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Mm final slides sort
1.
2. Overview
• Identify the diagnostic criteria for
multiple myeloma
• Compare first & second line
therapies, using data from
clinical trials
• Describe adjunctive & supportive
therapies
3. Multiple Myeloma
• Plasma cell malignancy
• Second most common
hematologic malignancy
• Characterized by monoclonal
immunoglobulin
– MGUS
– Smoldering MM
– Amyloidosis
4. MM Epidemiology
• 19,900 new cases per yr, 50,000 total
cases, 2% cancer deaths in U.S.
• Higher incidence in African
Americans, Pacific Islanders
• Median age 71 yrs
• Exposure to radiation, petroleum
products, pesticides & Agent Orange
Greenlee RT. CA Cancer J Clin 2001;51:15. Bergsagel DE. Blood 1999;94:1174
5. Presenting Features
• Bone disease & hypercalcemia
• Recurrent infections
• Anemia and fatigue
• Renal failure due to multiple
causes
• Neuropathy
• Asymptomatic in a minority of the
patients
6. Signs & Symptoms in 1027 Newly
Diagnosed Myeloma Patients
80
70 79
60 73
66
% patients
50
40
30 32
20
19
10 13 12
0
Bone Bone Hb<12 Fatigue Cr >2 Ca >11 Wt loss
lesions pain g/dL mg/dL mg/dL (>9 kg)
Kyle RA. Mayo Clin Proc 2003;78:21-33
7. Criteria for Diagnosis
MGUS Active MM MM
Smoldering
• <3 g M spike ∀ ≥10%M spike
∀ ≥3 g PC
<10% PC ••MOR ≥10% PC
spike +
AND
AND
No anemia, bone lesions Anemia, bone lesions,
normal calcium and high calcium or
kidney function abnormal kidney function
Kyle RA. N Engl J Med 2002; 346: 564
9. Incidence of Chromosomal
Abnormalities in MM
Genomic Aberrations Incidence of aberration
Del (13) 48%
Del (17p) 11%
t(4;14) (p16;q32) 14%
Hyperdiploidy 39%
t(11;14) (q13;q32) 21%
• n = 1064 patients
• Chromosomal changes observed in 90% of patients
10. International Staging System (ISS)
for Symptomatic Myeloma
Median
Stage Criteria Survival (mo)
β2m < 3.5 mg/L
I 62
albumin ≥ 3.5 g/dL
II* Not stage I or III 44
III β2m ≥ 5.5 mg/L 29
*β2m < 3.5 mg/L and albumin < 3.5 g/dL or
β2m 3.5 - < 5.5 mg/L, any albumin
Greipp et al. J Clin Oncol 2005; 23: 3412-20
11. Initial Diagnostic Evaluation
• Hx and physical examination
• Blood work-up
– CBC with diff and platelet counts
– BUN, Creatinine
– Calcium, albumin
– Serum protein electrophoresis (SPEP)
and immunofixation
– Quantitative immunoglobulins
– Serum free lyte chains
β 2-microglobulin
12. Initial Diagnostic Evaluation
• Urine
– Bence Jones quantitation
– 24-hr protein electrophoresis (UPEP)
and immunofixation
• Other
– Skeletal survey
– Unilateral bone marrow aspirate and
biopsy for histology, cytogenetics and
FISH
13. Serum Protein Electrophoresis
Normal Monoclonal Protein
in Myeloma
Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
14. Immunofixation to Determine
Type of Monoclonal Protein
IgG kappa M protein Lambda Light Chains
Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
15. Distribution of Monoclonal
Proteins
• M protein found in serum or urine
or both at time of diagnosis: 97%
• Serum M spike by protein
electrophoresis: 80%
• Abnormal serum immunofixation:
93%
• Abnormal urine immunofixation:
75%
• Non-secretory myeloma: 3%
17. Bone Involvement in Different
Tumor Types
Disease Bone metastases in Median survival of
prevalence in US patients with patients with bone
advanced disease metastases
(in thousands) (%) (months)
Myeloma 49.61 843 37–587
Lung 3271 30–402 8–104
Breast 2,0511 65–752 19–255
Prostate 1,4771 65–752 30–356
1. National Cancer Institute. Available at: http://seer.cancer.gov/csr/1973-1999/prevalence.pdf.
Accessed 1/27/2005. 2. Coleman RE. Oncologist. 2004;9(suppl 4):14-27. 3. Kyle RA et al. Mayo Clin
Proc.
