Overview of Multiple Myeloma

Overview of Multiple Myeloma

The Basics of Multiple Myeloma
This program is supported by educational grants from Celgene Corporation, Millennium: , and Onyx Pharmaceuticals.

What Is Multiple Myeloma?
Cancer of the plasma cells in bone marrow Growth of myeloma cells: Disrupts normal bone marrow function Reduces normal immune function Results in abnormal production and release of monoclonal protein into blood and/or urine Destroys and invades surrounding bone Barlogie B, et al. In: Williams Hematology; Durie BG. IMF 2007. 3

Multiple Myeloma Epidemiology
New Cases, n (US, 2014) Deaths, n Mean Age at Diagnosis, Yrs 5-Yr Relative Survival Rates , % 24,050 11,090 62 44.9 Death rates Decreased during 11.3% decrease for women, % decrease for men Risk factors Unknown in the majority of cases Increased with age, male sex, obesity, and black race Variable response to treatment and variation in survival From a few mos to > 10 yrs High-risk attributes are thought to play a primary role 20% of patients survive > 10 yrs, regardless of therapy Novel agents may neutralize the effects of some high-risk features Badros AZ. J Natl Compr Canc Netw. 2010;8:S28-S34. Kurtin S. Oncology Nurse Ed. 2011;25. Siegel R, et al. CA Cancer J Clin. 2014;64:9-29. SEER Stat Fact Sheets: Myeloma.

Myeloma Can Result in a Broad Spectrum of Clinical Manifestations
Renal compromise (30%) M-protein Neuropathy (33%) Hyperviscosity Amyloidosis Immune deficiency Infection (15%) Multiple myeloma cells Marrow infiltration Hypercalcemia (15% to 20%) Destruction of bone Bone pain Lytic lesions (70%) Hoffman R. Hematology: basic principles and practice, 5th edition; Ropper AH, et al. N Engl J Med. 1998;338: Anemia (10% to 35%) 5 5 5

Classification of Myeloma
Heavy chain: IgG, IgA, IgD, IgM, IgE 77% of myeloma cases IgG and IgA most common Nonsecretory: No detectable immunoglobulin 1% to 2% of myeloma cases Light chain (Bence-Jones protein): Kappa (κ) or lambda (λ) 20% of myeloma cases Variable region Light chain Heavy chain Constant region Kumar SK, et al. Mayo Clinic Proc. 2009;84: Schmidt-Hieber M, et al. Haematologica. 2013;98: Serum free light chain

Disease Trajectory Plasma cell leukemia Stroma angiogenesis
Aggressive and Stromal Independent Nonmalignant Accumulation Malignant Transformation Plasma cell leukemia Stroma angiogenesis and IL-6 dependent MGUS Smoldering Myeloma Multiple Myeloma < 3 g M-protein < 10% clonal BMPC No MM-related end-organ damage 1%/yr risk of progression to MM ≥ 30 g/L M-protein ≥ 10% clonal BMPC No MM-related end-organ damage 10%/yr risk of progression to MM in the first 5 yrs ≥ 10% clonal BMPC M-protein in serum and/or urine ≥ 1 CRAB features of disease related to organ damage C: Calcium elevation > 11.5 mg/L or ULN R: Renal dysfunction (serum creatinine > 2 mg/dL) A: Anemia (Hb < 10 g/dL or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis) BMPC, bone marrow plasma cells; Hb, hemoglobin; MGUS, monoclonal gammopathy of unknown significance; MM, multiple myeloma; IL-6, interleukin-6; ULN, upper limit of normal Kuehl WM, et al. Nat Rev Cancer. 2002;2: Vacca A, et al. Leukemia. 2006;20: Agarwal A, et al. Clin Cancer Res. 2013;19: Durie BG, et al. Hematol J. 2003;4: Kurtin SE. JAdPrO, 2010;1:19-29.

Role of Bone Marrow Microenvironment in Myeloma
Myeloma cells IL-6 TNF IL-1 Bone marrow stromal cells ICAM-1 Bone marrow vessels VEGF bFGF IL-2 IFN  PBMC CD8+ T cells NK cells Hideshima T, et al. Blood. 2000;96: Davies FE, et al. Blood. 2001;98: Gupta D, et al. Leukemia. 2001;15: Mitsiades N, et al. Blood. 2002;99: Lentzsch S, et al. Cancer Res. 2002;62:

Diagnostic Evaluation
Establish diagnosis of MM MGUS Smoldering Active Determine subtype Heavy chain/light chain Nonsecretory Solitary plasmacytoma Determine stage International Staging System Durie-Salmon staging system Estimate prognosis Cytogenetics Albumin β2-microglobulin Ploidy Identify need for immediate intervention Severe hypercalcemia Acute renal failure Cord compression Severe pain or impending fracture History and physical CBC, differential and platelet count Additional laboratory tests Serum immunoglobulins Quantitative (IgG, IgM, IgA, IgD) SPEP Serum free light chain assay (kappa, lambda) BUN, creatinine, electrolytes Serum calcium (corrected) Serum albumin β2-microglobulin LDH Additional testing based on preliminary analysis 24-hr urine Bone marrow biopsy and aspiration Hematopathology Presence of plasma cells, % Cellularity Ploidy Cytogenetics FISH Gene expression profiling Radiology Skeletal survey MRI if vertebral compression fractures suspected PET/CT BUN, blood urine nitrogen; CBC, cell blood count; CT, computed tomography; FISH, fluorescence in situ hybridization; LDH, lactate dehydrogenase; MGUS, monoclonal gammopathy of undetermined significance; MRI, magnetic resonance imaging; PET, positron emission tomography; SPEP, serum protein electrophoresis. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v Kurtin S. JAdPrO. 2010;1:19-29.

Monoclonal Protein—M Spike
Normal SPEP Abnormal SPEP Amount/type of M-protein varies among patients (IgG, IgA 80% of cases) Abnormal M-protein (immunoglobulin) loses immune function and adheres and binds to tissues Barlogie B, et al. In: Williams Hematology; p Durie. IMF MMRF. Intro to Myeloma 10

International Staging System
Stage Criteria Median OS, Mos I Serum β2m < 3.5 mg/L Serum albumin ≥ 3.5 g/dL 62 II Serum albumin < 3.5 g/dL OR Serum β2m 3.5 through < 5.5 mg/L 44 III Serum β2m ≥ 5.5 mg/L 29 Serum β2m reflects tumor load and is elevated in renal failure β2m, β2-microglobulin; OS, overall survival. Greipp PR, et al. J Clin Oncol. 2005;23: Dimopoulos M, et al. Leukemia. 2009;23:

Cytogenetic Testing Methodologies
Methodology Advantages Disadvantages Karyotype analysis Highly sensitive for the detection of chromosomal abnormalities in dividing cells Low yield of karyotype abnormalities from MM bone marrow samples Does not detect some aberrations Cannot describe possible heterogeneity within a population of clonal cells FISH Can be performed in non dividing cells Can detect translocations Validation with positive and negative controls is standard Variable scoring criteria Some aberrations technically difficult to detect GEP May be helpful with prognosis May lead to development of more targeted therapies Not performed locally Expensive Unclear what should be done with the information FISH, fluorescence in situ hybridization; GEP, gene expression profiling; MM, multiple myeloma.

Cytogenetic Classification
mSMART 2.0: classification of active myeloma High Risk 20% Intermediate Risk 20% Standard Risk 60% FISH Del(17p) t(14;16) t(14;20) GEP High-risk signature FISH t(4;14) 1q gain Complex karyotype Metaphase deletion 13 or hypodiploidy High PCLI All others including: Trisomies t(11;14) t(6;14) FISH, fluorescence in situ hybridization; GEP, gene expression profiling; OS, overall survival; PCLI, plasma cell labeling index. OS 3 Yrs OS 4-5 Yrs OS 8-10 Yrs Dispenzieri A, et al. Mayo Clin Proc. 2007;82: Kumar SK, et al. Mayo Clin Proc. 2009;84: Mikhael JR, et al. Mayo Clin Proc. 2013;88:

Normal Karyotypes Female Male
Strupp C, et al. Leukemia. 2003;17:

Hyperdiploidy Belurkar S, et al. Ind J Med Sci. 2013;67:

Fluorescence in Situ Hybridization Analysis
Chromosome stained green Chromosome stained red Stralen E, et al. Leukemia. 2009;23:

Gene Expression Profiling in Myeloma
Heat map showing normalized expression levels of the high-risk enriched signature for extreme-risk MM Decaux O, et al. J Clin Oncol. 2008;26:

Natural History of Myeloma
Asymptomatic Symptomatic 100 2. RELAPSE ACTIVE MYELOMA REFRACTORY RELAPSE M-Protein (g/L) 1. RELAPSE 50 MGUS or smoldering myeloma Plateau remission 20 MGUS, monoclonal gammopathy of undetermined significance. First-line therapy Second-line therapy Third-line therapy Kuehl WM, et al. Nat Rev Cancer. 2002;2: Vacca A, et al. Leukemia. 2006;20: Siegel DS, et al. Community Oncol. 2009;6:12: Durie BG, et al. Hematol J. 2003;4: ; adapted with permission from Durie B. 18

