1. Myeloma 101 and Standards of Care for Myeloma
Joanne Hewitt PhD, NP, CON(C)
Nurse Practitioner
Cross Cancer Institute
October 13, 2018
MASS Education Conference

2. What Is Multiple Myeloma?
Cancer of the plasma cells in bone marrow
Growth of myeloma cells:
Disrupts normal bone marrow function
Reduces normal immune function
Results in abnormal production and release of monoclonal protein into blood and/or urine
Destroys and invades surrounding bone
Barlogie B, et al. In: Williams Hematology; Durie BG. IMF 2007.BG. IMF 2007. 2

3. Canadian Statistics - 2017 Incidence: Canada: Alberta
Total:
Males:
Females:
Per 100,000: (M = 9.1; F = 5.6) M = 7.9; F = 5.4
Canadian Cancer Society: 2017
2nd most common blood cancer; 1% of all cancers; 2% of all cancer deaths; median age at diagnosis = 65-69; 5 year net survival in Canada = 42%
15% of cases diagnosed before age 55; slightly more common among males; higher in African Americans (2:1) than in Caucasians
The highest incidence of MGUS, smoldering, and symptomatic myeloma is actually on the African subcontinent, and the lowest incidence, is in China and the Far East.

4. Normal bone marrow produces 2. 5 billion red cells, 2
Normal bone marrow produces 2.5 billion red cells, 2.5 billion platelets & 1 billion granulocytes per kg of body weight per day. Production rate depends on body’s needs – under stress the production may increase 5-10 fold
Red blood cells carry oxygen from the lungs to the rest of the body and return carbon dioxide to the lungs.
Platelets help the blood to clot when a blood vessel is damaged.
White blood cells help prevent and fight infection by destroying bacteria, viruses and other foreign cells or substances.
Neutrophils and monocytes fight infection by ingesting (eating) or engulfing (surrounding) foreign cells, such as bacteria.
Eosinophils helps control inflammation and allergic reactions. They attack and destroy certain parasites.
Basophils have a role in certain allergic reactions.

5. Normal Plasma Cell Function
Origins of plasma cells
Normal immunoglobulin molecule containing paired heavy chains with one smaller light chain attached to each
Like most blood cells, plasma cells develop from stem cells in the bone marrow. Stem cells can develop into B cells (B lymphocytes), which travel to the lymph nodes, mature, and then travel throughout the body.
Part of humoral immunity. When foreign substances (antigens) enter the body, B cells develop into plasma cells that produce immunoglobulins (antibodies) to help fight infection and disease.
Myeloma Plasma cell: malignant
Immunoglobulins (Ig) are Y-shaped protein molecules, called antibodies, that are made by plasma cells. An immunoglobulin is made up of 4 parts called chains. There are 2 light chains and 2 heavy chains that are attached to each other by chemical bonds.
There are 5 types of immunoglobulins – IgG, IgA, IgM, IgD and IgE. Each of the 5 types of immunoglobulins is named after the type of heavy chain that it contains.
light chains – kappa, lambda
heavy chains – G, A, M, D, E
Each mature plasma cell produces thousands if identical Ig every second

6. Myeloma Plasma Cells
Normally, plasma cells make up about 2%–3% of the cells in bone marrow. In people with multiple myeloma, abnormal plasma cells make up at least 10% of the cells in the bone marrow.
Malignant plasma cells from a single clone produce one type of Ig
i.e. billions of cancer cells each secreting thousands of identical Ig every second.
Billions of cancer cells each secrete thousands of identical Ig every second
NCI :

7. Monoclonal Protein Also referred to as: M-protein Para-protein M-spike
Bence Jones Proteins (urine light chains)
Dr. Henry Bence Jones
1813 – 1873
When B cells develop into abnormal plasma cells (myeloma cells), they make large amounts of one type of immunoglobulin (called a monoclonal immunoglobulin) and release it into the blood. This monoclonal immunoglobulin is also called an M-protein or paraprotein. An M-protein can be measured in the blood and urine. If a lab test finds an M-protein, there is a problem with the plasma cells.
Sometimes the myeloma cells don’t make whole immunoglobulins and only release the light chains into the blood. These light chains aren’t attached to heavy chains (called free light chains). When free light chains are found in the urine, they are also called Bence-Jones proteins.

8. Distribution of Monoclonal Proteins in MM
Serum electrophoresis can detect the high quantities of M protein being secreted by the neoplasm (M protein spike). In 97% of patients, protein is present in serum or urine, or both. About 75% have M protein in urine alone; 3% will show no protein but have MM. The major M protein is usually of the IgG class, however
Kyle RA et al. Mayo Clin Proc. 2003;78:21
International Myeloma Working Group. Br J Haematol. 2003;121:749
Jacobson JL et al. Br J Haematol. 2003;122:441 8 8

9. Kyle & Rajkumar, Blood, 2008
Timeline depicting the history and treatment of multiple myeloma from 1844 to the present.

