramedullary Waldenström s Macroglobulinemia Primary Amyloidosis (AL) Heavy chain disease POEMS syndrome / osteosclerotic myeloma Type I and II cryoglobulinemia Light chain deposition disease

3 Distribution of Monoclonal Gammopathies n=1296 Lymphoproliferative 2.5% (31) Amyloidosis (AL) 10% (130) Mayo Clinic Experience SMM, 3.5% (44) Solitary or extramedullary, 1.5% (20) Macro, 3% (41) Other, 2.5% (34) Myeloma 15% (193) MGUS 62% (803)

4 Background and biology

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7 Criteria for Diagnosis of Myeloma MGUS <3 g M spike <10% PC AND Smoldering MM 3 g M spike OR 10% PC Active MM 10% PC M spike + AND No anemia, bone lesions normal calcium and kidney function Anemia, bone lesions, high calcium or abnormal kidney function Kyle RA. N Engl J Med 2002; 346: 564

8 Multiple Myeloma Malignancy of plasma cells Hallmarks: Anemia Renal failure Bone destruction (lytic bone lesions) Hypercalcemia Presence of monoclonal protein Increased risk of infection

9 Multiple Myeloma Prevalence 2nd most common hematologic malignancy 1% of all malignant diseases About 10% of hematologic malignancies Annual incidence: 4/100,000 Median age at diagnosis is 66 years Younger than 50 years: 10% Median survival from diagnosis: 3-5 years 5-year survival: 31% 10-year survival: 10% 5-year survival: 5%

10 Multiple Myeloma Population subgroups Incidence twice as high in African Americans More frequent in men than women This disease remains incurable in most patients

11 Historical Perspective of Multiple Myeloma 1st patient diagnosed with bone pain and heat soluble and "animal matter" in urine Termed MM BM involvement recognized Plasma cell discovered MM associated with plasmacytosis Peak on serum protein electrophoresis noted Bence Jones and MM serum IgG proteins identical

12 Historical Perspective of Multiple Myeloma ABMT VAD High-dose therapy with autologous stem cell support Proteasome inhibitors Other immunomodulatory agents High-dose melphalan Oral melphalan and prednisone High-dose dexamethasone Bisphosphonates Thalidomide

13 Plasma Cell Morphology

14 Normal Serum Protein Electrophoresis

15 Serum Protein Electrophoresis Showing Monoclonal Protein in Myeloma

16 Immunofixation to Determine Type of Monoclonal Protein IgG kappa M protein

17 Bone Marrow in Myeloma

18 Immunophenotyping Light-chain restriction: kappa/lambda Typically CD 138+ and CD 38+/CD45- Usually CD19-/CD56+ normal plasma cells: CD19+/CD56- CD20(+) in only 15-20% of MM patients (11;14) Lymphoplasmacytic or small mature plasma cells

19 Evolution of MM: The MGUS to Myeloma Progression

20 Distinguishing Multiple Myeloma from MGUS Myeloma MGUS Bone marrow plasma cells 10% on aspirate < 10% on aspirate Serum paraprotein Variable concentration in serum; IgG usually > 3gm/dl IgG usually < 3gm/dl IgA usually <1gm/dl Bence-Jones proteinuria >50% cases Rare Immune paresis > 95% cases Rare Lytic bone lesions Often present Absent Symptoms Frequent Absent Anemia Frequent Absent Hypercalcemia May be present Absent Abnormal renal function May be present Absent

21 MGUS: Rate of Progression to Any Lymphocytic Disorder

22 MGUS: Risk of Progression Based on Initial M-spike

23 MGUS Size of monoclonal (M) protein and risk of progression to myeloma or related malignancy M-Protein Size (g/dl) Risk of Progression at 10 years (%) Risk of Progression at 20 years (%)

24 Relative Risk Diagnosis of Patients Who Have Progressed from MGUS MM 2.4 IgM lymphoma 8.4 Primary amyloidosis 0.9 Chronic lymphocytic leukemia 8.5 Macroglobulinemia Plasmacytoma Disease

