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.
Mm final slides sort
Overview• Identify the diagnostic criteria for multiple myeloma• Compare first & second line therapies, using data from clinical trials• Describe adjunctive & supportive therapies
Multiple Myeloma• Plasma cell malignancy• Second most common hematologic malignancy• Characterized by monoclonal immunoglobulin – MGUS – Smoldering MM – Amyloidosis
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 OrangeGreenlee RT. CA Cancer J Clin 2001;51:15. Bergsagel DE. Blood 1999;94:1174
Presenting Features• Bone disease & hypercalcemia• Recurrent infections• Anemia and fatigue• Renal failure due to multiple causes• Neuropathy• Asymptomatic in a minority of the patients
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
Criteria for DiagnosisMGUS 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
Incidence of Chromosomal Abnormalities in MMGenomic 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
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 albuminGreipp et al. J Clin Oncol 2005; 23: 3412-20
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
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
Serum Protein Electrophoresis Normal Monoclonal Protein in MyelomaKyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
Immunofixation to DetermineType of Monoclonal Protein IgG kappa M protein Lambda Light ChainsKyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004
Distribution of MonoclonalProteins• 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%
Bone Involvement in DifferentTumor 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 30–3561. 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.
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.
Bone Scans in Myeloma CanUnderestimate Bone Involvement
Bone Cell Stimulation inMalignancy Osteoclasts OsteoblastsMultiple myelomaOsteolytic solidtumors includingbreast cancer
Initial Approach to TreatmentClearly not a transplant Potential transplant candidate candidateCan include melphalan- Non-alkylator based based combinations induction Stem cell harvest
VTE Prevention withImmunomodulating 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
Treatment Options-RelapsedPatient• 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
Treatment of Bone Disease• Bisphosphonates• Surgical procedures – Vertebroplasty – Balloon Kyphoplasty• Radiotherapy• Treatment of myeloma
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 discretionKyle RA et al. J Clin Oncol. 2007;25:2464-72.
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
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
Anemia Treatment Goals• Treat the underlying malignancy• Decrease fatigue• Decrease need for PRBC transfusions• Treat the patient, not the number
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