Extremity:

Multiple Myeloma
Olivia Rozsits

Bone Cancer: Epidemiology

Primary bone cancers account for less than 0.2% of all cancers

Bone metastasis accounts for 60-70% of all bone lesions

Mets occur primarily in the spine and pelvis, less common in extremities

60% of primary bone tumors occur between 10-20 years of age

Incidence of bone cancer is highest during adolescence

Bone Cancer: Etiology and Risk Factors

Genetics (Osteosarcoma and Chordoma)
Paget Disease

Chronic bone disorder characterized by deterioration of bone tissue

that may result in pain, arthritis, and fractures

Radiation
Previous Injuries Possible Cause
Retinoblastoma

Mutation of the RB1 gene which also increases risk of developing bone
or soft tissue sarcomas

Bone Cancer: Histologies

Sarcomas
Fibrosarcoma
Osteosarcoma
Chondrosarcoma

Multiple Myeloma
Non-Hodgkins Lymphoma

Ewings Sarcoma

Giant Cell Tumor

Chordoma

Malignant Fibrous Histiocytoma

Bone Cancer Histologies

Ewing's Sarcoma; 18%

Chordoma; 9%

Fibrosarcoma; 6%

Osteosarcoma; 39%

Chondrosarcoma; 28%

Bone Cancer: Presenting Signs

Pain
Swelling, palpable mass
Pathological fracture
Weight loss, anemia
Fatigue
Numbness, tingling
Distant Mets
Most common?

Multiple Myeloma
Malignant plasma cell tumor
Generally develop in bone, but rarely develop in other tissues
Plasma cells: type of white blood cell that makes antibodies
Isolated Plasmacytoma: a single plasma cell tumor
Multiple Myeloma: more than one plasmacytoma (spreads through the
bone

marrow)

Multiple Myeloma Incidence & Risk Factors

In the U.S. the lifetime risk of developing
MM is 1 in 143 (0.7%)

More common in males than females

Higher incidence in African Americans

Estimates for 2016

Median age at diagnosis is 50-60 years

About 33,330 new cases (17,900 men,

12,430 women)

Familial history increases chance by 4x

as likely

About 12,650 deaths

Plasma cell diseases (MGUS or solitary

plasmocytoma)

Cause is unknown

Multiple Myeloma Incidence per Age

35%
30%
25%
20%
15%
10%
5%
0%

20-30

30-40

40-50

50-60
Age

60-70

70-80

Multiple Myeloma: Presenting Signs

Bone Pain
Renal Failure
Fracture
Monoclonal Gammopathy: condition of having many copies of the same antibody
Light Chain Amyloidosis
Heart problems, enlarged liver and spleen, enlarged tongue, skin changes, diarrhea,
carpal tunnel syndrome
Anemia, Thrombocytopenia, Leukopenia
Infections
Bleeding

Multiple Myeloma Detection

Blood Counts
Quantitative Immunoglobins
Electrophoresis
Free Light Chains
Beta-2 Microglobulin
Bone Marrow Biopsy
Blood Chemistry Tests
(BUN & Cr)

Cytogenetics
Bone x-rays
CT
MRI
PET
Echocardiogram
Measures level of amyloid in heart

Anatomy

Diaphysis: main shaft of the bone

Epiphyses: ends of the long bones

Red Marrow: consists of myeloid tissue,

develops RBCs, platelet and WBCs

Yellow Marrow: mostly fat cells, may

produce some WBCs, replaces the red
marrow in long bones after 5 years of
age

Methods of Spread

Spread by way of bone marrow

niches
Niche: local tissue
microenvironment that
maintain and regulate stem
cells

Staging
International Staging System
System divides myeloma into 3 stages based
only on the beta-2 macroglobulin and albumin
levels

Class

Median Survival

Stage 1

62 Months

Stage 2

44 Months

Stage 3

29 Months

Stage 1: beta-2 macroglobulin less than 3.5 mg/L, and albumin 3.5 g/dL or greater
Stage 2: neither stage 1 or 3
Beta-2 between 3.5 and 5.5
Albumin below 3.5 while beta-2 less than 3.5
Stage 3: beta-2 macroglobulin is 5.5 or greater

Chemotherapy
Systemic treatment useful for
cancers that spread widely
Induction
Consolidation Chemo
Maintenance Therapy

Melphalan

Vincristine
Cyclophosphamide
Etoposide (VP-16)
Doxorubicin
Liposomal doxorubicin
Bendamustine

Radiation

Most common treatment for solitary plasmacytomas

Treat to a dose of 4500-5500cGy
Borders:
Treat affected bone with 2-3cm margin
Spine
Include involved vertebrae and 2 above and 2 below