Survival in Myeloma Is Improving With Novel Agents
5-Yr Survival by Age 1.0 Median 7.3 yrs ≤ 65 Yrs > 65 Yrs 73% 56% 63% 31% 0.9 0.8 0.7 0.6 Proportion Surviving 0.5 The use of novel agent inductions with melphalan and ASCT have doubled median survival for nearly all patients 0.4 0.3 ASCT, autologous stem cell transplantation. 0.2 0.1 1 2 3 4 5 6 7 8 9 10 Follow-up From Diagnosis (Yrs) Kumar SK, et al. ASH Abstract 3972. 19

Treatment of Multiple Myeloma
Confirmed Diagnosis of Multiple Myeloma: CRAB Criteria Determination of transplant eligibility Immediate interventions for serious adverse events Individualized Treatment Selection for Induction Therapy Transplant Eligible Works rapidly (CR, nCR, VGPR) Well tolerated Spares stem cells Level of evidence: 1 or 2A Transplant Ineligible Achieving a CR or nCR Level of evidence: 1 or 2A Tolerability and QoL PS and comorbidities CRAB, calcium elevation, renal insufficiency, anemia, bone disease; CR, complete response; nCR, near complete response; PS, performance score; QoL, quality of life; VGPR, very good partial response. Continued Treatment Salvage therapy Maintenance therapy NCCN. Clinical practice guidelines in oncology: multiple myeloma. v

Clinical Considerations in Deciding Induction Therapy
High tumor burden Pulse dexamethasone Combination therapies with alkylators and IMiDS and bortezomib Renal failure Combination therapies with alkylators and thalidomide and bortezomib (role of lenalidomide uncertain) Hypercalcemia Bisphosphonates Frail Avoid high-dose dexamethasone Clotting or bleeding history Assess risk of use of lenalidomide/ thalidomide and anticoagulation Preexisting neuropathy Assess use of bortezomib/ thalidomide Cytogenetic abnormalities Indication for bortezomib/ lenalidomide IMiD, immunomodulatory drug. Niesvizky R, et al. Oncology (Williston Park). 2010;24: NCCN. Clinical practice guidelines in oncology: multiple myeloma. v Stadtmauer EA. Oncology (Williston Park). 2010;24:7-13.

NCCN Recommendations for Adjunctive Treatment
Bone disease Bisphosphonates (category 1) Radiation therapy Orthopedic consultation Vertebroplasty or kyphoplasty Hypercalcemia Hydration, steroids, furosemide Zoledronic acid preferred Hyperviscosity Plasmapheresis Anemia Consider erythropoietin Infection IVIG for recurrent infections Pneumovax and influenza vaccine PCP, herpes and antifungal prophylaxis for high-dose or long-term steroids Herpes zoster prophylaxis with bortezomib Renal dysfunction Avoid aggravating factors: contrast, NSAIDs, dehydration Not a contraindication to HCT Monitor bisphosphonates closely Coagulation/thrombosis Prophylactic anticoagulation with IMiDs HCT, hematopoietic cell transplantation; IMiD, immunomodulatory drug; IVIG, intravenous immunoglobulin; NSAID, nonsteroidal antiinflammatory drug; PCP, Pneumocystis pneumonia. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v Miceli T, et al. Clin J Oncol Nurs. 2011;15(suppl): Faiman B, et al. Clin J Oncol Nurs. 2011;15(suppl):66-76.

Epidemiology of Multiple Myeloma
23,500 new cases and 10,710 deaths from myeloma were expected in the United States in 2012 More common in men than in women Higher incidence in blacks vs whites (2:1) Median age at diagnosis: 70 yrs Cancer facts and figures American Cancer Society; Altekruse SF, et al, eds. SEER cancer statistics review, National Cancer Institute. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v

Multistep Pathogenesis of Multiple Myeloma
Early chromosomal abnormalities (immunoglobulin heavy chain translocations or trisomies) are shared by plasma cells in multiple myeloma and in monoclonal gammopathy of undetermined clinical significance (MGUS). Secondary translocations involving MYC (8q24), MAFB (20q12), and IRF4 (6p25) are common in multiple myeloma but quite rare in MGUS. Mutations of RAS or FGFR3, MYC dysregulation, deletion in p18, or loss of expression or mutation in TP53 are found only in multiple myeloma and play a key role in determining tumor progression and drug resistance. Also, changes in gene expression, in particular the up-regulation of transcription factors, have been reported in plasma cells from patients with MGUS but not in those from patients with multiple myeloma. Besides molecular alterations of plasma cells, abnormal interactions between plasma cells and bone marrow, as well as aberrant angiogenesis, are hallmarks (特徵) of disease progression

Natural History of Noncurable Malignancies
Asymptomatic Symptomatic 100 2. RELAPSE ACTIVE MYELOMA REFRACTORY RELAPSE M-Protein (g/L) 1. RELAPSE 50 MGUS or smoldering myeloma Plateau remission 20 M, monoclonal; MGUS, monoclonal gammopathy of undetermined significance. First-line therapy Second-line therapy Third-line therapy 25

Clinical Manifestations of Symptomatic Multiple Myeloma
Renal compromise (30%) M-protein Neuropathy (33%) Immune deficiency Infection (15%) Hypercalcemia (15% to 20%) Destruction of bone Bone pain (75% to 80%) Marrow infiltration Lytic lesions (70%) Adapted from: Hoffman R. Hematology: Basic Principles and Practice, 5th edition; Ropper AH. N Engl J Med. 1998;338: Rajkumar SV. Curr Probl Cancer. 2009;33:7-64. IMF update 2003 ( Anemia (70%)

Challenges in Treatment
“High-risk” disease, expected OS: 2-3 yrs t(4;14), t(14;16), del(17p), 1q21 amplification by FISH del(13q) by cytogenetics, hypodiploid cytogenetics High β2-M (≥ 5.5 mg/L) IgA, high plasma cell labeling index Clinical treatment challenges Renal failure Older population, median age at diagnosis: 70 yrs Significant comorbidities: heart, lung disease Extramedullary disease Managing light-chain disease β2-M, beta-2 microglobulin; FISH, fluorescence in situ hybridization; IgA, immunoglobulin A; OS, overall survival.

Patient Assessment

Diagnostic Criteria for Myeloma
Patient Criteria MGUS[1,2] Smoldering Myeloma[1] Symptomatic Myeloma[1] M-protein < 3 g/dL spike ≥ 3 g/dL spike and/or In serum and/or urine[2] Monoclonal plasma cells in bone marrow, % < 10 ≥ 10 ≥ 10[2] End-organ damage None ≥ 1 CRAB* feature[3] Hb, hemoglobin; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; ULN, upper level of normal. *C: Calcium elevation (> 10.5 mg/L or ULN) R: Renal dysfunction (serum creatinine > 2 mg/dL) A: Anemia (Hb < 10 g/dL or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis) 1. IMWG. Br J Haematol. 2003;121: Kyle RA, et al. N Engl J Med. 2002;346: Durie BG, et al. Hematol J. 2003;4:

Progression to Symptomatic Myeloma
MGUS: up to 3% of persons 50 yrs of age or older and ~ 6% of those older than 70 yrs For asymptomatic myeloma, maximum risk in the first 5 yrs 100 Smoldering Multiple Myeloma 80 78 73 60 66 Probability of Progression (%) 51 ß2-M, beta-2 microglobulin; ISS, International Staging System; MGUS, monoclonal gammopathy of undetermined significance. 40 MGUS 20 21 4 16 10 5 10 15 20 25 Yrs Since Diagnosis Kyle RA, et al. N Engl J Med. 2007;356: Greipp PR, et al. J Clin Oncol. 2005;23:

Initial Diagnostic Evaluation
History and physical Blood workup CBC with differential and platelet counts BUN, creatinine Electrolytes, calcium, albumin, LDH Serum quantitative immunoglobulins Serum protein electrophoresis and immunofixation β2-M Serum free light chain assay Urine 24-hr protein Protein electrophoresis (quantitative Bence-Jones protein) Immunofixation electrophoresis Other Skeletal survey Unilateral bone marrow aspirate and biopsy evaluation with immunohistochemistry or flow cytometry, cytogenetics, and FISH MRI and PET/CT as clinically indicated ß2-M, beta-2 microglobulin; BUN, blood urea nitrogen; CBC, complete blood count; FISH, fluorescent in-situ hybridization; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PET/CT, positron-emission tomography / computed tomography. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v

Symptomatic Myeloma Staging
Risk factors: higher M spike, higher plasma cell burden, type of M-protein, abnormal free light-chain ratio, circulating plasma cells Stage ISS Criteria for Symptomatic Myeloma Stage I ß2-M < 3.5 mg/L and serum albumin ≥ 3.5 g/dL Stage II Not stage I or III Stage III ß2-M ≥ 5.5 mg/L ß2-M, beta-2 microglobulin; ISS, International Staging System; MGUS, monoclonal gammopathy of undetermined significance. Kyle RA, et al. N Engl J Med. 2007;356: Greipp PR, et al. J Clin Oncol. 2005;23:

