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Diagnosing and Treating Multiple Myeloma in 2008

Diagnosing and Treating Multiple Myeloma in 2008. Craig Hofmeister, M.D. Assistant professor of medicine OSU Comprehensive Cancer Center Craig.Hofmeister@osumc.edu. Objectives. Review epidemiology and pathophysiology of multiple myeloma.

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Diagnosing and Treating Multiple Myeloma in 2008

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  1. Diagnosing and Treating Multiple Myeloma in 2008 Craig Hofmeister, M.D. Assistant professor of medicine OSU Comprehensive Cancer Center Craig.Hofmeister@osumc.edu

  2. Objectives • Review epidemiology and pathophysiology of multiple myeloma. • Obtain familiarity with International Myeloma Working Group criteria to diagnose plasma cell dyscrasias. • Be able to describe the most active drugs for myeloma: IMiDs and proteasome inhibitors. • Understand the eligibility and purpose of hematopoietic stem cell transplantation for myeloma. • Understand who will benefit from intravenous bisphosphonates and the most common complications.

  3. Epidemiology • Prevalence1,3,4 • Annual incidence about 4 per 100,000 • 19,900 new diagnoses in the United States in 2007 • 10,790 expected deaths • Usually occurs in individuals aged >60 years • The average age at diagnosis is 68 years • 1% diagnosed in individuals aged <40 years • Population subgroups4 • Incidence of multiple myeloma (MM) is twice as common in African Americans • Slightly more frequent in men than women • 10,960 men; 8940 women (estimated new cases in 2007) • Remains incurable 1. Multiple Myeloma Research Foundation. Causes & incidence. http://www.multiplemyeloma.org/about_myeloma/2.03/php. Accessed May 2, 2007. 3. Multiple Myeloma Research Foundation. Multiple myeloma: disease overview. 2006. http://www.multiplemyeloma.org/downloads/about_myeloma/ Disease_Overview.pdf. Accessed April 30, 2007. 4. American Cancer Society. Detailed guide: multiple myeloma - what are the risk factors for multiple myeloma? http://www.cancer.org/docroot/CRI/content//CRI_2_4_2X_What_are_the_risk_factors_for_multiple_myeloma_30.asp?sitearea=. Accessed April 30, 2007.

  4. Epidemiology • Second most common hematologic cancer • Common clinical features include • Bone pain, fractures, osteolytic lesions • Anemia, hypercalcemia • Renal insufficiency • Bleeding tendency • Peripheral neuropathy Estimated Annual Cases in the United States 1. American Cancer Society. Cancer facts & figures. 2002. 2003. 2004. 2005. 2006. 2007. http://www.cancer.org. Accessed April 30, 2007. 2. International Myeloma Foundation. Concise review of the disease and treatment options. 2006. http://www.myeloma.org/pdfs/ConciseReview2006.pdf. Accessed April 30, 2007.

  5. Myeloma is a plasma cell cancer • Plasma cells are normally present in the bone marrow and are responsible for immunoglobulin production in response to infection/other immune system-triggering events • In MM, monoclonal plasma cells infiltrate the bone marrow and replace normal cells, leading to • Tumor formation • Monoclonal immunoglobulin (M protein) production • Reduced immune response • Bone resorption and bone lesions Multiple Myeloma Research Foundation. Multiple myeloma: disease overview. 2006. http://www.multiplemyeloma.org/downloads/about_myeloma/Disease_Overview.pdf. Accessed April 30, 2007.

  6. Bone pain Cord compression Osteoporosis Bone marrow Infection Anemia (73%) Clinical presentation • Headaches • Blurry vision • Renal insufficiency (25-50%) • Hypercalcemia • Somnolence • Nausea and vomiting 1. International Myeloma Foundation. Concise review of the disease and treatment options. 2006. http://www.myeloma.org/pdfs/ConciseReview2006.pdf. Accessed April 30, 2007.2. Multiple Myeloma Research Foundation. Multiple myeloma: disease overview. 2006. http://www.multiplemyeloma.org/downloads/about_myeloma/Disease_Overview.pdf. Accessed April 30, 2007. Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