10. Calcium, renal insufficiency, anemia, bone lesions

11. MGUS – 1-2/100 adults > 50 yrs;
Smoldering (asymptomatic) MM – 5-7/1,000,000
Symptomatic MM – 40% of pts with MM have M protein level < 30 g/L; 5% of pts have < 10% plasma cells in bone marrow.

12. Presenting Features of MM
Kyle et al reviewed the records of 1027 patients in whom a diagnosis of MM was initially diagnosed at the Mayo Clinic in Rochester, Minnesota, USA, from January 1, 1985, to December 31, 1998, to determine the clinical and laboratory features of newly diagnosed patients with the disease
The initial findings were bone pain in 58% of patients, anemia in 73%, renal insufficiency (serum creatinine ≥176 mmol/l) in 19%, hypercalcemia in 13%, a palpable liver in 4%, and a palpable spleen in 1%. 97% of patients had serum/urine M-protein
Amyloidosis was found in 4% of the patients; an additional 2% developed the disorder 30 days after the diagnosis of MM was established
Kyle RA et al. Mayo Clin Proc. 2003;78:21 12 12

13. Bone Destruction Types of bone cells:
Osteoblasts – make bone
Osteoclasts – break down & remodel bone as bones grow or if there is stress on the skeleton
In normal adult bone, the activity of both of these types of cells is balanced so that bones do nto weaken or keep getting bigger
When osteoclasts work faster than osteoblasts, bone becomes weak. When osteoblasts work faster than osteoclasts, bone gets bigger and stronger
In multiple myeloma, myeloma cells stop osteoblasts from making new bone. Myeloma cells also make osteoclasts work harder to break down bone, so bone gets weaker. Osteoclasts also make chemicals called cytokines that stimulate myeloma cells to grow and divide.

14. The combination of myeloma cells collecting in the bone marrow and osteoclasts breaking down bone causes it to become weak and thin. Areas of bone weakness can be seen on an x-ray as thin, dark lines called fractures or dark circular spots called osteolytic lesions. Osteolytic lesions may mean that there is a plasmacytoma or other disease of the bone. Weakened bone may break under normal stresses like walking, lifting and coughing. Thinning of the bone can also lead to osteoporosis.
Bone disease occurs in 80–90% of myeloma patients. The development of bone disease, either focal or diffuse, can result in pain, pathological fractures, spinal cord compression and hypercalcaemia. Skeletal events compromise mobility and day-to-day independence, decrease quality of life and increase overall treatment costs.

15. Renal Impairment Common – 20-25 % of patients at diagnosis
- up to 50% at some time during disease course
Approx. half of these will have some degree of persistent renal impairment, with 2-12% requiring dialysis
Cause: damage to renal tubules by free light chains (cast nephropathy or “myeloma kidney”)
Other factors can also contribute to this damage
Renal failure occurs as a result of damage caused to renal tubules by free light chains (cast nephropathy, or ‘myeloma kidney’). A variety of other nephrotoxic processes may also contribute to this damage including dehydration, hypercalcaemia, nephrotoxic drugs and infection. The risk of renal damage is directly proportionate to the level of urinary free light chain excretion and not attributable to the light chain class or the presence or absence of whole
M-proteins. Only 2% of patients without urinary free light chain excretion have renal impairment. This percentage
increases to 50% with higher levels of urinary free light chain excretion.

16. Standard Therapy for Newly Diagnosed Multiple Myeloma

17. Treatment – Transplant Eligible
Induction chemotherapy
Cyclophosphamide, bortezomib, dexamethasone (CyBorD or CVD) for 4 to 6 cycles
Mobilization and collection of peripheral blood stem cells
Transplant
High dose melphalan and autologous stem cell transplant (ASCT)
Consolidation/Remission Maintenance
Lenalidomide
Bortezomib (for those with higher risk cytogenetics (del 17p).