25 Chromosomal Abnormalities in Myeloma Incidence Conventional G-banding: 30-50% of patients Difficult due to low proliferative activities Interphase FISH: > 90% of cases Poor prognosis Deletion of chromosome 13 or 13q14 t(4;14) t(14;16) 17p- Chromosome 1q21 aberration

26 Chromosomal Abnormalities 14q32(IgH locus): most common 11q13: most common (bcl-1 locus, 30%) 4p16 (FGFR3, MMSET, 25%) 8q24 (c-myc, 5%) 16q23 (c-maf, 1%) 6p25 (IRF4, rare) P53 Chromosome 1q21 aberration 13 deletion (Rb) 10-20% of patients using conventional cytogenetics and 50% using FISH

27 Clinical presentations and staging

28 Major Symptoms at Diagnosis Bone Pain 58% Fatigue 32% Weight Loss 24% Paresthesias 5% 11% are asymptomatic or have only mild symptoms at diagnosis

29 Clinical Features at Presentation Monoclonal (M) protein (93%) Lytic bone lesions (67%) Increased plasma cells in the bone marrow (96%) Anemia (normochromic normocytic; 73%) Hypercalcemia >11 (13%) Renal failure, serum creatinine >2.0 (19%) Infection

30 Distribution of Monoclonal Proteins in Multiple Myeloma M protein found in serum or urine or both at time of diagnosis in 97% of patients (3% are non-secretory) Serum M spike: 80% Abnormal immunofixation: 90% Detectable urine paraprotein: 75% IgG: 50% 54% IgA: 20% Monoclonal light chain: 16% <20% IgD: 2%

31 Percentage Types of Serum Monoclonal Proteins in 1027 Patients With Multiple Myeloma % % 15 13% 10 8% 9% 7% 7% % 0.2% 1% 1% IgG IgG IgA IgA IgM IgM IgD IgD Free Free Biclonal Negative only only Type of Monoclonal Protein 2%

32 Categories of Multiple Myeloma Classification Characteristics Management MGUS Smoldering MM Serum M protein <3 g/dl Bone marrow plasma cells <10% if done Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions Serum M protein <3 g/dl and/or Bone marrow plasma cells <10% if done Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions Observation with treatment beginning at disease progression Observation, with treatment beginning at disease progression

33 Categories of Multiple Myeloma Classification Characteristics Management Indolent MM Symptomatic MM Presence of serum/urine M protein Bone marrow plasmacytosis Mild anemia or few small lytic bone lesions Absence of symptoms Presence of serum/urine M protein Bone marrow plasmacytosis Anemia, renal failure, hypercalcemia, or lytic bone lesions Patients with primary systematic amyloidosis and bone marrow plasma cells 30% are considered to have both MM and amyloidosis Monitoring every 3 mo, with treatment beginning at disease progression Immediate treatment

34 Durie-Salmon Staging System for Myeloma Stage Criteria Myeloma cell mass ( cells/m 2 ) I All of the following: Hemoglobin >10 g/dl Serum calcium level 12 mg/dl (normal) Normal bone or solitary plasmacytoma on x-ray Low M component production rate: IgG <5 g/dl; IgA <3 g/dl Bence Jones protein <4 g/24 hr <0.6 (low) II Not fitting stage I or III (intermediate) III One or more of the following: Hemoglobin <8.5 g/dl Serum calcium level >12 mg/dl Multiple lytic bone lesions on x-ray High M-component production rate: IgG >7 g/dl; IgA >5 g/dl Bence Jones protein >12 g/24 hr >1.2 (high) Subclassification A B Criteria Normal renal function (serum creatinine level <2.0 mg/dl) Abnormal renal function (serum creatinine level 2.0 mg/dl)

35 International Staging System for Myeloma Stage 1 2 M <3.5 and ALB 3.5 ALB <3.5 and Stage 2 2 M <3.5 ALB <3.5 or 2 M 3.5 <5.5 Stage 3 2 M M=serum 2 microglobulin in mg/dl; ALB=serum albumin in g/dl

36 Major Adverse Prognostic Factors Karyotypic deletion 13 or hypodiploidy High plasma cell labeling index Molecular genetics: t(4;14), t(14;16) or 17p- High LDH, 2 M, or CRP Increased circulating plasma cells Plasmablastic morphology Low albumin

