Research Project

1. MULTIPLE MYELOMA
OSCAR KWAN
PHARM.D 2018 CANDIDATE
ST. JOHN’S UNIVERSITY

2. KEY STATISTICS
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Multiple Myeloma is a relatively uncommon cancer.
In the United States, the lifetime risk of getting multiple myeloma is 1 in 132 (0.76%)
The American Cancer Society’s estimates for multiple myeloma in the United States for 2018 are:
• About 30,770 new cases will be diagnosed (16,400 in men and 14,370 in women)
• About 12,770 deaths are expected to occur (6,830 in men and 5,940 in women)
• Slightly more common in men than women
• Twice as common among Blacks as among Whites
• Average age at diagnosis is 65 – 70 years

3. WHAT IS MULTIPLE MYELOMA?
• A CANCER of plasma cells (fully mature B cell)
• Lymphocytes: Main types of WBCs (B cells, T cells, NK cells)
• Overproduction of monoclonal Antibodies (immunoglobulins)
• Adaptive Immunity vs. Innate Immunity
3

4. PATHOLOGY
• Bone Marrow: Home site for hematopoiesis (Disrupted balance in Multiple Myeloma)
• Neoplastic proliferation in the bone marrow of a SINGLE CLONE of malignant plasma cells
• Immortal cancerous plasma cells accumulate and deplete the production of normal healthy blood cells
• Production of abnormal antibodies known by monoclonal immunoglobulin, M-protein, monoclonal protein,
M-spike, or paraprotein
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5. RISK FACTORS
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• Genetic predisposition (Familial clusters of Multiple myeloma has been reported)
• Environmental factors:
q Radiation exposure (Hiroshima and Nagasaki atomic bomb survivors, Radiologists, Nuclear plant workers)
q Organic chemicals (Aromatic hydrocarbons; benzene)
q Herbicides
q Insecticides
• Old age ≥65 years old
• Gender: Male > Female
• Race: African Americans >2x more common than White Americans
• Weight: Overweight or Obesity (↑ BMI 5 kg/m2 = ↑ 11% Risk)
• Plasma cell diseases: MGUS (Monoclonal Gammopathy of Undetermined Significance)
Solitary plasmacytoma
SMM (Smoldering Multiple Myeloma)

6. RISK STRATIFICATION
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High-Risk Cytogenetics: 15% of MM patients
1. Deletion of a piece (p13) of Chromosome 17
2. Translocation between Chromosomes 14 and 20
3. Translocation between Chromosomes 14 and 16
4. Elevated Lactate dehydrogenase levels 2x ULN (200 units/L)
• Associated with poor prognosis and shorten survival
• Requires more aggressive treatment

7. RISK STRATIFICATION
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Intermediate-Risk Cytogenetics: 10% of MM patients
1. Translocation between Chromosomes 4 and 14
Standard-Risk Cytogenetics: 85% of MM patients
1. All patients that lack High-risk and Intermediate-risk
genetic abnormalities
2. Estimated median survival of 8 – 10 years

8. ETIOLOGY
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The cause of Multiple Myeloma remains unknown.
Genetic mutations: Recent studies have shown primary cytogenetic abnormalities play a major role in MM development
1. MYC oncogene – Plasma cell tumors
2. RAS oncogene – Myeloma cells in the bone marrow after treatment
3. p53 tumor suppressor gene – Metastasis to other organs
4. Immunoglobulin Heavy Chain Translocations = “Class Switching” or “Switch Recombination”
v 11q13 – cyclin D1 gene
v 6p21 – cyclin D3 gene
v 4p16.3 – multiple myeloma set domain (MMSET)
v 16q23 – musculoaponeurotic fibrosarcoma (c-maf)
v 20q11 – musculoaponeurotic fibrosarcoma oncology family, protein B (mafB)