Multiple Myeloma: Risk Categories
Risk Factors Standard Risk (Expected OS: 6-7 Yrs) High Risk (Expected OS: 2-3 Yrs) FISH t(11;14) t(6;14) Del(17p) Del(1p) Gain(1q) t(4;14)* t(14;16) Cytogenetics Hyperdiploidy Hypodiploidy β2-microglobulin* Low (< 3.5 mg/L) High (≥ 5.5 mg/L) Isotype -- IgA Gene expression profile Good risk High risk FISH, fluorescence in situ hybridization; Hb, hemoglobin; OS, overall survival; PCLI, plasma cell labeling index. *Patients with t(4;14), β2-microglobulin < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease. Kumar SK, et al. Mayo Clin Proc. 2009;84: Fonseca R, et al. Leukemia. 2009;23: Kyle RA, et al. Clin Lymphoma Myeloma. 2009;9: Munshi N, et al. Blood. 2011;117:

Effect of t(4;14), FISH Status, ISS Staging and Age on OS in Multiple Myeloma
100 80 Patients remaining alive, % 60 Patients Remaining Alive (%) A vs B: P < C vs D: P < .03 E vs F: P < .05 A vs B: P < C vs D: P < .03 E vs F: P < .05 40 20 5 10 15 Yrs From Start of Treatment FISH, fluorescent in-situ hybridization; ISS, International Staging System; MM, multiple myeloma; OS, overall survival. Events, n/N Estimated 4-Yr OS, % (Range) a. ISS I/II & -FISH & aged < 65 yrs 270/935 75 (72-78) b. ISS I/II & -FISH & aged ≥ 65 yrs 159/409 62 (56-67) c. ISS/II/III & -FISH or ISS I & + FISH & aged < 65 yrs 278/526 48 (44-53) d. ISS II/III & -FISH or ISS I +FISH & aged ≥ 65 yrs 136/230 38 (31-45) e. ISS II/III & +FISH & aged < 65 yrs 241/378 37 (32-43) f. ISS II/III & +FISH & aged ≥ 65 yrs 113/160 24 (16-32) Avet-Loiseau H, et al. Leukemia. 2013;27:

Initial Approach to Treatment of Myeloma
Transplantation candidate Nontransplantation candidate (based on age, performance score, and comorbidities) Induction treatment (nonalkylator-based induction x 4-6 cycles) Induction treatment Maintenance Stem cell harvest MM, multiple myeloma. Stem cell transplantation Consolidation therapy ? Maintenance

Case: 43-Yr-Old Male Presents With Acute Severe Lower Back Pain From Lifting Groceries
Patient assessment: X-ray of lumbar spine: L4 compression fracture, lytic disease in L2 and L5 Blood work: Hb 9.5 mg/L, plt 178/mm3, creatinine mg/dL, albumin 3.5 mg/dL, β2-M 3.1 mg/L, Ca mg/dL, LDH 190 U/L SPEP M-protein 4.5 g/dL, IgG lambda, IgG 5200 mg/dL, IgA 35 g/L, IgM 25 g/L, UPEP + lambda light chains Bone marrow: 40% plasma cells, cytogenetics normal; FISH: no t(4;14), t(14;16), or del(17p) Skeletal survey: multiple lytic lesions β2-M, beta-2 microglobulin; Ca, calcium; FISH, fluorescent in situ hybridization; Hgb, hemoglobin; LDH, lactate dehydrogenase; M-protein, monoclonal protein; Plt, platelets; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.

Overview of Induction Regimens

Induction Therapies: Transplantation Eligible
Curatio PowerPoint Template 二○一七年四月二十一日 Induction Therapies: Transplantation Eligible NCCN Category 1 Bortezomib/dexamethasone (VD) Bortezomib/thalidomide/dexamethasone (VTD) Bortezomib/doxorubicin/dexamethasone (PAD) Lenalidomide/dexamethasone (RD) NCCN Category 2A Bortezomib/cyclophosphamide/dex (CyBorD) Bortezomib/lenalidomide/dexamethasone (VRD) NCCN Category 2B Thalidomide/dexamethasone (TD) Dexamethasone Liposomal doxorubicin/vincristine/dexamethasone (DVD) New (3/8/2013): Carfilzomib in combination with lenalidomide and dexamethasone NCCN, National Comprehensive Cancer Network. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v 39

CR rate improved by 23% (TV), 11% (T), 19% (a2-IFN)
Phase III Trials: Novel Agent Induction for Transplantation-Eligible Patients Trial Regimens n ≥ VGPR, % After Induction After First ASCT After Maintenance Cavo[1] VTD x 3 TD 241 239 62 28 79 58 IFM [2] VD x 4 VAD 223 218 37.7 15.1 54.3 37.2 HOVON-65/GMMG-HD4[3] PAD x 3 371 373 42 14 36 PETHEMA/GEM[4] TV T a2-IFN 74 CR rate improved by 23% (TV), 11% (T), 19% (a2-IFN) PETHEMA/GEM[5] VTD VMBCP/VBAD/B 130 127 129 60 29 E4A03[6] RD Rd 445 422 50 40 ASCT, autologous stem cell transplantation; GMMG, German Multiple Myeloma Group; HOVON, Dutch-Belgian Cooperative Trial Group for Hematology-Oncology; IFM, Intergroupe Francophone du Myelome; IFN, interferon; nCR, near-complete response; PAD, bortezomib, doxorubicin , and dexamethasone; TD, thalidomide and dexamethasone; VAD, vincristine, doxorubicin , and dexamethasone; VD, bortezomib, dexamethasone; VMBCP/VBAD/B, vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib; VTD, TD plus bortezomib. 1. Cavo M, et al. Lancet. 2011;376: Harousseau JL, et al. J Clin Oncol. 2010;28: Sonneveld P, et al. J Clin Oncol. 2012;30: Rosiñol L, et al. ASH Abstract Rosiñol L, et al. Blood. 2012;120: Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

Lenalidomide/Dexamethasone Induction Followed by SCT: OS
E4A03 trial RD vs Rd Landmark analysis: 4 mos Early SCT after 4 cycles vs continued therapy with lenalidomide 94% OS at 3 yrs for those undergoing SCT vs 78% for those continuing protocol therapy 94% 78% 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 Log-rank test: Chi sq = (P = .008) 0.3 0.2 Early SCT: no (n = 141) Early SCT: yes (n = 68) OS, overall survival; Rd, lenalidomide, low-dose dexamethasone; RD, lenalidomide, standard-dose dexamethasone; SCT, stem cell transplant. 0.1 12 24 36 48 Early SCT: no 141 Early SCT: yes 68 132 68 122 64 53 34 0 0 Mo Siegel D, et al. ASH Abstract 38. Reprinted with permission.

VTD vs TD for SCT Induction in Newly Diagnosed Myeloma
Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy VTD vs TD for SCT Induction in Newly Diagnosed Myeloma Progression-free survival[1] Median follow-up: 36 mos Estimated 3-yr OS: 86% for VTD vs 84% for TD (P = .30)[2] PFS[1] 100 VTD 75 TD 60% PFS (%) 50 48% Events TD VTD N 71 51 % 44 32 P = .042 25 CI, confidence interval; HR, hazard ratio; OS, overall survival; SCT, stem cell transplantation; TD, thalidomide, dexamethasone; VTD, bortezomib, thalidomide, dexamethasone. HR: 0.69 (95% CI: ; P = .043) 6 12 18 24 30 35 Mos From Start of Consolidation Therapy Patients at Risk, n TD VTD 84 86 43 53 21 26 1. Cavo M, et al. Blood. 2012;120: Cavo M, et al. Lancet. 2010;376: 42 42

How would you treat this patient now?
Case Your 43-yr-old patient receives bortezomib/lenalidomide/ dexamethasone (VRD) for 3 cycles Re-evaluation M-protein not detectable in blood or urine, IFE positive Serum free light chain: kappa 0.8 mg/dL, lambda mg/dL Bone marrow: 2% PC, 0.8% clonal PC by flow cytometry Skeletal survey unchanged CBC, creatinine, calcium within normal limits How would you treat this patient now? CBC, complete blood count; IFE, immunofixation electrophoresis; M protein, monoclonal protein; PC, plasma cells

CR to Novel Agents Correlates With Long-term PFS and OS in Elderly Patients
Retrospective analysis of frontline treatment in 3 randomized European trials (GISMM-2001, GIMEMA MM0305, and HOVON groups; N = 1175) Regimens: MP (n = 332), MPT (n = 332), VMP (n = 257), VMPT-VT (n = 254) PFS OS 1.0 1.0 0.8 0.8 0.6 0.6 Probability of PFS Probability of OS 0.4 CR, complete response; MP, melphalan, prednisone; MPT, melphalan, prednisone, thalidomide; OS, overall survival; PFS, progression-free survival; PR, partial response; VGPR, very good partial response; VMP, bortezomib, melphalan, prednisone; VMPT-VT, bortezomib, melphalan, prednisone, thalidomide with bortezomib and thalidomide maintenance. 0.4 0.2 0.2 P < .001 P < .001 24 48 72 24 48 72 Mos CR VGPR PR Mos Gay F, et al. Blood. 2011;117:

