MULTIPLE MYELOMA. Dr Malkit S Riyat. MBChB, FRCPath(UK) Consultant Haematologist

MULTIPLE MYELOMA Dr Malkit S Riyat MBChB, FRCPath(UK) Consultant Haematologist

Multiple myeloma is an incurable malignancy that arises from postgerminal centre, somatically hypermutated B cells. Median survival for patients diagnosed with MM ranges from 3-5 years, with variation largely dictated by genetic heterogeneity. Non-random somatic mutations in CDR s of Ig heavy chains indicates characteristics of an antigen driven process N Engl J Med(2004) 351:860

International staging system for plasma cell myeloma Stage Criteria Median Survival (mo.) I Serum β2-microglobulin <3.5 mg/l 62 Serum albumin >3.5g II Not stage I or III* 44 III Serum B2-microglobulin >5.5mg/L 29 *There are two categories for stage II: serum β2-microglobulin <3.5 mg/l but serum albumin <3.5g/dL; or serum β2-microglobulin 3.5 to <5.5 mg/l irrespective of the serum albumin level [From Greipp PR, etal International staging system for multiple myeloma. J Clin Oncol 2005;23:3412-3420]

Cytogenetic prognostic groups Unfavorable risk: Deletion 13 or aneuploidy by metaphase analysis t(4;14) or t(14;16) or t(14;20) by FISH Deletion 17p13 by FISH Hypodiploidy Favorable risk: Absence of unfavorable risk genetics and presence of: Hyperdiploidy t(11;14) or t(6;14) by FISH [Modified from: Stewart AK, etal. Leukemia 2007;21:529-534]

INCIDENCE 1% of all malignancies in caucasians 2% of all malignancies in blacks 10%-20% of all haematologic malignancies M: F = 1.4:1 J Nat Cancer Inst (2001)93:824 (1988)79:701

PRESENTATION OF MULTIPLE MYELOMA Bone marrow failure Susceptibility to infection Hypercalcaemia Bone destruction pain, pathological fractures Renal failure Amyloidosis

34 plasma cell dyscrasias seen at AKUH, Nairobi (1999-September 2005) Multiple myeloma - 31 MGUS - 1 Smoldering multiple myeloma - 1 Waldenstroms Macroglobulinemia - 1

Total of 34 cases identified 7 7 5 4 5 3 3 1999 2000 2001 2002 2003 2004 2005

Which is the proliferative myeloma cell pool? Myeloma cells display morphology of mature plasma cells Myeloma cells are not capable of sustained proliferation

Does a B-cell precursor of malignant plasma cells exists in bone marrow and peripheral blood? VDJ rearrangement and generation of CDRs and heavy chain switching indicates that this is so

B cell maturation: from naïve to an antigen-experienced cell T cell-independent response Unmutated Naïve Plasma cell V D J cμ cγ T-cell dependent Antigen selection Ig somatic mutations class switch Memory Mutated

MULTIPLE MYELOMA B cell malignancy of neoplastic plasma cells which accumulate within the bone marrow Cell expansion and survival dependant on normal bone marrow microenvironment Lancet (2004) 363:875 NEJM (2004) 351:1860

ROLE OF ADHESION MOLECULES IN MYELOMA These play a critical role in pathogenesis of disease progression Mediate homing of myeloma cells to the bone marrow Mediate adhesion of myeloma cells to BMSCs and ECM Adhesion localizes tumor cells to bone marrow microenvironment, stimulates IL-6 transcription and secretion from BMSCs (paracrine growth of myeloma cells)

BONE MARROW MICROENVIRONMENT INFLUENCES Bone destruction Tumor growth and survival Drug resistance

The MM microenvironment consists of Clonal myeloma cells Extracellular matrix proteins Bone marrow stromal cells (BMSC s) Osteoblasts and osteoclasts

Repeated administrations of melphalan at low doses Inflicts only sublethal tumor cell damage Promotes additional mutations, increasing genomic instability Increases risk of t -MDS Compromises PBSC procurement

VAD First effective treatment for MP-resistant myeloma Efficacy mainly due to high dose glucocorticoids Emerged induction therapy of choice prior to HSC procurement

Recent novel therapies target The deregulated intracellular signalling in MM cells Myeloma cell interation with the B.M. microenvironment

Thalidomide as a single agent can induce PR in approximately 30% of patients with refractory myeloma Optimal dose not established Probability for 1- and 2- year survival is 58% and 48% respectively Singhal et al NEJM 341:1565 1999

Thalidomide mechanisms of action Direct inhibition of growth and survival of MM cells Disruption of host marrow-mm cell interaction Inhibition of angiogenesis Induction of apoptosis and G1 growth arrest of MM cells Interferes with DNA binding of nuclear factor KB Immunomodulatory effects - decrease levels of TNF α - activation and expansion of T-cells - augment NK cell-mediated cytoloxicity

Bone targeting modalities Bisphosphonates (pamidronate-zolendronateibandronate) - Delay onset of skeletal events - Induce osteoclast apoptosis - Reduce IL-6 levels (antiapoptotic molecule) - Directly induce myeloma cell apoptosis