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Multiple Myeloma Malignant proliferation of plasma cells. Normal plasma cell form Ig which contain heavy and light chain Normal variety of Ig polyclonal & each contain Kappa & Lambda light chain Myeloma plasma cell : Ig of single heavy and light chain lead to monoclonal protein (para protein) In some light chain may be only produced and appear in urine as Bence-Jones proteinuria. Incidence : 4 new cases/100,000 peoples/year. Sex ratio : M:F → 2:1 Age : median age 60-70 years. Etiology : Unknown,chemical, enviromental

Classification of MM Paraprotein frequency % IgG 55% IgA 21% Light chain only 22% Other (D, E, non secretory) 2% The diagnosis of MM requires two of the following marrow plasmacytosis. Serum and/or urinary paraprotein + ≥ 1 of `` CRAB``

MM: Clinical Manifestations Series of genetic mutations, translocations, normal cell turns malignant Hallmarks of myeloma: CRAB (also known as myeloma defining events;MDE) C = Hypercalcemia R = Renal Complications MM, multiple myeloma; MDE, myeloma-defining events FROM PREVIOUS SLIDE: Multiple Myeloma is generally symptomatic. Unlike with MGUS or SMM, there is end organ damage—CRAB criteria-- Calcium elevation (serum calcium >11.5 mg/dL) Renal insufficiency (serum creatinine >2 mg/dL) Anemia (hemoglobin <10 g/dL or 2 g/dL <normal) Bone disease (lytic lesions or osteopenia) Recurrent infections* A = Anemia * Not an MDE, yet relatively common B = Bone Disease Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

Multiple Myeloma Symptoms Effect Pathology Pain Severe local pain Lethergy, thirst Anaemia& tiredness Bone erosion due to stimulation of oesteoclast. Pathological fracture Hypercalcaemia BM failure Marrow involvement with malignant plasma cell Renal damage Increased blood viscosity Amylidosis -renal damage Excess production of light chains and paraprotein Infection (Resp.) Impaired immune function Reduction in number of normal plasma cells

Clinical features Weight loss ,malaise and fatigue. Bone pain found in 60% of cases at the back and ribs. Anorexia , diarrhea, vomiting, constipation, polyuria, polydipsia occur with hypercalcemia in 30%, Renal impairment due to hypercalcaemia and dehydration present in 50% . Pneumococcal, chest and urinary tract infection due to low immunoglobulin(Ig) production. Headache , Confusion, Breathlessness, Visual Disturbance and bleeding can occur secondary to hyperviscosity (IgA). 5% present with paralysis secondary to spinal cord compression by extra-dural plasma cell mass. Carpal-tunnel syndrome, nephrotic syndrome, cardiac failure and neuropathy secondary to amyloid deposition.

Absence of immunoparaesis should cast doubt on diagnosis. Only about 5% of pts with ESR persistently above 100 mm in the 1st hour have meyeloma.

Revised IMWG Criteria (2014) MM, multiple myeloma; IMWG, International Myeloma Working Group; SPEP, serum protein elecrophoresis; UPEP, urine protein electrophoresis; CMP, complete chem panel ; CBC + diff, complete blood count with differential; k/l, kappa/lambda; MPA, monoclonal protein analysis; cyto, cytogenetics; GEP, gene expression profiling; MRI, magnetic resonance imaging; CT, computed tomography; FISH, fluorescence in situ hybridization; Clonal evolution in a permissive microenvironment. Progression from MGUS to SMM to symptomatic MM involves clonal evolution and heterogeneity, which is not only cell autonomous but also dependent on the interactions of the tumor cells with the bone marrow microenvironment. This includes immune cells such as T-regulatory cells (Tregs), myeloid derived suppressor cells (MDSCs), natural killer (NK) cells, osteoclasts, osteoblasts, angiogenesis, and MSCs. Republished with permission of American Society of Hematology, from Ghobrial, IM, et al. How I treat smoldering multiple myeloma, Blood. 2014;124:3380-3388; permission conveyed through Copyright Clearance Center, Inc.