Phase III Trials: Novel Agent Induction for Transplantation-Ineligible Patients
Regimens n Median Follow-up, Mos Median OS Median PFS, Mos IFM 99-06[1] MP MPT MEL100 51.5 33.2 mos mos mos IFM 01/01[2] MPT MP 47.5 44.0 mos mos Rajkumar SV et al[3] RD Rd 1-yr interim 96%* 87%* MM-015[4] MPR-R MPR MP 30 45.2 mos NR NR VISTA[5] VMP MP 60 56.4 mos 43.1 mos NA NA FU, follow up; IFM, Intergroupe Francophone du Myelome; MEL 100, melphalan 100 mg/m2; MM, multiple myeloma; MP, melphalan and prednisone; MPR, melphalan, prednisone, and lenalidomide; MPR-R, melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance; MPT, melphalan, prednisone, and thalidomide; NA, not available; NR, not reached; OS, overall survival; PFS, progression-free survival; RD, lenalidomide and high-dose dexamethasone; Rd, lenalidomide low-dose dexamethasone; VISTA, Velcade as Initial Standard Therapy in Multiple Myeloma; VMP, bortezomib, melphalan, and prednisone. *Median OS not yet reached; % alive at time of follow-up is reported. 1. Facon T, et al. Lancet. 2007;370: Hulin C, et al. J Clin Oncol. 2009;27: Rajkumar SV, et al. Lancet Oncol. 2010;11: Palumbo A, et al. N Engl J Med. 2012;366: San Miguel JF, et al. J Clin Oncol. 2013;31:

MM-015: MPR Induction Plus Lenalidomide in Newly Diagnosed Elderly MM Patients
Updated analysis of randomized, multicenter, placebo-controlled phase III trial Stratified by age and disease stage Cycles 1-9 (28-day cycles) Cycles 10+ MPR-R Melphalan 0.18 mg/kg on Days Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg/day on Days 1-21 Continued lenalidomide Newly diagnosed transplantation-ineligible MM patients 65 yrs of age or older (N = 459) MPR Melphalan 0.18 mg/kg on Days Prednisone 2 mg/kg on Days 1-4 + Lenalidomide 10 mg/day on Days 1-21 Discontinued lenalidomide, placebo added Lenalidomide 25 mg/day ± Dexamethasone Disease progression MM, multiple myeloma; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance; PFS, progression-free survival. MP Melphalan 0.18 mg/kg on Days 1-4 + Prednisone 2 mg/kg on Days 1-4 + Placebo on Days 1-21 Continued placebo Primary endpoint: PFS Double-blind treatment phase Open-label extension/ follow-up phase Palumbo A, et al. N Engl J Med. 2012;366:

MM-015: Progression-Free Survival
All Patients 66% Reduced Risk of Progression 65-75 Yrs of Age 70% Reduced Risk of Progression Median PFS, Mos MPR-R 31 MPR 14 MP 13 Median PFS, Mos MPR-R 31 MPR 15 MP 12 100 100 75 75 HR: (P < .001) MPR-R vs MPR: HR: 0.49 (P < .001) HR: (P = .006) 50 50 Patients (%) Patients (%) HR, hazard ratio; MM, multiple myeloma; MP, melphalan and prednisone; MPR, melphalan, prednisone, and lenalidomide; MPR-R, melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance; PFS, progression-free survival. MPR-R vs MP: HR: 0.40 (P < .001) 25 25 5 10 15 20 25 30 35 40 10 20 30 40 Mos Mos Data cutoff : May 11, 2010 Palumbo A, et al. ASH Abstract 475. Reprinted with permission. Palumbo A, et al. N Engl J Med. 2012;366:

MM-015: Overall Survival All Patients 65-75 Yrs of Age MPR-R MPR-R 100
50 Patients (%) Patients (%) 50 MM, multiple myeloma; MP, melphalan and prednisone; MPR, melphalan, prednisone, and lenalidomide; MPR-R, melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance. 25 25 10 20 30 40 50 10 20 30 40 50 Mos Mos Data cutoff : February 28, 2011 Palumbo A, et al. ASH Abstract 475. Reprinted with permission. Palumbo A, et al. N Engl J Med. 2012;366:

VISTA: VMP vs MP in Patients With Multiple Myeloma > 65 Yrs of Age
100 90 80 70 60 50 40 30 20 10 Median OS benefit: 13.3 mos 5-yr OS rates: 46.0% vs 34.4% Patients Alive (%) Group n Events Median HR (95% CI) P Value MP VMP ( ) .0004 CI, confidence interval; HR, hazard ratio; MP, melphalan and prednisone; OS, overall survival; VMP, bortezomib, melphalan, and prednisone. Mos Pts at Risk, n Delforge M, et al. Eur J Haematol. 2012;89:16-27.

VMPT + VT Maintenance vs VMP as Frontline Therapy
PFS 1.00 VMPT VMP P 5 yr PFS % 13% < yr TTNT 41% % < yr OS % % 0.75 Median 35.3 months Patients (%) 0.50 CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; VMP, bortezomib, melphalan, and prednisone; VMPT, bortezomib, melphalan, prednisone, thalidomide. 0.25 Median 24.8 months HR 0.58 (95% CI, , P < ) 0.00 10 20 30 40 50 60 70 Palumbo A, et al. ASH Abstract 200. Reprinted with permission.

Novel Agents for Frontline Treatment of Myeloma
Study Treatment n Outcomes Safety Richardson et al[1] RVD 66 ≥ VGPR: 67%; 18-mo PFS: 75%; 24-mo OS: 97% Sensory neuropathy: 80% (mostly grade 1); fatigue: 64% (mostly grade 1) Jakubowiak et al[2] Carfilzomib/Rd 53 ≥ nCR: 62% ORR: 98% Only grade 1/2 PN Berdeja et al[3] Ixazomib/ Rd 15 No DLT up to 2.23 mg/m2 ixazomib; MTD: 2.97 mg/m2/wk Only grade 1 PN in 3 pts; 6 pts required dose reductions due to AEs Lonial et al[4] Elotuzumab/Rd 73 ORR: 82% ≥ VGPR: 48% Grade 3/4 cytopenias: 16%, grade 1/2 diarrhea: 56% Kaufman et al[5] Vorinostat/ RVD 11 1 pt completed 8 cycles, 1 completed 4 cycles and transplantation DLTs (1 each): syncope, grade 3 ALT elevation; PN: 6 pts AEs, adverse events; ALT, alanine aminotransferase; CRd, carfilzomib, lenalidomide, low-dose dexamethason; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; nCR, near-complete response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PN, peripheral neuropathy; Rd, lenalidomide, low-dose dexamethasone; RVD, lenalidomide, bortezomib, dexamethasone; VGPR, very good partial response. 1. Richardson PG, et al. Blood. 2010;116: Jakubowiak, et al. Blood. 2012;120: Berdeja JG, et al. ASH Abstract Lonial S, et al. ASH Abstract Kaufman JL, et al. ASH Abstract 3034.

Maintenance Therapy

Case: 43-Yr-Old Male With Stage I Myeloma
He received VRD induction x 3 cycles and achieved CR. He then received melphalan 200 mg/m2 and ASCT, and by Day 60, he was fully recovered Patient assessment SPEP, UPEP no monoclonal protein IFE negative, normal serum free light chains ratio Bone marrow normal, no clonal plasma cells by flow cytometry Findings consistent with stringent CR How would you treat this patient now?

Phase III Maintenance Studies
Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Phase III Maintenance Studies Trial Planned Accrual, N Regimen Outcomes Nordic MSG 15[1] 400 Bortezomib x 21 wks vs no maintenance CR/nCR: 54% vs 35% IFM [2] 614 Lenalidomide vs placebo as maintenance following first or second ASCT 4-yr PFS: 60% vs 33% CALGB [3] 460 Lenalidomide vs placebo as maintenance therapy after ASCT Median TTP: 46 vs 27 mos UPFRONT[4] 423 Bortezomib/dexamethasone vs bortezomib/thalidomide/dexamethasone vs bortezomib/melphalan/prednisone CR/nCR: 30% vs 40% vs 33% ASCT, autologous stem cell transplantation; CALGB, Cancer and Leukemia Group B; CR/nCR, complete and near-complete responses; IFM, Intergroupe Francophone du Myelome; MSG, Myeloma Study Group; NCIC , National Cancer Institute of Canada; OS, overall survival; PAD, bortezomib, doxorubicin, and dexamethasone; PFS, progression-free survival; TTP, time to progression; VAD, vincristine, doxorubicin, and dexamethasone. 1. Mellqvist UH, et al. ASH Abstract Attal M, et al. N Engl J Med. 2012;366: McCarthy PL, et al. N Engl J Med. 2012;366: Niesvizky R, et al. ASH Abstract 478. 54