37 Del 13: Unfavorable Prognosis 1 Deletion of chromosome 13 is the single most powerful adverse prognostic factor for all times to events in patients referred for high-dose therapy OS 65.1 ± 9.8 vs 26.7 ± 4.1 months

38 Plasma cell labeling index

39 Plasmablastic Morphology

40 Circulating plasma cells

41 Chemotherapy

42 Initial Therapy Considerations Ensure patient does not have smoldering MM (asymptomatic MM) Approach to therapy for MM is based on whether a patient is a transplant candidate Consider clinical trials if available Improving complete response rates is a key goal of current trials

43 IBMTR (EBMT) Criteria for Complete and Partial Response* Complete response requires all of following No serum/urine M protein by IFE for 6 wk <5% plasma cells in bone marrow aspirate No increase in size or number of lytic bone lesions Disappearance of soft tissue plasmacytomas Partial response requires all of following 50% reduction in serum M protein 6 wk 90% reduction in 24-hr urinary light chain excretion 50% reduction in soft tissue plasmacytomas No increase in size or number of lytic bone lesions *

44 Initial Approach to Treatment of MM Clearly not a transplant candidate based on age, performance status and comorbidity Potential transplant candidate Conventional chemotherapy or clinical trial Non-alkylator based induction x 4 cycles *Thal/Dex, Dex, or VAD if immediate response is needed Stem cell harvest

45 Current Multiple Myeloma Treatment Adapted from NCCN Practice Guidelines Diagnosis Survival 3-5 yrs Survival < 6 mos without Rx ~12,000 deaths per yr Relapsed Disease Transient Response Survival 1-3 yrs Relapsed/Refractory Disease Shorter TTP Survival 6-9 mos Initial Therapy Cyclophosphamide Melphalan, Prednisone VAD, Doxil Dexamethasone (Dex) Thalidomide + Dex Bortezomib Lenalidomide Non- Transplant Candidate Transplant Candidate Salvage Therapy: Repeat primary therapy (if relapse > 6 mos) Cyclophosphamide, VAD, Doxil Etoposide, Dex, Cytarabine, Cisplatin Thalidomide/IMiDs (CC-5013: lenalidomide) +/- Dex Bortezomib +/- Dex Other Novel Therapies Stem cell harvest, subsequent auto SCT ( single vs double) +/- maintenance therapy Investigational therapy (e.g. Allo)

46 Primary Treatment Approaches for Myeloma Combination therapy examples MP VBAP VAD VBMCP Thal/Dex DT-PACE ABCM

47 Challenges in Management Currently incurable in most patients Chemotherapy response rates = 50% to 70% Long-term complete responses = rare Median survival with standard therapy = 3 years Stem cell transplant prolongs survival, but not curative Treatment of relapse No standard therapy Existing options inadequate New treatment options needed.

48 NCCN Treatment Guidelines for Myeloma Primary conventional therapy Melphalan/prednisone (MP) Vincristine/doxorubicin/dexamethasone (VAD) Dexamethasone Thalidomide/dexamethasone (Thal/Dex) Liposomal doxorubicin/vincristine/ dexamethasone (DVD)

49 Melphalan/Prednisone Treatment Alkylating agent + corticosteroid dosing Dosing: 0.25 mg/kg/day melphalan for 4 days + 20 mg prednisone tid for 4 days Duration: every 4 to 6 wk 40% remission (at least 75% reduction in serum myeloma protein, 95% reduction in Bence Jones proteinuria and >5% marrow plasma cells)

50 Melphalan/Prednisone Treatment Median duration of remission about 2 years At least 3 courses Median survival 3 years <10% live longer than 10 years No evidence of disease cured Drug resistance is an issue Not recommended for candidates for SCT Full benefit takes several months

51 Combination Chemotherapy vs Melphalan/Prednisone 3814 patients in 18 trials of combination chemotherapy vs melphalan/prednisone No difference overall Melphalan/prednisone superior for good prognosis patients MP inferior for poor prognosis patients patients in 27 trials of combination chemotherapy vs melphalan/prednisone Higher response rates to combination chemotherapy Equivalent mortality and survival 2