2003;78: 21-33. 4. Smith W et al. Semin Oncol. 2004;31(suppl 4):11-15. 5. Lipton A. J Support Oncol.
2004;2:205-213. 6. Tu S-M, Lin S-H. Cancer Treat Res. 2004;118:23-46. 7. Palumbo A et al. Blood.
2004;104:3052-3057.
18. Bone Imaging in MM
• Skeletal radiography is the primary
diagnostic test to detect destructive
bony lesions in multiple myeloma
• MRI is useful in assessing whether
spinal compression fractures are due
to a focal mass or from osteopenia
due to increased osteolysis
• PET scans can be used to detect soft
tissue or bone metastases
Angtuaco EJ et al. Radiology. 2004;231:11-
23.
19. Bone Scans in Myeloma Can
Underestimate Bone Involvement
20. Bone Cell Stimulation in
Malignancy
Osteoclasts Osteoblasts
Multiple myeloma
Osteolytic solid
tumors including
breast cancer
21. Initial Approach to Treatment
Clearly not a transplant Potential transplant
candidate candidate
Can include melphalan- Non-alkylator based
based combinations induction
Stem cell harvest
25. VTE Prevention with
Immunomodulating Agents
• As single agents: minimal risk; prophylaxis
may be considered
• Concomitant chemotherapy: especially dex,
anthracyclines & ESAs, increase risk as
much as 58%
• Low-dose warfarin: not protective
• ASA: adequate in lower risk patients
receiving dex & an immunomodulator
• LMWH (enoxaparin 40mg QD), full dose
warfarin, are recommended for patients at
high risk for VTE
26. Treatment Options-Relapsed
Patient
• Since no therapy is curative, all
options need to be tried sequentially
• No good data on optimum sequence
or regimen
• All patients should be encouraged to
participate in ongoing clinical trials
• Cumulative toxicities from prior
therapies may influence decision
27. Treatment of Bone Disease
• Bisphosphonates
• Surgical procedures
– Vertebroplasty
– Balloon Kyphoplasty
• Radiotherapy
• Treatment of myeloma
28. ASCO Guidelines for Treating
Bone Loss in Multiple Myeloma
MM patients with lytic disease or osteopenia
MM patients with lytic disease or osteopenia
on plain radiographs or imaging studies
on plain radiographs or imaging studies
Intravenous pamidronate 90 mg deliver over at least 2 hrs
Intravenous pamidronate 90 mg deliver over at least 2 hrs
or
or
zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks.
zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks.
Continue therapy for 2 yrs & consider stopping in
Continue therapy for consider
patients w/ responsive or stable disease; further use at
patients w/ responsive
physician’s discretion
physician’s discretion
Kyle RA et al. J Clin Oncol. 2007;25:2464-72.
29. Issues with BP Therapy
• Renal toxicity
• Osteonecrosis of the jaw
• Decreases skeletal events by 50%;
patients still progress but at a
slower rate
• No clear anti-tumor activity
30. Osteonecrosis of the Jaw
Features of Suspected ONJ
• Exposed bone in maxillofacial area
associated with dental surgery or
occurs spontaneously, with no
evidence of healing
Working Diagnosis of ONJ
• No evidence of healing after
8 weeks of appropriate dental care
• No evidence of metastatic disease in
the jaw or osteoradionecrosis
31. Anemia Treatment Goals
• Treat the underlying malignancy
• Decrease fatigue
• Decrease need for PRBC
transfusions
• Treat the patient, not the number
32. 2007 ASCO Practice
Guidelines for ESA
• General:
– Review peripheral smear; consider iron,
folate, and B12 deficiency as potential
causes for anemia, assess for occult
blood loss.