IFM 2005-02: Lenalidomide vs Placebo Maintenance After ASCT for Myeloma
Patients younger than 65 yrs of age with nonprogressive disease, ≤ 6 mos after first-line ASCT (N = 614) Consolidation: Lenalidomide 25 mg/day on Days 1-21 of every 28 days for 2 mos Placebo (n = 307) Lenalidomide mg/day (n = 307) ASCT, autologous stem cell transplantation; CR, complete response; IFM, Intergroupe Francophone du Myelome; OS, overall survival; PFS, progression-free survival; TTP, time to progression; VGPR, very good partial response. Stratified based on diagnostic β2-M, del(13q), VGPR after ASCT Primary endpoint: PFS Secondary endpoints: CR, TTP, OS, feasibility of long-term lenalidomide Attal M, et al. N Engl J Med. 2012;366: 55

IFM 2005-02: PFS and OS PFS OS 100 100 Placebo 75 Lenalidomide 75
23% 41% PFS (%) 50 OS (%) 50 25 25 Placebo HR: 0.50; P < .001 P = .29 IFM, Intergroupe Francophone du Myelome; OS, overall survival; PFS, progression-free survival. 6 12 18 24 30 36 42 48 6 12 18 24 30 36 42 48 Mos of Follow-up Mos of Follow-up Pts at Risk, n Lenalidomide Placebo Pts at Risk, n Lenalidomide Placebo 103 57 49 22 10 6 1 1 92 87 38 31 5 6 Attal M, et al. N Engl J Med. 2012;366:

IFM 2005-02: Second Malignancies at 3 Yrs
Type of Lesion, n Placebo (n = 302) Lenalidomide (n = 306) Total (N = 608) Hematologic 5 13 18 AML/MDS 4 9 ALL 3 Hodgkin’s lymphoma Non-Hodgkin’s lymphoma 1 2 Nonhematologic 10 14 Esophageal/hypopharynx Colon Prostate Breast Renal Melanoma Basal cell carcinoma 8 Total 6 25 31 ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; DCEP, dexamethasone, cyclophosphamide, etoposide, cisplatin; MDS, myelodysplastic syndromes. Risk factors for second malignancies (P = .01): treatment (placebo vs lenalidomide), age (≤ 55 vs > 55 yrs), sex (male vs female), ISS stage (I + II vs III), induction with DCEP (yes vs no; P = .02) Attal M, et al. N Engl J Med. 2012;366:

Mos Since Autologous HSCT Mos Since Autologous HSCT
CALGB : Lenalidomide vs Placebo as Maintenance Therapy After ASCT 1.0 1.0 Lenalidomide 2-sided P < .001 0.8 0.8 0.6 0.6 Lenalidomide Placebo Probability of PFS Probability of OS 0.4 0.4 2-sided P = .03 0.2 0.2 Placebo 10 20 30 40 50 60 70 10 20 30 40 50 60 70 ASCT, autologous stem cell transplantation; CI, confidence interval; HR, hazard ratio; HSCT, hematopoietic stem cell transplantation; NR, not reported; OS, overall survival; PFS, progression-free survival. Mos Since Autologous HSCT Mos Since Autologous HSCT Outcome Lenalidomide (n = 231) Placebo (n = 229) P Value HR (95% CI) Median PFS, mos 46 27 .001 NR 3 yr OS, % 88 80 0.62 ( ) McCarthy PL, et al. N Engl J Med. 2012;366:

CALGB 100104: Subgroup Analysis
TTP Subgroup HR (95% CI) P Value for Interaction Lenalidomide induction .06 Yes 1.10 ( ) No 0.57 ( ) Thalidomide induction .36 Yes 0.57 ( ) No 0.86 ( ) Elevated β2-M level .76 Yes 0.67 ( ) No 0.77 ( ) CR at randomization .38 Yes 0.53 ( to 1.1) No 0.86 ( ) -2 -1 1 2 OS Subgroup HR (95% CI) P Value for Interaction Lenalidomide induction .03 Yes 1.40 ( ) No 0.18 (-0.32 to 0.67) Thalidomide induction .05 CI, confidence interval; HR, hazard ratio; OS, overall survival; TTP, time to progression. Yes 0.01 (-0.62 to 0.64) No 0.89 ( ) Elevated β2-M level .56 Yes 0.37 (-0.39 to 1.1) No 0.58 ( ) CR at randomization .64 Yes 0.25 (-0.67 to 1.2) No 0.53 ( ) -2 -1 1 2 Placebo Better Lenalidomide Better McCarthy PL, et al. N Engl J Med. 2012;366:

HOVON-65 Phase III Trial: Bortezomib in Induction and Maintenance
PAD x 3 cycles Bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11 + Doxorubicin 9 mg/m2 on Days Dexamethasone 40 mg on Days 1-4, 9-12, (n = 371) Stem cell collection and transplantation Bortezomib 1.3 mg/m2 every 2 wks Newly diagnosed MM patients with stage II/III disease aged yrs (N = 744) 2 yrs VAD x 3 cycles Vincristine 0.4 mg on Days Doxorubicin 9 mg/m2 on Days Dexamethasone 40 mg on Days 1-4, 9-12, (n = 373) Stem cell collection and transplantation Thalidomide 50 mg/day ASCT, autologous stem cell transplant; GMMG, German Multiple Myeloma Group; MM, multiple myeloma; PAD, bortezomib, doxorubicin, dexamethasone; VAD, vincristine, doxorubicin, dexamethasone. Stem cell collection: cyclophosphamide/doxorubicin/dexamethasone + granulocyte colony-stimulating factor Transplantation: ASCT + melphalan 200 mg/m2. Allogeneic stem cell transplantation with no maintenance offered when possible. German patients enrolled through GMMG underwent 2 ASCTs. Sonneveld P, et al. J Clin Oncol. 2012;30: 60

HOVON-65 Phase III Trial of Bortezomib in Induction and Maintenance: PFS and OS
100 100 VAD PAD VAD PAD 80 75 60 PFS (%) 50 OS (%) n 40 F n D 25 VAD PAD P = .008 20 VAD PAD P = .07 D, deaths; F, treatment failure (progression, relapse, death); OS, overall survival; PAD, bortezomib, doxorubicin, dexamethasone; VAD, vincristine, doxorubicin, dexamethasone. 12 24 36 48 60 12 24 36 48 60 Mos Mos Pts at Risk, n Arm A:VAD Arm B: PAD Pts at Risk, n Arm A:VAD Arm B: PAD 44 51 8 9 86 104 16 18 Sonneveld P, et al. J Clin Oncol. 2012;30: 61 61

Maintenance: Why Not? No survival advantage in IFM or MM-015 trials
Longer follow-up needed in all trials Cost ~ $8000/mo Toxicities Myelosuppression Second primary malignancies Quality of life Unknown response to higher doses of lenalidomide at relapse Potential development of resistant clones

Case: What Would You Do if the Initial Patient Were 78 Yrs of Age Instead of 43?
Patient assessment: X-ray of lumbar spine: L4 compression fracture, lytic disease in L2,5 Blood work: Hb 9.5 mg/L, plt 178k/mm3, creatinine 1.5 mg/dL, albumin 3.5 mg/dL, β2-M 3.1 mg/L, Ca 9.8 mg/dL, LDH 190 U/L SPEP M-protein 4.5 g/dL, IgG lambda, IgG 5200 mg/dL, IgA 35 g/L, IgM 25 g/L, UPEP + lambda light chains Bone marrow: 40% plasma cells, cytogenetics normal; FISH: no t(4;14), t(14;16) or del(17p) Skeletal survey: multiple lytic lesions β2-M , beta-2 microglobulin; Ca, calcium; FISH, fluorescent in situ hybridization; Hgb, hemoglobin; LDH, lactate dehydrogenase; PC, plasma cells; Plt, platelets; SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis. In addition to zoledronic acid, what would you choose for induction therapy?

Case: 78-Yr-Old Male With Stage I Myeloma
He received VD induction x 8 cycles and achieved very good PR How would you treat this patient now? PR, partial response; VD, vincristine/dexamethasone.

