Multiple Myeloma Something Old, Something New, Something Borrowed

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1 Multiple Myeloma Something Old, Something New, Something Borrowed UCT Nicolas Novitzky Dip Med, PhD, FCP(SA) Haematology Clinical & Laboratory Science, Department of Medicine University of Cape Town

2 1. Monoclonal gammopathy 2. Smouldering or indolent myeloma. 3. Solitary plasmacytoma i) bone ii) soft tissue 3.Multiple plasmacytoma or myeloma i) medullary ii) extramedullary 4. Plasma cell leukaemia 7. Amyloidosis 5. Macroglobulinaemia 6. Heavy chain diseases Plasma Cell Dyscrasias

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4 Pathophysiology Plasma cell homeostasis Antigen dependent increase in proliferation of B-cells Cell cycle regulation Cycline dependent kynases Cytokine signals Upregulation of survival signals IL-6 IGF SDF-1 VEGF Reduction in apoptosis FAS TRAIL/Apo Karyotypic abnormalities common Inherent genetic instability VDJ recombination Somatic hypermutation Isotype switching Chromosomal translocations 14q32 (75% of myeloma cells) Karyotypic abnormalities in MM & MGUS Numeric abnormalities Hypo/hyper diploid Chromosome gains/losses Structural abnormalities Translocations

5 Myeloma is a Genetic Disease

6 Incidence of Chromosomal Abnormalities in MM Genomic Aberrations Incidence of aberration Del (13) 48% Del (17p) 11% t(4;14) (p16;q32) 14% Hyperdiploidy 39% t(11;14) (q13;q32) 21% N= 1064 patients Chromosomal changes observed in 90% of patients

7 From MGUS to Myeloma Definitions * MGUS (1-3% annual progression) IgG < 30g/L Plasma cells in BM < 10% No CRAB Smoldering myeloma (10% annual progression) IgG > 30 g/l Plasma cells > 10% No CRAB Multiple myeloma IgG > 30 g/l Plasma cells > 10% CRAB * International Myeloma Working Group, 2003

8 MGUS MGUS In 3% of > 55 years Asymptomatic Higher incidence among Africans Family history Precedes plasma cell disorder in all cases Myeloma Amyloidosis Waldestrom MG Progression (21, 37 & 58%) o o o M protein concentration > 15 g/l Aberrant plasma cell population by flowcytometry (CD38+, CD56+, lack of CD19, CD45) DNA aneuploidy All patients need evaluation o Marrow morphology, o Cytogenetics or FISH Bone imaging o o Skeletal survey Scanning (CT, MRI, PET)

9 Accumulation of clonal plasma cells Impaired haematopoiesis Secrete paraprotein Bone disease 2% of cancers 20% of deaths from haematological malignancies Presentation age depends on clinical variant MGUS 62 yr. (3% of >50 years) Myeloma 69 yr. Common among Africans Multiple Myeloma

10 Multiple Myeloma Abnormal proliferation of clonal plasma cells IgG IgA Light chain only (BJP) IgD, IgE IgM very rare in myeloma Common in Lymphoma esp. Waldenstrom s Non-secretory M protein found in serum or urine or both at time of diagnosis: 97% Serum M spike by protein electrophoresis: 80% Abnormal serum immunofixation: 93% Abnormal urine immunofixation: 75% Non-secretory myeloma: 3%

11 Diagnostic Criteria Plasma cells >10% in marrow Or (in any quantity) in a biopsy from other tissues (plasmacytoma) Monoclonal protein (paraprotein) in serum / urine except in non-secretory myeloma Evidence of end-organ damage Calcium >2.75 mmol/l) Renal failure attributable to myeloma Hb < 10gm/dl Lytic bone lesions Monoclonal gammopathy of undetermined significance (MGUS): Serum paraprotein <30 g/l AND Clonal plasma cells <10% on bone marrow biopsy AND NO myeloma-related organ or tissue impairment Asymptomatic (smouldering) myeloma: Serum paraprotein >30 g/l AND/OR Clonal plasma cells >10% on bone marrow biopsy AND NO myeloma-related organ or tissue impairment Multiple myeloma IgG > 30 g/l Plasma cells > 10% CRAB