  7. Renal manifestations • Myeloma kidney = Cast nephropathy (40%), i.e. tubular casts in the distal nephron • AL amyloidosis (15%) in glomeruli and blood vessels • Monoclonal Ig deposition disease, most commonly light-chain deposition disease (15%) • Cryoglobulinemic glomerulonephritis & proliferative glomerulonephritis (rare) Congo red birefringence of a glomerulus when viewed through crossed Polaroid filters

  8. “M-spike” In MM, there is overproduction of one subtype of immunoglobulin, called the M protein (monoclonal protein) Adapted from International Myeloma Foundation. Concise review of the disease and treatment options. 2006. http://www.myeloma.org/pdfs/ConciseReview2006.pdf. Accessed April 30, 2007.

  9. Dx: Myeloma • M-protein in serum and/or urine • Κ or λ restricted plasmacytoma or marrow plasma cells; clonality is often defined as the presence of only kappa or lambda light chains in these plasma cells (a.k.a. “light chain restriction”) • Related organ or tissue impairment (see next slide) IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

  10. Related organ or tissue impairment Buy – Lytic bone lesions – visible on x-ray in 85% of patients. Hint – Osteoclasts activated, not osteoblasts. C – Hypercalcemia (Ca > 11 mg/dL) A – Anemia (Hb < 10) V – Hyperviscosity – especially common in the rare IgM secreting myeloma I – Bacterial infections (>2) A – Amyloidosis R – Renal (Crt > 1.96 mg/dL): HINT – occurs 50% of the time because most often the light chains are toxic to the tubules. These are the end organ manifestations of myeloma

  11. Dx: Monoclonal gammopathy of undetermined significance • M-protein in serum < 3 g/dL • < 10% clonal PCs on BmBx • No evidence of other B-cell lymphoproliferative disorder • No related organ or tissue impairment IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

  12. Dx: Smoldering myeloma • M-protein in serum ≥ 3 g/dL and/or clonal plasma cells on BmBx ≥ 10%; • NO related organ or tissue impairment IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

  13. Dx: Non-secretory myeloma • No M-component  many would say this means a negative serum and urine immunofixation • Bone marrow biopsy shows clonal plasma cells ≥ 10% or there is a plasmacytoma • Related organ or tissue impairment IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

  14. Dx: Plasmacytoma • Small M-protein in serum and/or urine (if at all) • Κ or λ restricted plasmacytoma(s) • Single area of bone destruction if plasmacytoma is next to bone • No clonal plasma cells on bone marrow biopsy • NO related organ or tissue impairment except for adjacent bone if affected IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

  15. Differential diagnosis • Primary amyloidosis (AL) – clonal plasma cell disorder in which monoclonal light chains are deposited in kidney, liver, heart, or peripheral nervous system. Treatment somewhat similar to myeloma. Less than 30% PCs on BmBx. • Waldenstrom’s macroglobulinemia (a.k.a. lymphoplasmacytic lymphoma) – a B-cell non-Hodgkin’s lymphoma that secretes IgM monoclonal protein (> 3 gm/dL) into the serum. Treatment similar to that for CLL. IgM antibodies are viscous d/t their structure and patients often present with symptoms of hyperviscosity. • Other non-Hodgkin’s lymphomas can produce monoclonal proteins (e.g. CLL) – The circulating serum monoclonal protein is generally asymptomatic and is an incidental finding.

  16. Waldenstrom’s Macroglobulinemia • B-NHL secreting IgM • Gene expression profiling suggest more similar to CLL than myeloma • Responses may be best for agents that work for both: Velcade, Thal/Rituxan, Campath; standard of care is fludarabine based, despite concerns for transformation to DLBCL, MDS/AML Leleu, XP et al. Increased incidence of disease transformation and development of MDS/AML in Waldenstrom’s macroglobulinemia (WM) patients treated with nucleoside analogues. JCO 25(18S) 2007: 8018.