Management of Adverse Events

Risk Assessment for VTEs in Patients Receiving Thalidomide or Lenalidomide
VTE prophylaxis for individual risk factors or myeloma- related risk factors (eg, hyperviscosity) If ≤ 1 risk factor present, aspirin mg/day If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3) VTE prophylaxis for myeloma therapy–related risk factors (eg, high-dose dexamethasone, doxorubicin, multiagent chemotherapy) LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3) INR, international normalized ratio; LMWH, low–molecular-weight heparin; VTE, venous thromboembolism. Palumbo A, et al. Leukemia. 2008;22:

Current Treatment of MM Bone Disease
Bisphosphonates Pamidronate Zoledronic acid Denosumab (investigational) Surgical procedures Vertebroplasty Balloon kyphoplasty Radiotherapy Treatment of myeloma MM, multiple myeloma. Roodman GD. Hematology Am Soc Hematol Educ Program. 2008:

Bisphosphonates and Osteonecrosis
Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy Incidence unknown but IMF Web-based survey revealed 5% incidence with zoledronic acid 4% incidence with pamidronate IFM, International Myeloma Foundation. Durie BG, et al. N Engl J Med. 2005;353:

Peripheral Neuropathy

Thalidomide- and Bortezomib-Emergent Peripheral Neuropathy: Symptoms
Peripheral Neural Tract Symptom(s) Thalidomide Bortezomib Sensory Hypo-esthesia paresthesia: numbness, tingling, pin-prick sensation hyperesthesia Common Ataxia, gait disturbance Rare Neuropathic pain Motor Weakness Tremor Autonomic Gastrointestinal Constipation Others Impotence Bradycardia Orthostatic Hypotension 1. Chaudhry V, et al. Neurology 2002;59: Mileshkin L, et al. Leuk Lymphoma. 2006;47: Argyriou AA, et al. Blood 2008;112: Cata JP, et al. J Pain 2007;8:

Proposed Guidelines for Bortezomib Dose Modification for Management of PN
Severity of PN Signs/Symptoms Modification of Dose and Regimen Grade 1 (paresthesia, weakness, and/or loss of reflexes without pain or loss of function) Reduce current bortezomib dose by 1 level (1.3 to 1.0 to 0.7 mg/m2). For patients receiving a twice-weekly schedule, change to a once-per-wk schedule using the same dose. For patients with previous PN, consider starting with 1.3 mg/m2 once per wk Grade 1 with pain or grade 2 (no pain but interfering with basic activities of daily living) For patients receiving twice per wk bortezomib, reduce current dose by 1 level or change to a once-per-wk schedule using the same dose For patients receiving bortezomib on a once-per-wk schedule: reduce current dose by 1 level or consider temporary discontinuation; upon resolution (grade ≤ 1), restart once-per-wk dosing at lower dose level in cases of favorable benefit-to-risk ratio Grade 2 with pain, grade 3 (limiting self-care and activities of daily living), or grade 4 Discontinue bortezomib PN, peripheral neuropathy. Subcutaneous bortezomib substantially decreases PN Richardson PG, et al. Leukemia. 2012;26:

Drugs, Dietary Modifications, and Supplements Used for Neuropathy
Vitamins/supplements Multi-B complex vitamins with B1, B6, B12 Folic acid Vitamin E Magnesium for muscle cramps Potassium (ie, apple cider vinegar, bananas, oranges) for muscle cramps FDA-approved drugs for diabetic neuropathy Duloxetine Pregabalin Amino acid supplements Acetyl-carnitine α-lipoic acid Miscellaneous Topical creams, eg, cocoa butter (rich in vitamin E) Tonic water (quinine) for leg cramps Colson K, et al. Clin J Oncol Nurs. 2004;8: Maestri A, et al. Tumori. 2005;91: Pisano C, et al. Clin Cancer Res. 2003;9:

Conclusions All combination therapies provide high response rates during induction: the optimal choice depends on patient characteristics, patient and physician preference and toxicity profiles Doublets or triplets are appropriate induction for transplant ineligible patients Cytogenetics have the strongest prognostic significance Maintenance therapy is now an accepted standard for most myeloma patients, although gains need to balanced with cost and QOL Best treatment of neuropathy is prevention

Optimal Treatment of Relapsed/ Refractory Multiple Myeloma
This program is supported by educational grants from

Symptoms and End-Organ Damage
Bones Pain Lytic lesions, fractures High calcium Kidneys Elevated creatinine Reversible renal failure Hematopoietic organ Anemia Reversible cytopenias Peripheral nerves Humoral immune system Low Ig levels Hyperviscosity 75

Multiple Myeloma: Risk Categories
Risk Factors Standard Risk (Expected OS: 6-7 Yrs) High Risk (Expected OS: 2-3 Yrs) FISH t(11;14) t(6;14) del(17p) t(4;14)* t(14;16) Cytogenetics Hyperdiploidy Hypodiploidy del(13q) β2-M* Low (< 3.5 mg/L) High (≥ 5.5 mg/L) PCLI < 3% High (≥ 3%) Isotype -- IgA Gene expression profile Good risk High risk FISH, fluorescence in situ hybridization; Hb, hemoglobin; OS, overall survival; PCLI, plasma cell labeling index. *Patients with t(4;14), β2-M < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease. Kumar SK, et al. Mayo Clin Proc Dec;84(12): Fonseca R, et al. Leukemia. 2009;23: Kyle RA, et al. Clin Lymphoma Myeloma. 2009;9: Munshi N, et al. Blood. 2011;117:

Considerations in Patients With Relapsed/Refractory Myeloma
Types of previous therapy Response to previous therapy Patient characteristics and other prognostic factors Older than 65 yrs Increased β2-M, decreased serum albumin, low platelet count Cytogenetic abnormalities: t(4;14) Renal dysfunction Up to 50% of patients with MM have renal dysfunction Between 20% and 30% of patients have concomitant renal failure Extensive bone disease; extramedullary MM 2-M, beta-2 microglobulin; MM, multiple myeloma. Kyle RA, et al. Mayo Clin Proc. 2003;78: Kumar SK, et al. Mayo Clin Proc. 2004;79: Facon T, et al. Blood. 2001;97: Barlogie B, et al. Blood. 2004;103: Fonseca R, et al. Cancer Res. 2004;64: Kyle RA. Stem Cells. 1995;13(suppl 2): Bladé J, et al. Arch Intern Med. 1998;158:

Case 1 What would you do now?
A 65-yr-old male with ISS stage 1 MM received lenalidomide plus low-dose dexamethasone induction therapy for 4 cycles followed by HDT consolidation treatment. He declined lenalidomide maintenance treatment and was in CR for 2 yrs He now presents with M protein of 0.6 g/dL and no anemia or other abnormalities on skeletal survey Hb is 14 g/dL, UPEP is negative, serum free light chain ratio is 2:1, and creatinine and calcium levels are normal 3 mos later, repeat testing shows M protein of 0.8 g/dL 6 mos later, M protein is 0.9 g/dL with no changes in the other laboratory values What would you do now? CR, complete response; ISS, International Staging System; HDT, high-dose therapy; Hb, hemoglobin; M-protein, monoclonal protein; MM, multiple myeloma; UPEP, urine protein electrophoresis.

When to Consider Retreatment
Differences between biochemical relapse and symptomatic relapse need to be considered Patients with asymptomatic rise in M protein can be observed to determine the rate of rise and nature of the relapse Caveat: patients with known aggressive or high-risk disease should be considered for salvage even in the setting of biochemical relapse CRAB criteria are still listed as the indication to treat in the relapse setting C: Calcium elevation (> 11.5 mg/L or ULN) R: Renal dysfunction (serum creatinine > 2 mg/dL) A: Anemia (Hb < 10 g/dL or 2 g < normal) B: Bone disease (lytic lesions or osteoporosis) Hb, hemoglobin; M-protein, monoclonal protein; ULN, upper limit of normal.

Optimal Salvage Treatment

Case 2 What would you do now?
A 65-yr-old female presents with ISS stage 2 MM. She is treated with RVD followed by ASCT. Posttransplantation, she achieves a VGPR and is started on lenalidomide maintenance therapy After 2 yrs, she progresses on lenalidomide maintenance therapy. She has no neuropathy M protein is 1.2 g/dL, Hb is 9.3 g/dL, calcium is normal, serum free light chain ratio is 6:1, and IgG is 2900 mg/dL Skeletal survey shows new lytic disease. UPEP is negative, bone marrow shows 10% to 20% plasma cells with normal cytogenetics What would you do now? ASCT, autologous stem cell transplantation; Hb, hemoglobin; MM, multiple myeloma; RVD, lenalidomide, bortezomib, dexamethasone; UPEP, urine protein electrophoresis; VGPR, very good partial response.

Overview of Phase III Trials With Len and Bortezomib in Relapsed/Refractory MM
Regimen Trial ORR, % CR or nCR, % ≥ VGPR, % DOR, Mos TTP or PFS, Mos Median OS, Mos Len + dex MM-009[1] 61 24 NE 16 11 35[5] MM-010[2] 60 25 17 Bortezomib APEX[3] 43 8 6 30 Vdox MMY-3001[4] 44 13 27 10 9 CR, complete response; Dex, dexamethasone; DOR, duration of response; Len, lenalidomide; nCR, near complete response; NE, not evaluable; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TTP, time to progression; Vdox, bortezomib + pegylated liposomal doxorubicin; VGPR, very good partial response. 1. Weber DM, et al. N Engl J Med. 2007;357: Dimopoulos M, et al. N Engl J Med. 2007;357: Richardson PG, et al. Blood. 2007;110: Orlowski RZ, et al. J Clin Oncol. 2007;25: Weber D, et al. Blood. 2007;110:Abstract 412. 82

What would you recommend now?
Case 3 A 63-yr-old male with a history of relapsed MM after induction with RVD and transplantation presents now with relapse on maintenance therapy with lenalidomide. He is started on salvage therapy with RVD After 2 cycles, he has rapid and significant progression with progressive anemia and creatinine increasing to mg/dL M protein increases to 2.5 g/dL, Hb is 9 g/dL, creatinine is mg/dL, LDH is 250 mg/dL, marrow is packed, genetics shows del(17p) What would you recommend now? Cr, creatinine; Hb, hemoglobin; M-protein, monoclonal protein; MM, multiple myeloma; LDH, lactate dehydrogenase; RVD, lenalidomide, bortezomib, dexamethasone.