9. TRIGGERS OF GENETIC MUTATIONS
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Abnormal overproduction of Toll-like receptors and IL-6 receptors
Antigenic Stimulation
Abnormal and sustained growth signal
Increased proliferative rate of plasma cells
Increased risk of chromosomal changes and damage
Creation of a plasma cell clone
Overproduction of a single type of immunoglobulin
Toll-like receptors

10. CLINICAL PRESENTATION
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The signs and symptoms of MM are caused by the infiltration of plasma cells into the bone or other organs.
• Anemia
• Bone pain
• Osteolytic bone lesions (↑ Osteoclasts, ↓ Osteoblasts)
• Elevated creatinine
• Generalized malaise (fatigue, weakness)
• Hypercalcemia
• Weight loss (≥9 kg)
• Neurological diseases
• Hyperviscosity
• Frequent infections

11. RETROSPECTIVE ANALYSIS
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Institution: Mayo Clinic
Location: Rochester, Minn
Objective: To determine the clinical and laboratory features of newly diagnosed multiple myeloma.
Methods: Records of 1,027 patients in whom Multiple Myeloma was initially diagnosed from January 1, 1985 to
December 31, 1988 were reviewed.
Patients:
• 2% were younger than 40 years old
• 38% were 70 years old or older
• Median Age: 66 years old
Conclusion: The median duration of survival was 33 months and did not improve from 1985 through 1998.

12. ANEMIA
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• Based on the Mayo Clinic retrospective analysis:
v Normocytic, Normochromic
v Hgb ≤12 g/dl
v 73% of 1,027 patients at diagnosis
v 97% of 1,027 patients during the course of the disease
• Precipitating Causes:
v Bone marrow replacement by malignant plasma cells
v Kidney damage (↓ EPO hormone)
v Dilution due to large M-protein
• Symptoms:
v Fatigue
v Pallor
v Weakness
v Heart palpitations

13. BONE PAIN
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• Based on the Mayo Clinic retrospective analysis:
v Back or chest, less often in the extremities
v 60% of 1,027 patients at diagnosis
v Induced by movement
v Does NOT occur at night except with change of position
v Vertebral collapse à Reduction of height by several inches
v Plasmacytomas of the ribs

14. RENAL DISEASE
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• Based on the Mayo Clinic retrospective analysis:
v 20% of 1,027 patients’ SCr was >2 mg/dL
v Kidney failure à requires emergent treatment
v Symptoms: Weakness, shortness of breath, Itching, Leg swelling
• Precipitating Causes:
v Light chain cast nephropathy “Myeloma Kidney”: >1,500 mg/dL of free light chain levels
v Hypercalcemia
• Other causes:
v Light chain amyloidosis (AL)
v Light chain deposition disease
v Drug-induced renal damage

15. HYPERCALCEMIA
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• Based on the Mayo Clinic retrospective analysis:
v 13% of 1,027 patients’ serum calcium was ≥11 mg/dL
• Precipitating Causes:
v Break down of bone marrow tissue
v Binding of monoclonal protein with calcium
• Symptoms:
v Excessive thirst/Dehydration
v Frequent urination
v Stomach upset
v Nausea and vomiting
v Severe constipation
v Bone weakness
v Lethargy/fatigue
v Loss of appetite

16. NEUROLOGICAL DISEASES
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• Radiculopathy:
v Most common neurological complication of Multiple Myeloma
v Thoracic/lumbosacral area
v Compression of nerve by paravertebral plasmacytoma or collapsed bone
• Cord Compression:
v 5% of patients
v Compression by extramedullary plasmacytoma or bone fragment of vertebral bone fracture
v Symptoms: Severe back pain with weakness, lower extremity paresthesias, bladder/bowel dysfunction
• Peripheral Neuropathy “Pins and Needles”:
v Uncommon in Multiple Myeloma
v If present, due to amyloidosis
• CNS Involvement:
v Intracranial plasmacytomas are rare
v Poor prognosis: Leptomeningeal myelomatosis (Lactate dehydrogenase [LDH] levels ↑)
v Rare: Encephalopathy due to hyperviscosity or high blood levels of ammonia