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

14 Signs & Symptoms in 1027 Newly Diagnosed Myeloma Patients % patients Bone Bone Hb<12 Fatigue Cr >2 Ca >11 Wt loss lesions pain g/dl mg/dl mg/dl (>9 kg) Kyle RA. Mayo Clin Proc 2003;78:21-33

15 Skeletal radiography is the primary diagnostic test to detect destructive bony lesions in multiple myeloma MRI is useful in assessing spinal compression fractures, focal mass or from osteopenia due to increased osteolysis PET scans can be used to detect soft tissue or bone metastases Bone Imaging in MM Angtuaco EJ et al. Radiology. 2004;231:11-23.

16 Myeloma Bone Disease

17 Myeloma Bone Disease Appearance of multiple myeloma at FDG PET. Post-treatment appearance of multiple myeloma at FDG PET.

18 Age Specific Mortality by Race

19 Prognostic factors Salmon & Durie Stage I: all of Hb > 10g/dL Normal calcium Skeletal survey: normal or single plasmacytoma or osteoporosis Serum PP < 50 g/l IgG, < 3o g/l IgA Urinary light chain excretion < 4 g/24h Stage III: one or more of Hb < 8.5g/dL Serum calcium > 3mmol/l Skeletal survey: 3 or> lytic bone lesions Serum paraprotein > 70g/L IgG, > 50g/L IgA Urinary light chain excretion > 12g/24h Stage II: fulfilling the criteria of neither I nor III

20 International Staging System (ISS) for Symptomatic Myeloma Stage I Criteria β2m < 3.5 mg/l albumin 3.5 g/dl Median Survival (mo) 62 II* Not stage I or III 44 III β2m 5.5 mg/l 29 *β2m < 3.5 mg/l and albumin < 3.5 g/dl or β2m < 5.5 mg/l, any albumin Greipp et al. J Clin Oncol 2005; 23:

21 Multiple Myeloma Treatment Smoldering or Stage I myeloma Counseling and observation Follow up CBC, SPEP, chemistry every 3 mo Bone survey ± Bone marrow biospy every 6 mo Clinical trial of thalidomide or other biological therapy Progression to Stage II, III disease Treat accordingly Solitary plasmacytoma Radiation therapy 45 to 50 Gy Follow up CBC, SPEP, UPEP, chemistry every 3 months Bone Survey ± CT scan or MRI every 6 mo Yearly evaluation after one year and no disease

22 Therapy Melphalan & Prednisone (NCI; MY-2, n= 460) Objective response 46% o (50% reduction in tumour bulk) o CR: 2% Unchanged 10% Progressive disease 44% Increase in paraprotein Hypercalcemia Increase in plasmacytosis/omas Increase in number/size lytic lesions Duration of response: 18 month Overall survival: months Cycle is repeated every 4-6 weeks (Belch et al, 1988)

23 High Dose Therapy in Myeloma Autologous stem cell transplantation MRC Myeloma Working Party OR: 90% CR: 25-80% Intergroupe Francais du Mye lome VCMP/VBAP vs. ABMT Nº= OR : 74 vs. 42% 5 yr. : 28 vs. 10% 5 yr. : 52 vs. 12% Prognosis: Low b2mg, CRP and no Chr 11/13 abno

24 Cytokines and Myeloma

25 Biological Cell Modifiers in Myeloma Immuno-modulating agents Thalidomide Lenolidomide Pomalidomide Proteasome inhibitors Bortezomib Carfilzomib Histone deacetylases Vorinostat Panobinostat Mammalian target or rapamicin complex (mtor) Temsirolimus Everolimus Heat shock protein 90 Perifostine Tanepsimycin Monoclonal antibodies Elotuzumab

26 Thalidomide Thalidomide Old drug (1958) Sedative, anti emetic Teratogenic!!! Withdrawn from market in 1962 Anti inflammatory Immunomodulating Inhibits TNF and IL-1 Anti-angiogenesis Side effects Somnolence, tiredness Peripheral neuropathy Thrombophilia Constipation