Carfilzomib Approved for patients who progress within 60 days of last therapy and have received ≥ 2 therapies including bortezomib and an IMiD. Trial N* Population Previous Lines, n ORR, % MR/SD, % Median TTP, Mos 003-A0[1] 39 Relapsed/ refractory > 2 18 8/41 6.2 003-A1[2] 257 ≥ 2 24 12/-- -- 004 (Bz exposed)[3] 35 Relapsed/ refractory 1-3 17 12/35 4.6 004 (Bz naive)[4] 20 mg/m2 20/27 mg/m2 59 67 42 52 17/22 12/15 8.3 NR 006 (combo with len/dex)[5] 50 78 2/8 Bz, bortezomib; Dex, dexamethasone; Len, lenalidomide; MR, minimal response; NR, not reached; SD, stable disease; TTP, time to progression. *Evaluable for response. Neuropathy from phase II experience: 9.6% grades 1/2 and 1.4% grade 3 1. Jagannath S, et al. ASCO Abstract Siegel DSD, et al. ASCO Abstract Vij R, et al. Br J Haematol. 2012;158: Vij R, et al. Blood. 2012;119: Wang M, et al. ASCO Abstract 8025.

PX-171-003A1: Phase II Trial of Carfilzomib in Relapsed/Refractory MM
Study population (N = 266) Progression during treatment or within 60 days of completion of the treatment, or stable disease (SD) as a best response = refractory to last regimen Neuropathy: Grade 1 or 2 without pain Cycle 1: 20 mg/m2 IV Cycles 2-12: 27 mg/m2 IV BOR, bortezomib; CBR, clinical benefit rate; CR, complete response; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EBMT, European Bone Marrow Transplant organization; IMWG, International Myeloma Working Group; MR, minimal response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; TTP, time to progression; VGPR, very good partial response. Primary endpoint: ORR (CR + VGPR + PR [IMWG criteria]) Secondary endpoints: CBR (ORR + MR [EBMT criteria]), DOR, PFS, TTP, OS, safety Siegel DS, et al. Blood. 2012;120:

003A1: Overall Response Rate
Response Category, n (%) All Patients (n = 257) Patients With Unfavorable Cytogenetics/FISH Markers (n = 71) ORR 61 (23.0) 21 (3.0) CR 1 (0.4) 0 (0) VGPR 13 (5.1) 3 (4.2) PR 47 (18.3) 18 (25.4) MR 34 (13.2) SD 81 (31.5) 28 (39.4) PD 69 (26.8) 15 (21.1) Not evaluable 12 (4.7) 4 (5.6) CI, confidence interval; CR, complete response; DOR, duration of response; FISH, fluorescent in situ hybridization; MR, molecular response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response. Median DOR: 7.8 months (95% CI: ) Siegel DS, et al. Blood. 2012;120:

003A1: Progression-Free Survival
100 75 Median PFS: 3.7 mos (95% CI: ) 50 Proportion of Patients Alive and Without Progression (%) 25 CI, confidence interval; PFS< progression-free survival. Censored observations Confidence band 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 Mos From Start of Treatment Siegel DS, et al. Blood. 2012;120:

003A1: Overall Survival (N = 266)
100 Median OS: 15.6 mos (95% CI: ) 75 50 Proportion of Patients Alive (%) 25 CI, confidence interval; OS, overall survival. Censored observations Confidence band Mos From Start of Treatment Siegel DS, et al. Blood. 2012;120:

003A1: Common Hematologic AEs
AEs Regardless of Relationship, % All Grades Grade 3 Grade 4 Anemia 46 22 2 Thrombocytopenia 39 17 12 Lymphopenia 23 18 AE, adverse event. Siegel DS, et al. Blood. 2012;120:

003A1: Common Nonhematologic AEs
Nonhematologic AE, n (%) All Grades Grade 3/4 Fatigue 130 (49.0) 20 (7.5) Nausea 119 (45.0) 5 (1.9) Dyspnea 90 (34.0) 9 (3.4) Diarrhea 86 (32.0) 2 (0.8) Pyrexia 83 (31.0) 4 (1.5) Headache 74 (28.0) Upper respiratory tract infection 71 (27.0) 12 (4.5) Increased serum creatinine 67 (25.0) 7 (2.6) Vomiting 59 (22.2) Peripheral neuropathy 33 (12.4) 3 (1.1) Hypophosphatemia 32 (12.0) 16 (6.0) Pneumonia 25 (9.4) Hyponatremia 31 (11.7) 22 (8.3) Renal failure (acute) 13 (4.9) Febrile neutropenia Tumor lysis syndrome 1 (0.4) 0 (0) AE, adverse event. Siegel DS, et al. Blood. 2012;120:

Results: Cardiac Analysis
All Patients (N = 526) SMQ grouping, n (%) Cardiac arrhythmia 5 (10.9) 38 (14.3) 20 (12.2) 7 (14.0) 70 (13.3) Grade 3/4/5 8 (3.0) 3 (1.8) 1 (2.0) 12 (2.3) Cardiac failure 6 (13.0) 16 (6.0) 9 (5.5) 38 (7.2) 4 (8.8) 13 (4.9) 4 (8.0) 30 (5.7) Cardiomyopathy 2 (4.3) 4 (1.5) 2 (1.2) 9 (1.7) Grade 3/4 1 (2.2) 2 (0.8) 3 (0.6) Ischemic heart disease 3 (6.5) 11 (4.1) 4 (2.4) 18 (3.4) Grade 3 6 (2.3) 7 (1.4) Patient disposition in response to cardiac AEs Dose reduction 5 (1.9) 1 (0.6) 6 (1.1) Discontinuation 8 (4.9) 2 (4.0) 28 (5.3) Cardiac deaths* 5 (1.0) Cardiac component to other deaths† 3 (1.1) AE, adverse event; SMQ, standardized MedDRA query. *003-A1, 3 cardiac arrest, 1 dyspnea; 004, 1 cardiac disorder. †Three deaths reported as disease progression by the investigator. Lonial S, et al. ASH Abstract Reprinted with permission.

PX-171-004: PFS With Carfilzomib in Bortezomib-Naive Patients
Median 95% CI Cohort 1: 20 mg/m2 Cohort 2: 20/27 mg/m2 59 67 8.2 NR 11.3-NE 1.00 0.75 Survival Distribution Function 0.50 0.25 CI, confidence interval; NE, not estimable; NR, not reached. 5 10 15 20 25 30 Mos From the Start of Treatment Pts at Risk (n) Vij R, et al. Blood. 2012;119:

CCd: Time to Onset for Best Response in Newly Diagnosed MM Patients
CCd: Carfilzomib (20/36 mg/m2), cyclophosphamide, dexamethasone AEs: Grade 4: neutropenia (5%); Grade 3/4: infection (10%), cardiac (5%), renal failure (5%); discontinued due to AEs: 0% Median treatment duration, cycles (range): 5 (1-9) % of Patients Months PR sCR/CR/nCR VGPR 1.00 0.75 0.50 0.25 0.0 2.5 5.0 7.5 10.0 12.5 AE, adverse event; MM, multiple myeloma; PR, partial response; sCR/CR/nCR, stringent complete response, complete response, near-complete response. Palumbo A, et al. Blood 2012;120:730

Management of Adverse Events

Case 4 A 63-yr-old male with a history of relapsed MM after induction with RVD and transplantation now presents with relapse on maintenance therapy with lenalidomide. He is started on salvage therapy with VCD After 2 cycles of VCD, he develops PN with pain in the lower extremities. He is currently on twice-weekly dosing of IV bortezomib Laboratory tests show a PR and normal renal function, and Hb is 10.5 g/dL (improved). Examination shows painful grade 2 PN in the lower extremities What would you recommend now? Hb, hemoglobin; MM, multiple myeloma; PN, peripheral neuropathy; PR, partial response; RVD, lenalidomide, bortezomib, dexamethasone; VCD, bortezomib, cyclophosphamide, dexamethasone.