17. HYPERVISCOSITY
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• Thickening of the blood:
v Large amounts of M-protein
v Slow blood flow to the brain
• Symptoms:
v Confusion
v Dizziness
v One-sided body weakness
v Slurred speech
• Patients with these symptoms should call their doctor
• Plasmapheresis:
v Rapid reversal
v Removal of protein from blood
• CANNOT treat with “BLOOD THINNERS”

18. INFECTION
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• Patients with Multiple Myeloma are at increased risk of infection:
1. Immunocompromised:
v Leukopenia
v Impaired lymphocyte function
v Suppression of normal plasma cell function
v Hypogammaglobulinemia
2. Physical factors:
v Hypoventilation due to bone fracture and pain of the spine or rib cage
• Streptococcus pneumoniae and Gram-negative organisms are the most frequent pathogens

19. DIAGNOSIS
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Criteria:
• Presence of ≥10% plasma cells in the bone marrow
OR
• Biopsy proven plasmacytoma
AND at least one of the following:
v ≥ 60% plasma cells in the bone marrow
v Calcium (Serum Ca2+>11 mg/dL)
v Renal insufficiency (CrCl <40 ml/min or SCr >2 mg/dl)
v Anemia (Hgb <10 g/dL or <2 g/dL below normal)
v Bone lesions: (≥1 osteolytic lesions ≥5 mm in size on skeletal radiography, CT, or PET scan)
It is important to rule out other plasma cell dyscrasias (MGUS, SMM) for appropriate prognosis and treatment.
Treatment of MM is time-dependent, a major delay in diagnosis has been associated with a negative impact on disease course.

20. DIAGNOSTIC TESTS
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• Complete Blood Count:
v Red cells – Anemia
v White cells – Leukopenia
v Platelets – Thrombocytopenia
• Blood Chemistry Tests:
v Creatinine – Kidney function
v Albumin – Low levels in MM
v Calcium – Hypercalcemia
v Lactic dehydrogenase – High levels in more advanced MM with worse prognosis
v Beta-2 microglobulin – Prognosis indicator
• Blood Protein Tests:
v Serum Protein Electrophoresis (SPEP) – measures blood levels of intact whole monoclonal antibodies
v Immunofixation – determines the exact type of abnormal antibody

21. MONOCLONAL ANTIBODY
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Light chain ( λ, κ)
Normally, present in
equal amounts in
the blood; (1:1) ratio Bence Jones protein:
Light chains of M protein.
If found in the urine,
suggestive of Multiple Myeloma.

22. DIAGNOSTIC TESTS
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• Serum Free Light Chain (FLC) Analysis:
v Measures blood levels of light chain fragments
v Helpful when no whole M protein is found in SPEP
v Sign of Myeloma: Ratio of lambda to kappa light chains is NOT 1:1
• Urine Tests:
v Urine Protein Electrophoresis (UPEP): Detects proteinuria over a 24-hour time period
v Urine Immunofixation: Characterizes urine proteins
• Bone Marrow Aspiration and Biopsy:
v Immunohistochemistry: Special proteins identifies myeloma cells through color changes
v Flow cytometry: Bone marrow is treated with special proteins that stick only to cancer cells
v Fluorescent In Situ Hybridization (FISH): Locates translocations and deletions using fluorescent dyes
v Cytogenetics: Evaluates chromosomes for abnormalities to predict prognosis
• Fine Needle Aspiration Biopsy:
v Withdraw tissue from tumor or enlarged lymph node using a very thin needle and syringe
v Advantage: Does NOT require surgery
v Disadvantage: Insufficient amount of tissue removed due to thin needle

23. WHEN SHOULD TREATMENT START?
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• Treatment depends on many factors:
v Age
v Comorbidities
v Presence of symptoms
v Stage of multiple myeloma
v Genetic risk level
• Weigh the risks against the benefits of treatment with your doctor
Risk
Benefit