27 The Proteasome Pathway

28 Lenolidomide Synthetic immuno-modulatory agent Lower side effect profile No Peripheral neuropathy No constipation No sedation Not teratogenic Associated with Thombosis Marrow suppression Inhibits angiogenesis Reduced VEGF levels Decreased vascular density Immuno-stimulatory 2000 x more potent than thalidomide NK cells CD4+ IL-2 & IF- production Inhibits apoptosis & IL-6 production

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30 Treatment Decision Tree Transplant candidate Initial therapy Thalidomide based CTD Bortezomib based VCD Auto SCT (single / double) Maintenance Thalidomide Pamidronate / zeledronic acid Salvage Bortezomib or lenolidomide With anthacyclines (Doxyl) Non- transplant candidate Initial Therapy MPT VMP Maintenance Thalidomide Pamidronate / zeledronic acid Salvage Bortezomib based Lenolidomide based

31 Multiple Myeloma Treatment Lines a Front-line treatment Maintenance Relapsed Induction Consolidation Maintenance Rescue Bor/Dex Bor/Dex/Dox Bor/Thal/Dex Len/Dex SCT Observation Thal Thal/Pred Bor Bor/Liposomal Dox Len/Dex a Transplant eligible patients. Bor/Dex = bortezomib, dexamethasone; Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin; Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone; Len/Dex = lenalidomide, dexamethasone; SCT = stem-cell transplant; Thal/pred = thalidomide, prednsione; Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin. NCCN, 2009.

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33 Survival Benefits of New Agents Overall From relapse Median not yet reached P = mo 43mo P < mo British Columbia Cancer Agency, JCO, 2010

34 Treatment of Bone Disease Bisphosphonates Surgical procedures Vertebroplasty Balloon Kyphoplasty Radiotherapy Treatment of myeloma MM patients with lytic disease or osteopenia on plain radiographs or imaging studies Intravenous pamidronate 90 mg deliver over at least 2 hrs or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks. Continue therapy for 2 yrs & consider stopping in patients w/ responsive or stable disease; further use at physician s discretion

35 Clinical Problems: Renal Failure Incidence in myeloma Renal dysfunction in 20-40% Dialysis required in 5-10% 1-1.5% of all renal failure 2 year mortality 58 vs. 31% Mechanisms: Interstitial nephritis Ca++, uric acid, drugs, etc. Tubular necrosis Cast nephropathy Light chain deposition, tubular atrophy (MIDD) Amyloidosis Reversible 20-70% Creatinine< 500 mmol/l Proteinuria < 1 gr/ day Ca++ > 3 mmol/l Blade et al, Arch Int Med 1999; Leung et al, Kidney Int 2008

36 Clinical Problems: Renal Failure Management Supportive Hydration, alkalynisation of urine, biphosphonates (CrCl > 30 ml) Omit nephrotoxins, radiological contrast media, furosemide Prognosis related to response to therapy Plasmapheresis Useful to clear light chains (for MIDD only) If > 50% reduction response in 80% Renal replacement High cut-off dialyser to remove light chains Chronic haemodialysis Median survival 2 years Specific therapy VAD 40% CR; 20% PR Bortezomib based 75% CR High dose melphalan AST

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38 Myeloma Drugs Bach NEJM 2009; 360:

39 Monthly and Median Costs of Cancer Drugs at the Time of Approval by the FDA from 1965 through 2008 Bach NEJM 2009; 360:

40 Risk Adapted Therapy Age Renal function Co morbid conditions Risk Profile Geography Access Patient Preference

41 Conclusions Multiple myeloma is a heterogeneous malignancy Adverse factors include high ISS, adverse cytogenetics and poor response to initial therapy Older age and aggressive disease remain substantial challenges Myeloma has become a chronic disorder for patients with favourable prognostic factors Combination of newer drugs, with older cytotoxic agents lead to a new paradigm New agent are costly staining health resources