Proposed Guidelines for Bortezomib Dose Modification for Management of PN
Severity of PN Signs/Symptoms Modification of Dose and Regimen Grade 1 (paresthesia, weakness, and/or loss of reflexes without pain or loss of function) Reduce current bortezomib dose by 1 level ( mg/m2). For patients receiving a twice-weekly schedule, change to a once-per-wk schedule using the same dose. For patients with prior PN, consider starting with 1.3 mg/m2 once per wk Grade 1 with pain or grade 2 (no pain but interfering with basic activities of daily living) For patients receiving twice-weekly bortezomib, reduce current dose by 1 level or change to a once-per-wk schedule using the same dose For patients receiving bortezomib on a once-per-wk schedule, reduce current dose by 1 level, OR consider temporary discontinuation; upon resolution (grade ≤ 1), restart once-per-wk dosing at lower dose level in cases of favorable benefit-to-risk ratio Grade 2 with pain, grade 3 (limiting self-care and activities of daily living), or grade 4 Discontinue bortezomib PN, peripheral neuropathy. Subcutaneous bortezomib causes less peripheral neuropathy Richardson PG, et al. Leukemia. 2011;26:

Risk Assessment for VTEs in Patients With MM Receiving Thal or Len
VTE prophylaxis for individual risk factors or myeloma- related risk factors (eg, hyperviscosity) If ≤ 1 risk factor present, aspirin mg/day If ≥ 2 risk factors present, LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3) VTE prophylaxis for myeloma therapy–related risk factors (eg, high-dose dexamethasone, doxorubicin, multiagent chemotherapy) LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3) INR, international normalized ratio; Len, lenalidomide; LMWH, low–molecular-weight heparin; MM, multiple myeloma; Thal, thalidomide; VTE, venous thromboembolism. Palumbo A, et al. Leukemia. 2008;22:

Len/Dex: Cytopenia Management
Monitoring CBCs At least biweekly monitoring Standard dose reductions Neutropenia For grade ≥ 3, monitor WBCs and consider G-CSF prophylaxis or lenalidomide dose reduction Thrombocytopenia For grade ≥ 3, monitor platelet count and consider interrupting treatment or dose reductions Anemia Consider ESAs for Hb < 10 g/dL CBCs, complete blood cell counts; Dex, dexamethasone; ESA, erythropoiesis-stimulating agent; G-CSF, granulocyte colony-stimulating factor; Hb, hemoglobin; Len, lenalidomide; WBCs, white blood cells. Palumbo A, et al. N Engl J Med ;364:

Herpes Zoster Prophylaxis With Bortezomib Treatment
Immunocompromised patients at risk of developing VZV infection Bortezomib is associated with increased risk of VZV infection[1] Acyclovir and other antiviral prophylaxis appear effective at preventing VZV infection in patients treated with bortezomib for MM (with or without corticosteroids)[2] Vaccine not recommended MM, multiple myeloma; VZV, Varicella zoster virus. 1. Chanan-Khan AA, et al. J Clin Oncol. 2008;26: Vickrey E, et al. Cancer. 2009;115:

Renal Dysfunction To avoid renal failure
Maintain hydration Avoid use of NSAIDs Avoid IV contrast Plasmapheresis (NCCN category 2B) Renal dysfunction is not a contraindication to transplantation With chronic use of bisphosphonates, it is crucial to monitor for renal dysfunction NCCN, National Comprehensive Cancer Network; NSAIDs , nonsteroidal anti-inflammatory drugs. NCCN Clinical Practice Guidelines: Multiple Myeloma (V ).

Lenalidomide Starting Dose Adjustment for Renal Impairment
Category Renal Function (Cockcroft-Gault) CLcr, mL/min Dose Moderate renal impairment 30-60 10 mg Every 24 hr Severe renal impairment < 30 (not requiring dialysis) 15 mg Every 48 hr End-stage renal disease (requiring dialysis) 5 mg Once daily (on dialysis days, administer following dialysis) CLcr, creatinine clearance. Lenalidomide [package insert].

Current Treatment of MM Bone Disease
Bisphosphonates Pamidronate Zoledronic acid Denosumab (investigational) Surgical procedures Vertebroplasty Balloon kyphoplasty Radiotherapy Treatment of myeloma MM, multiple myeloma. Roodman GD. Hematology Am Soc Hematol Educ Program. 2008:

Bisphosphonates and Osteonecrosis
Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapy Incidence unknown but 2004 IMF web-based survey revealed: 5% incidence with zoledronic acid 4% incidence with pamidronate IFM, International Myeloma Foundation. Durie BG, et al. N Engl J Med. 2005;353(1):

Novel Strategies

Case 5 A 63-yr-old man, with a history of relapsed MM after induction with RVD and transplantation, relapsed on maintenance therapy with lenalidomide and progressed after 2 cycles of RVD M protein increased to 2.5 g/dL, Hb was 9 g/dL, creatinine mg/dL, LDH 250 mg/dL, marrow was packed, and cytogenetics showed del(17p) Carfilzomib was begun and the dose increased to 36 mg/m2 with stable disease After 7 cycles of carfilzomib, he has progressive anemia and M-protein increase of 0.9 g/dL What would you recommend now? Cr, creatinine; Hb, hemoglobin; M-protein, monoclonal protein; MM, multiple myeloma; LDH, lactate dehydrogenase; RVD, lenalidomide, bortezomib, dexamethasone.

PX-171-006: Phase II Trial of Carfilzomib Plus Len/Dex in Relapsed/Refractory MM
Carfilzomib 20/27 mg/m2 IV 20 mg/m2 cycle 1 Days 1 and 2 only, 27 mg/m2 all days, all cycles thereafter D1/D2 D8/D9 D15/D16 Week 1 Week 2 Week 3 Week 4: rest Lenalidomide D1-D21 25 mg/day PO D1 D8 D15 D22 Dexamethasone 40 mg/day PO Response (N = 51) n (%) CR/nCR VGPR PR MR SD ORR 12 (24) 9 (18) 19 (37) 1 (2) 3 (6) 40 (78) CR/nCR, complete response, near-complete response; MM, multiple myeloma; MR, minimal response; ORR, overall response rate; PO, orally; PR, partial response; SD, stable disease; VGPR, very good partial response. Niezvizky R, et al. Clin Cancer Res. 2013;19: 106 106

MM-002: Study Design Open-label, randomized phase I/II trial[1]
Phase I portion previously presented[2] Pomalidomide 4 mg on Days Low-Dose Dexamethasone 40 mg/wk 28-day cycle (n = 113) Patients with relapsed/ refractory MM (N = 221) PD Pomalidomide* 4 mg on Days day cycle (n = 108) MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; RBC, red blood cell. Primary endpoint: PFS Secondary endpoints: ORR, duration of response, OS, safety *Option to add low-dose dexamethasone 40 mg/wk in cases of PD or no response after 4 treatment cycles (n = 61). Anticoagulants and granulocyte colony-stimulating factor added after cycle 1 Erythroid growth factors, bisphosphonates, platelet, and/or RBC transfusions added as clinically indicated 1. Richardson PG, et al. ASH Abstract Richardson PG, et al. ASH Abstract 864.

MM-002: Response and Survival Outcomes
Pomalidomide + Low-Dose Dexamethasone Pomalidomide Overall population (n = 113) (n = 108) ORR, % 34 13 Median time to response, mos 1.9 2.9 Median duration of response, mos 7.9 8.5 Median PFS, mos 4.7 2.7 Median OS, mos 16.9 14 For patients with PD as best response 5.4 Double-refractory population (n = 69) (n = 64) 30 16 1.8 2.0 6.5 8.3 3.9 13.7 12.7 4.6 MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival. Richardson PG, et al. ASH Abstract 634. Reprinted with permission.

Low-Dose Dexamethasone
MM-002: Adverse Events Grade 3/4 Adverse Event in ≥ 5% Patients, % Pomalidomide + Low-Dose Dexamethasone (n = 112) Pomalidomide (n = 107) Hematologic Neutropenia 38 45 Requiring dose reduction 4 7 Thrombocytopenia 19 21 5 9 Anemia 17 Nonhematologic Pneumonia 8 Fatigue 10 MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival. Richardson PG, et al. ASH Abstract 634. Reprinted with permission.

MM-003: Pomalidomide and Low-Dose Dex in Relapsed/Refractory Myeloma
Randomized, phase III trial Pomalidomide 4 mg on Days Low-Dose Dex (LoDex)40 mg/day Days 1, 8, 15, 22; 28-day cycles (n = 302) Patients with relapsed/ refractory multiple myeloma with ≥ 2 previous treatments, incl failure of lenalidomide and bortezomib (N = 455) PD or unacceptable toxicity Dex (HiDex) 40 mg/day Days 1-4, 9-12, 17-20; 28-day cycles (n = 153) HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response. Primary endpoint: PFS Secondary endpoints: ORR (≥ PR), duration of response, OS, safety Dimopoulos, et al. ASH Abstract LBA-6.

MM-003: PFS (ITT Population)
4 8 12 16 0.0 0.2 0.4 0.6 0.8 1.0 Median PFS POM + LoDEX: 3.6 mo HiDEX: 1.8 mo Proportion of Patients Without Progression HR: 0.45; P < .001 HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival; POM, pomalidomide; Months Dimopoulos et al. ASH 2012, Abstract LBA-6. Reprinted with permission.

MM-003: Other Findings Median OS (95% CI)
Pom + LoDex: Not reached (11.1 mos – NE) HiDex: 7.8 mos (5.4 – 9.2) ORR significantly higher for Pom + LoDex Response Pom + LoDex HiDex P value ORR (≥ PR), % 21 3 < .001 VGPR 1 -- Median DOR (range) 10.1 mo (6.2 – 12.1) NE DOR, duration of response; HiDex, high-dose dexamethasone; LoDex, low-dose dexamethasone; NE, not estimated; ORR, overall response rate; Pom, pomalidomide; VGPR, very good partial response. Dimopoulos et al. ASH Abstract LBA-6. Reprinted with permission.

Overview of Multiple Myeloma

Similar presentations

Presentation on theme: "Overview of Multiple Myeloma"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Overview of Multiple Myeloma

Similar presentations

Presentation on theme: "Overview of Multiple Myeloma"— Presentation transcript:

Similar presentations

About project

Feedback