24. 24
SYSTEMIC
THERAPY

25. CHEMOTHERAPY
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• Stops or slows cancer cells’ ability to grow and divide
• Enters the bloodstream and reaches almost all areas of the body (NON-TARGETED THERAPY)
• Routes of Administration:
v PO
v IV
• Chemo drugs used to treat MM include:
v Melphalan (AlkeranTM)
v Vincristine (Oncovin®)
v Cyclophosphamide (Cytoxan®)
v Etoposide (Toposar®)
v Doxorubicin (Adriamycin®)
v Liposomal doxorubicin (Doxil®)
v Bendamustin (Treanda®)

26. CHEMOTHERAPY
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• To increase effectiveness, combined with other types of treatment, such as:
v Targeted therapies
v Corticosteroids
• If a stem cell transplant is planned, avoid using bone-marrow damaging chemo drugs (e.g. Mephalan)
• Chemo drugs kill cancer cells, but also can damage normal cells
• Dose carefully to avoid or reduce side effects of chemotherapy
• Common side effects of chemotherapy:
v Alopecia
v Mouth sores
v Loss of appetite
v Nausea, vomiting, and diarrhea
v Pancytopenia
v Peripheral neuropathy
v Hemophilia

27. TARGETED THERAPY
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• Immuno-modulating agents: Suppression of angiogenesis, strengthen immune attack on cancer cells
v Thalidomide (Thalomid®, Synovir®): severe constipation, permanent neuropathy, blood clots (DVT, PE)
v Lenalidomide (Revlimid®): thrombocytopenia, leukopenia, neuropathy, lower blood clot risk
v Pomalidomide (Pomalyst®): anemia, leukopenia, less severe neuropathy, thromboembolism
• Proteasome inhibitors: Activates the apoptosis of cancer cells by inhibiting the breakdown of proteins that control it
v Bortezomib (Velcade®): IV/SQ once or twice a week
SQ preferred, due to less peripheral neuropathy
May cause shingles (prevent with acyclovir)
v Carfilzomib (Kyprolis®): IV every 4 weeks
Allergic reactions (prevent with dexamethasone before each dose in 1st cycle)
Serious side effects (pneumonia, heart, kidney/liver failure)
Alternative if other drugs failed
v Ixazomib (Ninlaro®): PO once weekly for 3 weeks, then 1 week off
Alternative if other drugs failed

28. TARGETED THERAPY
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• Histone deacetylase (HDAC) inhibitors: Uncoils DNA & activates genes for apoptosis, blocks aggresome (escape route)
v Panobinostat (Farydak®): PO three times a week for 2 weeks, then 1 week off
Common side effects (NVD, fatigue, arm/leg swelling, fever, weakness)
Severe side effects (electrolyte imbalance, internal bleeding, liver damage, arrhythmias)
• Monoclonal antibodies: Bind to antigens of myeloma cells and label them for immune attack and removal
v Daratumumab (Darzalex®): Attaches on the CD38 protein
IV infusion
Acute allergic reactions (coughing, wheezing, SOB, chest tightness, rhinitis, rash)
Side effects (back pain, nausea, fatigue, fever, cough, bruising, bleeding)
Alternative if other drugs failed
v Elotuzumab (Empliciti®): Attaches on the SLAMF7 protein
IV infusion
Acute allergic reactions (coughing, wheezing, SOB, chest tightness, rhinitis, rash)
Side effects (peripheral neuropathy, upper respiratory tract infections, loss of appetite)
Alternative if other drugs failed

29. OTHER DRUG THERAPIES
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• Corticosteroids: Decrease nausea and emetogenic potential of chemotherapy
v Dexamethasone (Decadron®)
v Prednisone (Intensol®)
v Given alone or in combination with chemotherapy
v Side effects: Hyperglycemia
Weight gain
Increased appetite
Insomnia
Agitation
Weak bones
Immunosuppression
Diaphoresis
Hiccups
v Most of these side effects are temporary, and go away after stopping treatment

