1 / 33

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.

rowdy
Download Presentation

Diagnosing and Treating Multiple Myeloma in 2008

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related