18. Treatment – Non-Transplant Eligible
Induction chemotherapy
Cyclophosphamide, bortezomib, dexamethasone (CyBorD or CVD) for 9 – 12 cycles
Maintenance
Bortezomib every 2 weeks for 2 years OR
Lenalidomide and dexamethasone
Clinical Trial
Which one is recommended depends on presenting symptoms, organ function, co-morbidities, pt preference

19. Getting to Minimal Residual Disease: New Definitions for CR
Newly diagnosed
1 x 1012
S.S. Patient
Disease burden CR
1 x 108
Stringent CR
CR, complete response.
So, if our goal is to get patients ultimately to a CR, is there any benefit for ongoing therapy or maintenance therapy in the context of achieving a CR with either conventional therapy or conventional therapy and high-dose therapy? This figure can illustrate the idea that while we may achieve a CR, what you can see here is that if you think about the total disease burden being an iceberg, we have a lot further down to go to really get patients to molecular of flow cytometric CR, or, ultimately, to cure. And the way that we are going to do this is to drive the disease beyond CR, to go beyond stringent CR, and to really push to molecular flow CR if we are going to ultimately cure patients.
Bortezomib
Lenalidomide
Combinations
1 x 104
Molecular/flow CR
?Cure?
0.0

20. MM Disease Progression20

22. Therapy for Relapsed Disease

23. Medications Available to Treat Myeloma
Proteasome Inhibitors (Pls)
Bortezomib (s/c)
Carfilzomib (iv)
Ixazomib (oral)
Immunomodulatory agents (IMiDs)
Thalidomide (po)
Lenalidomide (po)
Pomalidomide (po)
Monoclonal Antibodies
Daratumumab (iv)
Alkylating Agents
Cyclophosphamide (po or iv)
Melphalan (po or iv)
Other Chemotherapy Agents
Doxorubicin (iv)
Etoposide (po or iv)
Cisplatin (iv)
Steroids
Dexamethasone (po or iv)
Prednisone (po)
Transplant
Autologous stem cell
Agarwal A et al. Clinical Lymphoma Myeloma and Leukemia 2016;

24. RELAPSED / REFRACTORY MULTIPLE MYELOMA Management
When to treat?
Treatment indicated when patients develop symptomatic relapse, a rapidly rising monoclonal protein level, or extramedullary disease
General Management:
A patient naïve to an agent (or class of agents) is generally treated with that agent
A second transplant can be considered in selected patients if the benefit from the first exceeds months
A patient with relapsed myeloma who has not previously undergone ASCT, can be considered for high-dose therapy (if they can tolerate high-dose therapy)
A patient who responded to a particular doublet with previous duration of response (DOR) of ≥6–9 months can be retreated at relapse with similar agents
Consider adding an alkylator to a doublet regimen if the desired response is not seen
Duration of therapy:
Determined by clinical context
Treatments:
Combine treatments with different mechanisms of action
Depends on previous therapies and response durations, marrow reserve, and comorbidities
Laubach L, et al. Leukemia 2016;30:1005–17; doi: /leu
Nooka AK, et al. Blood 2015;125(20):3085–99. 24 24

25. General Treatment Principles
Patient Considerations
Disease Considerations
Evidence / Access
Refractory to previous treatment
1st, 2nd, 3rd relapse
Depth and duration of response
Genetic features of myeloma
Pace of disease
Consider triple therapy where possible
Evidence to support treatment decision
Is clinical trial an option
Funding situation
Patient support systems
Is the patient a transplant candidate?
Comorbidities
Patient adherence
Patient preferences
Side effects of treatment
Laubach L, et al. Leukemia 2016;30:1005–17; doi: /leu
Nooka AK, et al. Blood 2015;125(20):3085–99.

26. Patient and Caregiver Education
Landgren, Medscape Education, 2016

27. Contributing Factors to Fatigue
Dexamethasone – try taking at night rather than AM – works for some pts
Dose modifications may be required if fatigue severe & impacting daily activities/QofL
Other medications that may impact – eg. analgesics, sedatives etc.
Hypercalcemia
Borneman 2013 Journal of Hospice & Palliative Nursing

28. Individualized assessment - sleep, nutrition, depression, medications, activities, comorbidities
Balance activity & energy conservation
Nutrition consultation
Sleep evaluation (i.e for sleep apnea);
Check thyroid function – lenalidomide can contribute to hypothyroidism/lead to requirement for increased doses of synthroid supplementation

29. Kurtin, S., APSHO Regional Lecture Series

30. Summary
Chronic disease with need for continuous therapy & regular hospital visits, blood tests, F/U visits with various HCPs
Drug therapy monitoring:
Medication review for drug interactions
Adjust regimens as needed for renal dysfunction
Adherence: drug calendars & patient buy-in for continuous therapy
Ensure proper monitoring of blood counts requiring dose adjustments
Patient education:
Educate patients on adverse events and strategies for managing them
Education on how to take multi-drug treatments properly
Reinforce adherence with oral regimens
Supportive care:
Nausea/vomiting, anemia, pain management, etc
Prophylactic anticoagulation when required, monitoring and adjustment of doses
Viral prophylaxis
Bisphosphonates
Monitor for infection
Ashjian E, Redic K. J Oncol Pharm Practice 2016;22(2):

31. THANK YOU