Initial Approach to Treatment of Myeloma Transplant Candidate Nontransplant Candidate (based on age, performance status, and comorbidities) Induction treatment (4-6 cycles) Induction treatment Maintenance Stem cell harvest Stem cell transplantation Consolidation therapy? Maintenance

Increased Treatment Options in MM MM Therapies Introduction FDA Approved in MM 1950 1960 1970 1980 1990 2000 2010 2015 2008 Bortezomib frontline 1983 Autologous transplantation 1958 Melphalan 2003 Bortezomib 3rd line 2012 Carfilzomib 3rd line; Bortezomib SC 1962 Prednisone 2005 Bortezomib 2nd line 1986 High-dose dexamethasone FDA, US Food and Drug Administration; MM, multiple myeloma; SC, subcutaneous. The treatment options for patients with multiple myeloma have increased greatly over the last decade. You can see by the diagram in this slide that the left half of the timeline represents 40 years and the right half of the diagram represents 20 years. The number of novel agents and combinations developed in the last 2 decades has changed the treatment paradigm for multiple myeloma. These novel agents have also changed the expected survival for patients with multiple myeloma. 1969 Melphalan + prednisone 2006 Lenalidomide + dex 2nd line; Thalidomide + dex 1st line 2013 Pomalidomide 3rd line 2014 Bortezomib retreatment 2007 Doxorubicin + bortezomib 2nd line 2015 Panobinostat 3rd line; Lenalidomide 1st line

Supportive Care Bone: 85% will develop bone disease All should receive monthly bisphosphonates after dental exam; monitor renal function long term Infection: major cause of death in MM Impaired antibody formation after antigenic stimulations Immunizations: pneumococcal (PCV13, PPSV23), seasonal inactivated influenza Shingles prophylaxis (proteasome inhibitor, transplant) Renal: monitor status, dose reductions may be necessary Acute renal failure can occur due to NSAIDs, CT dyes, antibiotics Hydrate (carefully), monitor monthly MM, multiple myeloma; PCV13, pneumococcal conjugate vaccine; PPSV23, pneumococcal polysaccharide vaccine; NSAIDS, nonsteroidal anti-inflammatory drugs; CT, computed tomography. Bilotti E, et al. Clin J Oncol Nurs. 2011;15(suppl):5-8. Miceli TS, et al. Clin J Oncol Nurs. 2011;15(suppl):9-23. Faiman B, et al. Clin J Oncol Nurs. 2011;15 66-76. MMWR. 2014;46:1-24.

Management- Cont… • Allopurinol to prevent urate nephropathy. • Plasmapheresis, if necessary, for hyperviscosity **Chemotherapy with or without HSCT In older patients, thalidomide combined with the alkylating agent melphalan and prednisolone has increased the median overall survival to more than 4 years. In younger, fitter patients, standard treatment includes first-in chemotherapy to maximum response and then an autologous HSCT

Cont.-Management 1-BORTEZOMIB(VELCADE) VTD+Z 2- Thalidomide 3-Lenalidomide(Revlimid) VRD+Z 4- Dexamethasone 5-Bisphosphonate (Zoledronate) Treatment is administered until paraprotein levels have stopped falling. This is termed‘plateau phase’ and can last for weeks or years. Radiotherapy; for localised bone pain and for pathological fractures. It is also useful for the emergency treatment of spinal cord compression complicating extradural plasmacytomas

Long-term Effects of Treatment Diarrhea (lenalidomide) Peripheral neuropathy (bortezomib, MM, diabetes) Secondary cancers Cardiovascular/pulmonary disease Health maintenance is important as patients are at risk for same illnesses as those without MM Financial Chronic illnesses are costly Loss of income, hospital and medical bills can be high Refer to patient care organizations, copay foundations MM, multiple myeloma. Faiman B. J Adv Pract Oncol. 2013;4:354-360. Kurtin S, et al. Clin J Oncol Nurs. 2013;17(suppl):7-11. Faiman B, et al. Blood. 2013;122:5397.

Waldenstrӧm macroglobulinaemia This is a low-grade lymphoplasmacytoid lymphoma associated with an IgM paraprotein. Patients classically present with features of hyperviscosity,such as nosebleeds, bruising, confusion and visual disturbance. Anaemia, systemic symptoms, splenomegaly or lymphadenopathy Investigation; have an IgM paraprotein associated with a raised plasma viscosity. The bone marrow with infiltration of lymphoid cells and prominent mast cells.

TREATMENT 1-Plasmapheresis for anaemia and hyperviscosity. 2- Chlorambucil 3- Fludarabine 4- Rituximab *Monoclonal gammopathy of uncertain significance (MGUS); a paraprotein is present in the blood but with no other features of myeloma, Waldenstrӧm macroglobulinaemia, lymphoma or related disease. The bone marrow may have increased plasma cells but these usually constitute less than 10% of nucleated cells. After follow-up of 20 years, only one-quarter of cases will progress to myeloma or a related disorder (i.e.around 1% per annum)