  17. Risk of MGUS  Myeloma Rajkumar, V et al. Blood . 2005

  18. Smoldering myeloma  Active myeloma Kyle RA et al. NEJM . 356: 2582-90, 2007

  19. Update on current staging for myeloma Stage Criteria Median Survival (mo) I β2m < 3.5 mg/L 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/dL, any albumin Greipp et al. J Clin Oncol 2005; 23: 3412-20

  20. 1.00 0.75 0.50 0.25 0.00 0 100 200 300 400 500 600 700 Future staging… No t(4;14), no del(17p), low 2m Other Overall Survival T(4;14) or del(17p), and high 2m Time (d) Avet-Loiseau H, et al, IMW 2007, Abstract S1.5.

  21. OSU initial diagnostic studies • Laboratory studies • CBC/d/p, Creatinine • Ca, 25-OH-Vit D, testosterone • B2Microglobulin, LDH • M-protein assessment – SPEP/IFE, UPEP/IFE, serum immunoglobulins • Serum free light chains • Bone marrow biopsy, CD138-selected myeloma FISH panel & karyotype • Skeletal survey • If back pain present, MRI entire spine

  22. History of myeloma treatment

  23. VELCADE Bortezomib (Velcade) 26S Proteasome b1 b2 Post- glutamylSite TrypticSite 19SCap b7 b3   20SSubunit b6 b4 19SCap Chymo- trypticSite b5 • Degrades ubiquitinated proteins • Proteolysis is adenosine triphosphate (ATP) dependent • Chymotryptic site is rate limiting in protein degradation 1. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. 2. DeMartino GN, Slaughter CA. J Biol Chem. 1999;274:22123-22126.3. Seemuller E, et al. Science. 1995;268:579-582.

  24. Lenalidomide (Revlimid) Anti-neoplastic Immunomodulatory Anti-angiogenic

  25. OSU upfront treatment algorithm Velcade Melphalan Prednisone • 17p- [p53] or • t(4,14) or • t(14;16) or • 13q- w/ 14q32 • Tetraploidy • 1p/1q karyotype  (VMP) Velcade Dexamethasone Phase I clinical trial At relapse High risk  Melphalan Prednisone Revlimid (MPR) Velcade Dexamethasone Autologous hematopoietic stem cell transplant  or   All others Standard risk Revlimid Dexamethasone We believe that all myeloma patients should be treated on a clinical trial for all phases of their care. The above algorithm applies only to patients ineligible or unwilling to be treated on a clinical protocol.

  26. What is a stem cell transplant? • Autologous transplant (1% transplant-related mortality) • Essentially just high dose chemotherapy done safely • Melphalan 200 mg/m2 autologous transplant improves survival over standard cytotoxic chemotherapy • Goal is to find myeloma that is sensitive to melphalan • Eligibility: Age < 75 y.o., kidneys optional • Allogeneic (20% 1-year all-cause mortality) • Graft-versus-myeloma effect; • Chemo just prevents rejection • Graft-versus-host disease is significant detriment

  27. Progression OSU post autologous transplant care Stem cell transplant OSU clinical trials CR VGPR Observe until relapse • Maintenance • Revlimid 10 daily, or • Thalidomide 100 qHS • Velcade weekly Protocol ineligible Less than VGPR Melphalan conditioned Autologous transplant Progression Relapsed/refractory OSU clinical trials Progression

  28. What is the hope for allo transplant? Bruno B et al. A comparison of allografting with autografting for newly diagnosed myeloma. NEJM 356: 1110-1120, 2007.

  29. 100 80 60 40 20 0 Probability of survival after transplant 1998-2004 Auto (N=12,565) Probability, % HLA-id sib (N=763) Unrelated (N=103) 1 3 0 2 4 5 6 Years

  30. Bisphosphonates

  31. Bisphosphonates Renal safety profile of ZOMETA compared with pamidronate and placebo* 50% 40% 30% 20% 10% 0% ZOMETA Pamidronate Placebo Patients with deterioration in renal function vs baseline† 17% 13% 11% 11% 9% 7% Breast and multiple myeloma (N=540)P=NS Prostate (N=170) P=NS Lung and other solid tumors (N=328) P=NS *Patients with both normal and abnormal baseline renal function. †Renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline serum creatinine(<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (>1.4 mg/dL). ZOMETA Prescribing Information.

  32. Osteonecrosis of the jaw 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

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