• Comparative effectiveness:
– Agents are considered equivalent in
terms of safety and efficacy
– No reason to believe that a patient who
fails to respond to one ESA will have a
response to a different ESA
Notas del editor
Bone Metastases in Different Tumor Types The prevalence of metastatic bone disease is highest in breast and prostate cancer, with these 2 primary tumor types accounting for approximately 80% of all cases of bone metastases. 1 This is attributed to the high overall prevalence and relatively long clinical course of these tumors Metastases to bone occur in 65% to 75% of patients with advanced breast or prostate cancer, 30% to 40% of patients with advanced lung cancer, and 20% to 25% of patients with advanced renal cell carcinoma. 1 Bone lesions occur in almost all patients with multiple myeloma 2 Survival after the development of bone lesions is variable, and can be significant in some tumor types 2-6 References: 1. Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev . 2001;27:165-176. 2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc . 2003;78:21-33. 3. Smith W, Khuri FR. The care of the lung cancer patient in the 21st century: a new age. Semin Oncol . 2004;31(suppl 4): 11-15. 4. Tu S-M, Lin S-H. Clinical aspects of bone metastases in prostate cancer. Cancer Treat Res . 2004;118:23-46. 5. Lipton A. Pathophysiology of bone metastases: how this knowledge may lead to therapeutic intervention. J Support Oncol . 2004;2:205-213. 6. Palumbo A, Bringhen S, Petrucci MT, et al. Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood . 2004;104:3052-3057. CORE
Bone Imaging in Multiple Myeloma Skeletal radiography continues to be the primary diagnostic study to detect destructive bony lesions in multiple myeloma. Four distinct x-ray patterns of involvement have been described: The solitary lesion (plasmacytoma) is typically a lytic lesion primarily involving the spine, pelvis, skull, ribs, sternum, or proximal appendages Diffuse skeletal involvement (myelomatosis) classically manifests as osteolytic lesions with discrete margins and uniform size Diffuse skeletal osteopenia without well-defined lytic lesions is typically seen involving the spine. Multiple compression fractures can be seen as an x-ray manifestation of this condition Sclerosing myeloma lesions are seen in association with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) Magnetic resonance (MR) imaging can provide detailed imaging of the bone and bone marrow Possible MR findings in multiple myeloma include an expansile focal mass, multiple focal masses in the axial skeleton, diffuse marrow involvement, or multiple compression fractures MR is useful in assessing whether spinal compression fractures are due to a focal mass or to the diffuse osteopenia that can result from increased osteolysis in multiple myeloma Computed tomography (CT) scan is a sensitive tool for detecting the bone destructive effects of multiple myeloma CT scan can help define possible lytic or sclerotic lesions CT scan is used to guide biopsy of focal spinal and pelvic lesions Bone scans with technetium-99m rely on an osteoblastic response, which is often absent in multiple myeloma. Bone scan results can underappreciate the extent of bone disease in multiple myeloma and are not useful for screening Reference: Angtuaco EJ , Fassas AB, Walker R, et al. Multiple myeloma: clinical review and diagnostic imaging. Radiology . 2004;231:11-23.
Long considered to be the “gold standard” for the non-transplant candidate. Use as standard treatment dates to 1960’s.
Cost : $2,810 per “cycle” (4 doses @ BSA = 2)
Typical locations of ONJ: Top: posterior lingual part of mandible Bottom: nonhealing extraction socket Clinical Features of Suspected ONJ Exposed bone in maxillofacial area that occurs in association with dental surgery or occurs spontaneously, with no evidence of healing* Working Diagnosis of ONJ No evidence of healing after 6 weeks of appropriate evaluation and dental care No evidence of metastatic disease in the jaw or osteoradionecrosis *Refer for appropriate dental evaluation and care as soon as possible.