30. OTHER DRUG THERAPIES
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• Bone-modifying Agents: Strengthen bones, reduce bone pain, and decrease the risk of bone fractures
v Bisphosphonates: Decreases bone resorption by inhibiting osteoclastic activity
1. Zoledronic acid (Zometa®): 4 mg IV over 15 minutes every 3 – 4 weeks
NOT recommended in renal impairment
2. Pamidronate (Aredia®): 60 – 90 mg IV over at least 2 hours every 3 – 4 weeks
Dose decreased over longer time in renal impairment
3. Common side effects: Flu-like symptoms, join pain, anemia, muscle pain
4. Osteonecrosis of the Jaw (ONJ): Infection and death of jaw bone à Open sores, tooth loss, jaw pain
Triggered by tooth removal or jaw surgery, AVOID them!
Maintain good oral hygiene (flossing, brushing, properly-fitted dentures)
Have regular dental checkups
Treat tooth or gum infections right away
If ONJ occurs, stop bisphosphonate immediately
v Denosumab (Xgeva®): 120 mg SQ every 4 weeks
Monoclonal antibody to RANK (Receptor Activator of Nuclear Factor Kappa B) ligand
Better option for patients with severe kidney disease
More expensive, but equally efficacious to bisphosphonates

31. STEM CELL TRANSPLANT
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• Replacement of cancer cells with hematopoietic stem cells, that develop into healthy RBCs, WBCs, & platelets
• If successful, leads to remission and prolonged survival
• Limitations: Not curative, relapse after transplantation due to residual cancer cells left after chemotherapy
• Source of blood stem cells:
v Allogeneic (ALLO): Donated stem cells of matching tissue type
v Autologous (AUTO): Patient’s own stem cells from blood or bone marrow (MORE COMMON)
• In most U.S. centers, patients with one or more of the following are NOT eligible for autologous stem transplant:
v Age >77 years
v Direct bilirubin >2.0 mg/dL (34.2 µmol/liter)
v Eastern Cooperative Oncology Group (ECOG) score of 3 or 4 unless due to bone pain
v New York Heart Association functional status Class III or IV

32. AUTOLOGOUS STEM CELL TRANSPLANT
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33. LOCAL THERAPY
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• Treats cancer tumor without affecting the rest of the body
• More useful for earlier stage (less advanced) cancers
• Types:
v Surgery: Used to relief symptoms of MM, does NOT treat the disease
Spinal cord compressions à paralysis, severe muscle weakness, numbness
Remove single plasmacytomas
Prevent or treat bone fractures with metal plates and rods
v Radiation: Use of high-energy rays or particles to kill cancer cells
Eases bone pain unresponsive to other drugs
Prevents paralysis in spinal cord collapse
External beam radiation therapy: machine outside the body
Side effects: skin changes in treated area (redness, peeling, blistering), fatigue,
nausea, diarrhea, low blood counts [SEs go away once treatment is over]

34. SUPPORTIVE CARE
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• Antibiotics: To treat or prevent infections due to leukopenia
• Pain medications (Tylenol, Opiates, AVOID NSAIDs): To alleviate bone pain
• Antivirals: To prevent viral infections such as herpes zoster, particularly treatment with proteasome inhibitors
• Blood thinners: To prevent blood clots in patients treated with immuno-modulating agents
• Antidepressants: To help cope emotionally with cancer battle and/or treat neuropathy
• Exercise: To maintain bone strength, reduce loss of calcium, and prevent fatigue
• Drinking water: Hydrate with adequate amount of fluids to flush out impurities from the blood and kidneys
• High-calorie protein diet: Prevent fatigue and infection
• Rest: Reduce stress and fatigue, increase overall health

35. REFERENCES
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36. REFERENCES
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