1. m

2. 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 years.
Etiology : Unknown,chemical, enviromental

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

4. 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.

5. 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

6. 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.

8. 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.

9. 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: ; permission conveyed through Copyright Clearance Center, Inc.

10. 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

11. 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

12. 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; MMWR. 2014;46:1-24.

13. 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

14. 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

15. 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: Kurtin S, et al. Clin J Oncol Nurs. 2013;17(suppl):7-11. Faiman B, et al. Blood. 2013;122:5397.

16. 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.

17. 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)