52 Estimated percentage still alive Mortality of Combination Chemotherapy vs Melphalan/Prednisone Years Allocated cct (% ± SD) Allocated MP (% ± SD) 23.0% 24.4% 18.0% 19.4% 1.4% SD 1.4 (log-rank 2P >.1; NS) Deaths/person-years: CCT 642/ / / / / /1130 MP 576/ / / / / /839

53 Thalidomide With Melphalan and Prednisone in Elderly Patients With Multiple Myeloma Response MPT Arm, % MP Arm, % CR + ncr 27.7* 5.4 PR (all combined) 75% to 99% M-protein reduction 50% to 74% M-protein reduction Median EFS, mo 25.2* 13.7 P<0.001 P<0.001 Median follow-up, 13.6 months

54 Thromboembolism in MPT-Treated Elderly Patients Reduced With Prophylaxis More DVT with MPT than with MP (P=0.003) DVT prophylaxis: enoxaparin, 0.4 ml/day for 4 months Adverse Event No Prophylaxis (n=61) Incidence, % With Prophylaxis (n=28) DVT Pulmonary thromboembolism Arterial occlusion

55 Toxicities MPT MP Toxicity, % G 1/2 G 3/4 G 1/2 Gr 3/4 Hematologic Constipation Infection Neurologic Thromboembolism 19 4 Deaths comparable Thal decreased in 28%, discontinued in 42%

56 Thalidomide (Thalomid ) Oral immunomodulator Derivative of glutamic acid Immunomodulatory agent with antiangiogenic and apoptotic properties O O H N N O O

57 Thalidomide in Myeloma: Overview Affects multiple pathways, multiple targets Oral administration Listed by NCCN as Primary conventional therapy with dexamethasone Salvage therapy as monotherapy Optimal dosing and drug combinations being studied

58 Thalidomide in Multiple Myeloma: Multiple Pathways, Multiple Targets Immunomodulatory effects Inhibits TNF Inhibits angiogenesis (bfgp, VEGF) Stimulates T cells (CD8+) Inhibits IL-12 Induces apoptosis Alters cytokines Affects stromal cells Cool RM et al. Pharmacotherapy. 2002;22:1019; D Amato RJ et al. Proc Natl Acad Sci USA. 1994;91:4082; Meierhofer C et al. BioDrugs. 2001;15:681; Thalidomide s various effects in myeloma [figure]. Available at: Weber D et al. J Clin Oncol. 2003;21:16; Bartlett JB et al. Nature Reviews/Cancer. 2004;4:314

59 Thalidomide/Lenalidomide Target MM Cells in the BM Microenvironment C. Thalidomide/IMiD MM cells IL-6 A.Thalidomide /IMiD B.Thalidomide /IMiD ICAM-1 TNF IL-1 Bone Marrow Stromal Cells VEGF bfgf Bone Marrow Vessels PBMC IL-2 IFN D. Thalidomide /IMiD CD8+ T Cells NK Cells E. Thalidomide /IMiD

60 Interaction of MM Cells and Their Bone Marrow Microenvironment MM cell Cytokine-mediated signaling Adhesion-mediated signaling VEGF TNF PI3K/AKT MAPK JAK/STAT3 IL-6 VEGF IGF1 SDF-1 MAPK NF-kB NF-kB Adhesion molecules MM cell ICAM1 VCAM1 LFA1 MUC1 VLA4 CRE c-fos SRE homology BMSC Reprinted with permission from Hideshima T, Anderson KC. Nat Rev Cancer. 2002;2:927

61 Signaling Cascades Mediate Growth, Anti-Apoptosis, and Migration in Myeloma IL-6 IGF1 VEGF TNF IL-21 SDF-1 RAF MEK p42/44 MAPK Proliferation MM cells IL-6 IL-21 JAK STAT3 BCL-X L MCL1 Anti-apoptosis (drug resistance) IL-6 IGF1 VEGF TNF SDF-1 PI3K AKT (PKB) Caspase-9 BAD NF- B FKHR Cyclin D KIP1 Cell cycle PKC Migration BMSC Reprinted with permission from Hideshima T, Anderson KC. Nat Rev Cancer. 2002;2:927

