Special Thanks to… For sponsorship of LMEF programs: Supported by an educational grant from Lilly USA, LLC Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org. Multiple Myeloma 2010 Wael Harb MD Horizon Oncology Center Overview Introduction: epidemiology, clinical presentation, diagnosis, staging Autologous stem cell transplantation Initial approaches to treatment • Current options • Novel agents and combinations Considerations in nontransplantation-eligible patients Prevention of skeletal complications What is MM? Multiple myeloma (MM) is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. Plasma Cell Multiple Myeloma: Incidence The lifetime risk of getting MM is 1 in 159 (0.63%). 20,180 new cases will be diagnosed in 2010 (11,170 in men and 9,010 in women) 10,650 deaths are expected to occur in 2010 (5,760 in men and 4,890 in women) The 5-year relative survival rate for MM is around 35% Incidence MM occurs in all races and all geographic locations African Americans and blacks from Africa is two to three times the risk in whites Risk is lower in Asians from Japan and in Mexicans Slightly more frequent in men than in women (1.4:1) Age MM is a disease of older adults The median age at diagnosis is 66 years Only 10 percent of patients are younger than 50 years Only 2 percent of patients are younger than 40 years MM: Clinical Presentations Anemia - 73 percent Bone pain - 58 percent Elevated creatinine - 48 percent Fatigue/generalized weakness - 32 percent Hypercalcemia- 28 percent Weight loss - 24 percent, one-half of whom had lost ≥ 9 kg Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Immunoglobulin Immunoglobulins SPEP: Normal SPEP: M-protein, M-spike Renal Failure Cast nephropathy (also called myeloma kidney) from light chains Hypercalcemia Light chain amyloidosis Drug-induced renal damage Anemia Normocytic, normochromic anemiais present in 73% at diagnosis and in 97%at some time during the course of the disease This anemia can be related to: • Bone marrow replacement • Kidney damage • Dilution in the case of a large M-protein • B12 deficiency in 14% Rouleaux Formation Lytic Bone Lesion MM: PET Scan Extramedullary Plasmacytoma Differential Diagnosis of MM Monoclonal gammopathy of undetermined significance (MGUS) Smoldering multiple myeloma (SMM) Waldenstrom macroglobulinemia Solitary plasmacytoma Primary amyloidosis (AL) POEMS syndrome Metastatic carcinoma Multiple Myeloma All 3 criteria must be met: 1. Presence of a serum or urinary monoclonal protein 2. Presence of clonal plasma cells in the bone marrow or a plasmacytoma 3. Presence of end organ damage felt related to the plasma cell dyscrasia, such as: • • • • Increased calcium concentration Lytic bone lesions Anemia Renal failure Smoldering Multiple Myeloma SMM, Asymptomatic Both criteria must be met: Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent No end organ damage related to plasma cell dyscrasia Monoclonal Gammopathy of Undetermined Significance (MGUS) All 3 criteria must be met: Serum monoclonal protein <3 g/dL Bone marrow plasma cells <10 percent No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder POEMS Syndrome Osteosclerotic myeloma • Polyneuropathy • Organomegaly • Endocrinopathy • Monoclonal protein • Skin changes MM: Evaluation CBC and differential,peripheral blood smear Chemistry:serum calcium, creatinine, albumin, LDH , beta-2 microglobulin, and C-reactive protein Serum protein electrophoresis (SPEP) + IF Quantification of immunoglobulins Urinalysis and a 24-hour urine collection for electrophoresis (UPEP) + IF Serum free monoclonal light chain (FLC) MM Evaluation Serum viscosity should be measured if the M-protein concentration is high Bone marrow aspiration and biopsy with immunophenotyping, conventional cytogenetics, and fluorescence in situ hybridization (FISH) Metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. Bone Marrow Cytogenenetics, Interphase FISH Poor prognosis (median survival 25 months): t(4;14)(p16;q32), t(14;16)(q32;q23), and -17p13 Intermediate prognosis (median survival 42 months): -13q14 Good prognosis (median survival 50 months): all others Staging for MM International staging system (ISS) Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months MM: Treatment Decisions Indications for treatment Risk stratification Eligibility for stem cell transplantation Smoldering (asymptomatic) myeloma Deferral of chemotherapy until progression to symptomatic disease Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop MM: Indications for Treatment Anemia (hemoglobin <10 g/dL or 2 g/dL below normal) Hypercalcemia (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine>2 mg/dL) Lytic bone lesions or severe osteopenia Extramedullary plasmacytoma MM: RISK STRATIFICATION FISH for detection of t(4;14), t(14;16), and del17p13 Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment Current Frontline Options Conventional chemotherapy • Survival ≤ 3 yrs Transplantation • Prolongs survival 4-5 yrs Novel agents targeting stromal interactions and associated signaling pathways have shown promise Chng WJ, et al. Cancer Control. 2005;12:91-104. MM: INITIAL THERAPY The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation Initial Approach to Treatment of MM Clearly not transplantation candidate based on age, performance score, and comorbidity Potential transplantation candidate MPT, MPV, Len/dex or clinical trial* Nonalkylator-based induction x 4 cycles *Thal/dex or dex are additional options especially if immediate response is needed. Stem cell harvest DETERMINING TRANSPLANT ELIGIBILITY Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational NOT Eligible for Autologous HCT Age >77 years Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain New York Heart Association functional status Class III or IV Transplantation vs Conventional Chemotherapy 100 100 54 75 High dose Survival (%) OS (%) 75 50 Conventional dose 25 Intensive therapy 42 50 Standard therapy 25 P = .03 by Wilcoxon test P = .04 by log-rank test 0 0 0 15 30 Mos 45 60 0 20 40 Mos Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 60 80 Autologous Stem Cell Transplantation Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary, cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves, not contraindications Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010. Stem Cell Transplantation Key issues Efficacy compared with conventional chemotherapy Timing: early vs delayed Single vs tandem Role of allogeneic and miniallogeneic transplantations Maintenance post-SCT Novel Frontline Options Immunomodulatory drugs (IMiDs) • Thalidomide • Lenalidomide Proteasome inhibitors • Bortezomib • Carfilzomib Proposed Mechanism of Action for Multiple Myeloma Therapies Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Thalidomide: Proposed Mechanism of Action Proposed mechanisms • Inhibition of TNF- • Suppression of angiogenesis • Increase in cell-mediated cytotoxic effects • Modulation of adhesion molecule expression Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models • Dose-dependent decrease in TNF-α and interleukin-6 • Directly induces apoptosis, G1 growth arrest • Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950. Bortezomib: A Reversible Proteasome Inhibitor Cross section of b ring b1 O N N N H H N OH B OH PostGlutamyl Site Tryptic Site b7 b3 Bortezomib O b6 b4 b5 Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. b2 Chymotryptic Site Initial Approach to Treatment of MM Clearly not a transplantation candidate Potential transplantation candidate MPT, MPV, Len/dex or clinical trial* Nonalkylator-based induction Stem cell harvest Melphalan/Prednisone/Thalidomide Melphalan/ Prednisone (n = 164) Melphalan/ Prednisone/ Thalidomide (n = 167) HR (95% CI) P Value Median PFS, mos 14.5 21.8 0.63 (0.48-0.81) .0004 No. of events 125 111 -- -- Median OS, mos 47.6 45.0 1.04 (0.76-1.44) .79 No. of events 70 77 -- -- Outcome Palumbo A, et al. Blood. 2008;112:3107-3114. Len + High or Low-Dose Dex in Newly Diagnosed Myeloma (E4A03) Courses repeat every 28 days ≤ 1 yr in absence of PD or unacceptable toxicity Untreated, symptomatic myeloma, no age cutoff Lenalidomide 25 mg/day PO on Days 1-21 + High-dose Dex 40 mg/day PO on Days 1-4, 9-12, 17-20 (n = 223) Lenalidomide 25 mg/day PO on Days 1-21 + Low-dose Dex 40 mg/day PO on Days 1, 8, 15, 22 (n = 222) Total Dex dose per cycle: 480 mg Total Dex dose per cycle: 160 mg Rajkumar SV, et al. ASCO 2008. Abstract 8504. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37 Len + High or Low-Dose Dex (E4A03): Response High Dose Low Dose P Value Overall response at 4 cycles, % 79 68 .008 ≥ VGPR within 4 cycles, % 42 24 < .0001 Best overall response, % 81 70 .009 ≥ VGPR, % 50 40 .040 CR (IF-), % 13 10 -- 1-yr OS 87 96 .0002 2-yr OS 75 87 -- OS, % 3-yr OS rates converged (P = .467) with all pts crossed over to low dose Successful stem cell harvesting in 97.6% (n = 167) 3-yr OS for high dose or low dose followed by SCT: 92% Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Len + High or Low-Dose Dex (E4A03): Adverse Events Toxicity Grade ≥ 3, % High Dose Low Dose P Value Toxicity (any) during first 4 mos, grade ≥ 3 52 35 .0001 Nonhematologic (any), grade ≥ 3 65 48 .0002 Death (early < 4 mos) 5 0.50 .003 DVT/PE 26 12 .0003 Infection/pneumonia 16 9 .04 Neutropenia 12 20 .02 Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Renal Impairment (CrCl) Moderate (30 to < 60 mL/min) Severe (< 30 mL/min, not requiring dialysis) ESRD (< 30 mL/min, requiring dialysis) Lenalidomide [package insert]. Lenalidomide Dosage 10 mg QD 15 mg Q 48 hrs 5 mg QD On dialysis days, administer following dialysis Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials 80% of patients entered these trials with preexisting peripheral neuropathy 3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy Richardson PG, et al. ASH 2003. Abstract 512. Frontline Therapy in Elderly MM Patients For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment • ORR: 60% • Long-term CR: < 5% Trials with MP-based combinations reported improved response rates and time to progression • MPT NCCN Practice Guidelines. Myeloma. V.3.2010. • VMP Conclusions In elderly patients, the addition of novel agents to standard MP has provided improved response rates • MP alone (ORR: 50%; CR: 5%) • MPR (50% to 95% reduction in myeloma protein in 55.6%) • VMP (ORR: 86%) Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE Care should be taken with bortezomibbased regimens to include herpes zoster prophylaxis MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey • Vertebrae: 65% • Ribs: 45% • Skull: 40% • Shoulders: 40% • Pelvis: 30% • Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12. The Central Role of the Osteoclast in Osteolytic Bone Destruction Tumor cells Osteoclast differentiation Growth factors Direct effects on osteoclast differentiation Active osteoclast Osteolysis Bone loss Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis[1] X Bisphosphonates may modulate signaling from osteoblasts to osteoclasts Increased OPG production[2] Decreased RANKL expression[3] New bone Bone Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] 1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154. Recommended Doses and Infusion Times Drug Dose/Infusion Time Interval Estimated CrCl > 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs 4 mg over 15 mins 3-4 wks 3-4 wks Estimated CrCl 30 to < 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs* Reduced dosage† 3-4 wks 3-4 wks Estimated CrCl < 30 mL/min Pamidronate *Consider dose reduction Zoledronic acid. 90 mg over 4-6 3-4 wks hrs* †3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Not recommended Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Bisphosphonates and Osteonecrosis Papapetrou PD. Hormones (Athens). 2009;8:96-110. 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 True incidence unknown Normal RANKL/OPG OPG RANKL Prevents Promotes Osteoclastic Activity Hofbauer LC, et al. JAMA. 2004;292:490-495. The RANK/RANKL/OPG Pathway in Osteolytic Bone Disease OPG Prevents RANKL Promotes Increased osteoclastic activity and decreased OPG Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664. Denosumab: Inhibiting RANK in Bone Disease High affinity human monoclonal antibody that binds RANKL Administered via SC injection Specific: does not bind to TNF-α, TNF-β, TRAIL, or CD40L Inhibits formation and activation of osteoclasts Multiple Myeloma = M-CRAB Monoclonal protein Calcium Renal failure Anemia Bone pain with lytic lesions Thank you