Stem Cell Transplant

High dose of chemo and possible total body irradiation to deplete cells in the
bone marrow
Autologous Transplant
Patients own stem cells are removed, chemo or radiation to deplete cancer cells, then
stored stem cells infused back into the patient
Tandem: 2 autologous transplants 6 to 12 months apart

Doesnt cure cancer, eventually myeloma will return

Allogenic Transplant
Patient receives stem cells from a donor
Much riskier but may be better at fighting the cancer

Supportive Treatments
Biophosphonates: drugs that help bones stay strong by slowing
down the destruction of bone by myeloma cells
Rare but serious side effect of osteonecrosis of the jaw

Intravenous Immunoglobin (IVIG): antibodies from donors

given to patient to help prevent infection

Plasmapheresis: used to remove myeloma protein from from the

blood
Machine separates blood cells from blood plasma then returns the
blood cells to the patient with either salt solution or donor plasma
Lowers the protein level and relieves symptoms for a period of
time, but does not kill myeloma cells

Arsenic Trioxide-based Therapy Systematic Review

Although some newly approved drugs demonstrate significant benefit, all MM patients
still relapse
ATO is the most active single agent in acute promyelocytic leukemia (antitumor
activity)
Phase I/II trials conducted in heavily pretreated patients with relapsed MM
Median age: 50.8-66 years
Number of patients ranged from 15-65
All studies published between 2003-2012

ATO Results
ATO combination therapy tolerated by most patients but most trials found limited effects on
MM patients
Trials have not been statistically capable to determine differences in progression-free
survival and overall survival
Most clinical trials found ATO has limited effects because of severe toxicity
Side effects: anemia, neutropenia, thrombocytopenia, vomiting, diarrhea
Large Phase III studies of ATO-based randomized clinical trials will be needed to establish
whether ATO has potential benefit

The Role ofPanobinostatPlus Bortezomib and

Dexamethasone
Panobinostat, in combination with bortezomib and dexamethasone, is authorized for
patients with relapsed or RRMM who have received2 prior treatment regimens
DACi prevents deacetylation, a process involved in gene regulation
Panobinostat is a potent panDACi that has shown potent antitumor activity, especially
when combined with other agents
Phase III Study
768 patients
PFS was 12.5 months in Panobinostat group and 4.7 months in placebo group
Side Effects: Thrombocypotenia, Diarrhea, fatigue, Neutropenia
One of the first agents with a new mechanism of action to be authorized for MM in over
a decade

Opinion
ATO is still a new therapy and
should be further reviewed in more
detail

Panibostat
More supportive data

Large amount of side effects and

toxicities

Fewer side effects and toxicities

Needs to have a phase III clinical

trial with effects of monotherapy

Illustrates how long new methods

of treatment take to be approved

Each of the discussed therapies are described for patients with relapsed MM
Very specific group of candidates
More research to be done for primary MM

 Gene Expression Profiling

Test that looks to see what genes are active in

Whats Next?

cancer cells
Test may be able to determine the outlook and
prognosis of the patient
Can determine if and when a patient with MM
will need to have chemotherapy and what
agents will be best for fighting specific genes

References
1. Anatomy and physiology related to multiple myeloma - Canadian Cancer S. www.cancer.ca.
http://www.cancer.ca/en/cancer-information/cancer-type/multiple-myeloma/anatomy-andphysiology/?region=on. Accessed November 8, 2016.
2. Chang H. Solitary Bone Plasmacytoma What Every Patient Should Know. The Myeloma Beacon.
3. opuch S, Kawalec P, Winiewska N. Effectiveness of targeted therapy as monotherapy or
combined therapy in patients with relapsed or refractory multiple
myeloma: A
systematic review
and meta-analysis.Hematology. 2014;20(1):1-10. doi:10.1179/1607845414y.0000000159.
4. Jordan S. Bone Tumors.Multiple Myeloma.
5. Multiple Myeloma - American Cancer Society.
http://www.cancer.org/acs/groups/cid/documents/webcontent/003121-pdf.pdf. Accessed
November 8,
2016.
6. San-Miguel JF, Einsele H, Moreau P. The Role of Panobinostat Plus Bortezomib and Dexamethasone
in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European
Perspective.Advances in Therapy.
2016;33(11):1896-1920. doi:10.1007/s12325-016-0413-7.
7. What's new in multiple myeloma research and treatment? What's new in multiple myeloma research
and treatment?
http://www.cancer.org/cancer/multiplemyeloma/detailedguide/multiplemyeloma-new- research.
Accessed November 8, 2016.