62 Apoptotic Signaling Triggered by Conventional and Novel Agents FAS/FASL, TRAIL Thal/IMiDs PS-341 As 2 O 3 Dexamethasone Caspase-8 Caspase-9 IL-6 IGF1 Conventional chemotherapy Ionizing radiation Caspase-3 PARP cleavage Apoptosis Reprinted with permission from Hideshima T, Anderson KC. Nat Rev Cancer. 2002;2:927

63 Lenalidomide (CC-5013; Revlimid ) More potent immunomodulator than thalidomide Up to 50,000 times more potent inhibitor of TNF 200- to 1000-fold in cytokine modulation Increased stimulation of T-cell proliferation Augmented stimulation OF IL-2 and IFN production Fewer side effects: no significant constipation, neuropathy, or sedation Not teratogenic O N O H N O Marriott JB et al.? 2003;3(3):181 Schey SA et al. J Clin Oncol. 2004;22:16? 2 Richardson P, Anderson K. J Clin Oncol. 2004;22:16? NH

64 Structure Thalidomide Lenalidomide

65 Lenalidomide Phase I Trial in Relapsed Myeloma: Adverse Events Lightheadedness Fatigue Grade 1 Grade 2 Grade 3 Grade 4 Rash Leg Cramps Thrombocytopenia Neutropenia Patients (%) (N=25)

66 NCCN Treatment Guidelines for Multiple Myeloma Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be limited to avoid compromising stem-cell reserve prior to stem-cell harvest in patients who may be candidates for transplant

67 Transplant Candidates: Most Commonly Used Induction Regimens VAD Cumbersome Toxicity 55-65% RR 85% of effect secondary to Dex Dexamethasone Oral Less toxicity than VAD or Thal/Dex 43% RR Thal/Dex Oral Increased toxicity compared to Dex 64-72% RR Transplant candidates should not receive alkylator-based therapy

68 VAD Combination of vincristine, Adriamycin (doxorubicin) and dexamethasone, cytotoxic antibiotic, and glucocorticoid steroid Dosing Vincristine: 0.4 mg/day IV daily for 4 days Doxorubicin: 9 mg/m 2 /day IV daily for 4 days Dexamethasone: 40 mg po days 1 4, 9 12, Repeat cycle q 28 days 4 cycles Reduction in tumor mass: 75% in 70% pts Remission: 70% pts Median time to response: 0.9 mo Can be used prior to SCT

69 Thalidomide/Dexamethasone vs Dexamethasone: Best Response Within 4 Cycles Endpoint Thal/Dex (n=99) Dex (n=100) Response rate, %* Adjusted response rate, % Median time to response, mo Disease progression within first 4 mo, % 2 4 *Response rate = Based on intention to treat, 50% reduction in serum and urine M protein, or 90% reduction in urine M protein if only urinary protein was evaluable for response; significantly higher response rate with Thal/Dex compared with Dex alone (P=0.002) Corrected response rate = Allowing for use of serum M protein levels in patients in whom measurable urine M protein was unavailable at follow-up Rajkumar SV et al. Blood. 2004;104(part 1):63a [abstract 205]

70 Thalidomide/Dexamethasone vs Dexamethasone: Drug-Related Adverse Events Drug-Related Adverse Event Thal/Dex, % (n=102) Dex, n % (n=102) DVT grade Rash grade Sinus bradycardia grade Neuropathy grade Any toxicity grade Total* Deaths within 4 cycles: Thal/Dex, 7%; Dex, 11% ]

71 Thalidomide/Dexamethasone vs Dexamethasone: Conclusions Superior response rates with Thal/Dex compared with Dex alone in newly diagnosed MM Thal/Dex associated with higher toxicities than Dex Need for DVT prophylaxis with Thal/Dex Higher response rates of Thal/Dex must be weighed against increased toxicity for individual patients

72 Lenalidomide (CC-5013) and Dexamethasone for Newly Diagnosed Myeloma: Adverse Events Profile Hematologic toxicity, % Grade 1/2 Grade 3/4 Anemia 3 7 Neutropenia 17 3 Lymphopenia 17 3 Non-hematologic toxicity, % Grade 1/2 Grade 3 DVT (all received prophylaxis) 0 0 Constipation 7 0 Sedation 30 7 Rash 3 3 Neuropathy 17 0 Anxiety 7 7 Rajkumar SV et al. Blood. 2004;104(part 1):98a [abstract 331]

