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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 non-transplantation-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:
Presence of a serum or urinary monoclonal protein
Presence of clonal plasma cells in the bone marrow or a plasmacytoma
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.
MRI, CT, or PET/CT
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 *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex
or clinical trial* Potential transplantation
candidate Nonalkylator-based
induction x 4 cycles Stem cell harvest Initial Approach to Treatment of MM 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 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test
P = .04 by log-rank test Transplantation vs Conventional Chemotherapy 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 Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved. Proposed Mechanism of Action for Multiple Myeloma Therapies 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 Chymo-
tryptic Site Post-
Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex
or clinical trial* Potential transplantation
candidate Nonalkylator-based
induction Stem cell harvest Melphalan/Prednisone/Thalidomide Palumbo A, et al. Blood. 2008;112:3107-3114. 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) 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 Total Dex dose per cycle:
480 mg Untreated, symptomatic myeloma, no age cutoff 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 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 Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. 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
VMP NCCN Practice Guidelines. Myeloma. V.3.2010. 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 bortezomib-based 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 Growth factors
Osteoclast differentiation Osteolysis Direct effects on
osteoclast differentiation Tumor cells Bone loss Active
osteoclast 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] Bisphosphonates are released locally during bone resorption[1] Bisphosphonates are concentrated under osteoclasts[1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone Increased OPG production[2]
Decreased RANKL expression[3] 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 *Consider dose reduction .
†3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. 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
True incidence unknown Papapetrou PD. Hormones (Athens). 2009;8:96-110. Normal RANKL/OPG Prevents Promotes Osteoclastic Activity RANKL OPG Hofbauer LC, et al. JAMA. 2004;292:490-495. The RANK/RANKL/OPG Pathway in Osteolytic Bone Disease
Prevents Promotes Increased osteoclastic activity and decreased OPG OPG RANKL 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
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