73 Bortezomib (PS 341; Velcade ) Mechanism of action Reversible inhibitor of chymotrypsin-like activity of 26S proteasome Inhibition of proteosome prevents proteolysis of ubiquitinated proteins This disrupts homeostasis and can lead to apoptosis

74 Ubiquitin-Proteasome Pathway O Ub OH ATP AMP PP i O NH 2 E2-S E1-SH O Ub E3 E1-S Ub E2-SH HN O Ub n ATP Ub Degraded proteins Lys Protein Substrate isopeptidases Lys 26S Proteasome Complex

75

76 Bortezomib: Mechanism of Action in MM A. PS-341 MM Cell Growth C. PS-341 IL-6 TNF VEGF B. PS-341 ICAM-1 VCAM-1 VEGF bfgf D. PS-341 Bone Marrow Vessels Bone Marrow Stromal Cells

77 Mechanisms of Bortezomib in Treatment of MM Cell adhesion chemosensitizing synergism Modified from NEJM 2004:351:1860

78 Bortezomib: Most Common Adverse Events pts Nausea Diarrhea Constipation Vomiting Anorexia Thrombocytopenia Anemia Neutropenia Fatigue Per. Neuropathy Fever Arthralgia Headache Insomnia Grade 1-2 Grade 3 Grade Richardson, ASH 2002 #385; Richardson NEJM 2003;348:

79 Mean Platelet Count During Treatment

80

81 Autologous stem cell transplant

82 Autologous Stem Cell Transplantation Mel 200/m 2 standard conditioning regimen Sufficient performance status, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher overall and event-free survival than conventional Rx Advanced age and impaired renal function are by themselves not contraindications.

83 Transplant versus Conventional Chemotherapy 54 42

84 Total Therapy 1*: Long-term F/U Survival (N = 231) CR Duration (N = 64) 100% 100% 80% 60% Median OS 7 yr 80% 60% Median 3 yr 40% 40% 20% Median EFS 3 yr 0% Years after Registration 20% 0% Years after Onset of CR *Tandem transplant followed by interferon maintenance therapy

85 Single vs Double Autologous Transplantation CR (%) EFS (median, mos) OS (median, mos) Fermand et al Single 37 No difference No difference Double 42 Attal et al Single Double MAG 95 Single 37 No difference No difference* Double 42 Bologna 96 Single No difference* Double Hovon Single Double * Overall survival was improved for pts not achieving CR or near CR with first Auto Fermand JP et al. Blood 2001; 98: 815a Attal M, et al. NEJM 2003; 349: 2495 Fermand JP Mult Myeloma 2004, Torino Italy Cavo M. Mult Myeloma 2004, Torino Italy Sonneveld. Mult Myeloma 2004, Torino Italy Sonneveld P et al. ASH 2004, abst 948

86 Single Versus Tandem Auto SCT: IFM 94 trial 399 pts Single SCT (M 140 mg/m 2 ; 8Gy) vs Tandem SCT (M 140 mg/m 2; ) then (M 140 mg/m 2 ; 8Gy) CR/VGPR 42% 50% p= yr prob EFS 10% 20% p= yr prob OS* 21% 42% p=0.001 *Survival benefit with tandem SCT restricted to patients failing to achieve CR or VGPR with first SCT

87 Attal N Engl J Med 2003; 349:2495 IFM 94 trial

88 Maintenance Therapy

89 Regimens for Maintenance Therapy Interferon alfa (IFN-α) Prednisolone Thalidomide

90 Outcomes with Maintenance Trend for higher OS p of 0.3 (NS) Higher PFS p of Dex did raise the risk of infections, hyperglycemia, and neuropsychiatric complications OS (yrs) Obs Dex PFS (yrs)

Multiple Myeloma F1 蘇 勇 誠 /MA 林 棟 樑

Multiple Myeloma F1 蘇勇誠 /MA 林棟樑