Plasma cell disorders ppt


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Plasma cell disorders is a difficult topic where most residents and students confuse with regarding to differentiating between various types of para-proteinemias or plasma cell dyscrasias. This simple presentation will highlight the key points in differentiating, diagnosing these orders. Initial management principles are discussed as well.

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  • The idea behind Upep with Immunofixation in addition to SPEP is that sometimes, a complete monoclonal protein ( complete intact immunoglobulin) may not detected in the blood but you may have light chain excretion in the urine ( bence jones proteinuria) which can be missed if UPEP is not done. Light chains only get excreted when their production goes beyond renal threshold – so, serum Free light chain assay will be always abnormal
  • Albumin + globulin . Globulin = alpha, beta and gamma. Immunoglobulins are gamma globulins….theyt migrate to gamma area
  • SPEP is a useful screening test however, an M-protein may be overlooked or an apparent M-protein may actually represent a polyclonal increase in immunoglobulins or a nonimmunoglobulin. Immunofixation will detect a serum M-protein at a concentration of at least 0.02 g/dL and a urine M-protein at a concentration of ≥0.004 g/dL. Only in initial diagnosis - When following patients with multiple myeloma, MGUS, or a related disorder, once the presence of a monoclonal protein and its type are initially confirmed by immunofixation, it is not necessary to repeat immunofixation unless needed to document complete response to therapy. Patients can usually be followed with electrophoresis of serum (SPEP) or urine (UPEP) proteins.
  • Remember to call it MGUS m-protein must be less than 3gm%. If it larger, it is no longer MGUS . So, periodic monitoring is important , usually on yearly basis, if initial m-protein is large, may monitor at shorter intervals– during monitoring, if any increase in size > 3 , BM biopsy may be needed to rule our malignant plasma cell disorder!!
  • HENCE, BOTH SPEP AND UPEP ARE IMP IN MM DIAGNOSIS. UPEP CAN BE REPLACED BY SERUM FLC ASSAY IN INITIAL DIAGNOSIS BUT NOT IN FOLLOW UP OF MM Note: no specific level of M-protein is used as a cutoff value since approximately 40 percent of patients with symptomatic MM will have an M-protein of less than 3 g/dL. Also note that, in true non-secretory MM (approximately 3 percent of MM), an M protein will not be detectable in the serum or urine Note: approximately 4 percent of patients may have fewer than 10 percent bone marrow plasma cells since marrow involvement may be focal , rather than diffuse. Repeat bone marrow biopsy should be considered in such patients. A diagnosis of MM can be made, if other diagnostic criteria are fulfilled, after histopathologic confirmation of a soft tissue or bony plasmacytoma.
  • With current first-line options, the median survival of patients with myeloma has been approximately 3 years with conventional chemotherapy and 4-5 years with autologous stem cell transplantation. With the introduction of new therapeutic agents, the median survival appears to be increasing even beyond 5 years. Chng. Cancer Control . 2005;12:91.
  • Len/dex, lenalidomide/dexamethasone; MM, multiple myeloma; MPT, melphalan/ prednisone/thalidomide ; MPV, melphalan/prednisone/bortezomib.   Patients considered eligible for transplantation typically have a good performance status; no significant comorbidities, such as severe cardiac disease or severe pulmonary disease; and are usually younger than 75 years of age. Stem cell transplantation is available through 3 centers in the VA Health System, located in Seattle, Washington; Nashville, Tennessee; and San Antonio, Texas.   Transplant candidates should not receive alkylator‑based therapy with agents such as melphalan hydrochloride, because these agents adversely affect stem cells as well as myeloma cells. Instead, non–alkylator‑based therapies are required for patients who are potential transplantation candidates. Once a patient is determined to be a transplantation candidate, he or she should undergo stem cell harvest.
  • OS, overall survival.   Stem cell transplantation was shown to be better than conventional therapy in a trial reported by Attal and colleagues in 1996. Patients undergoing stem cell transplantation had a markedly improved median survival compared with patients receiving conventional therapy, with a median survival of approximately 60 months compared with 30 months, respectively. This translated into an overall survival benefit with stem cell transplantation in these patients.
  • CR, complete response; EFS, event-free survival; Mel, melphalan; OS, overall survival; PR, partial response; Rx, therapy.   Treatment of patients who are undergoing autologous stem cell transplantation begins with induction regimens that exclude alkylating agents. Once stem cells are collected, patients are given high doses of an alkylating agent, such as melphalan 200 mg/m^2, as the standard conditioning regimen. To be eligible for stem cell transplantation, patients must have a good performance status; adequate liver, pulmonary, and cardiac function; and usually must be younger than 75 years of age. Patients who undergo stem cell transplantation have a higher partial response and complete response rate as well as longer overall survival and event‑free survival. Patients with impaired renal function, including those on dialysis, can be considered for stem cell transplantation.
  • SCT, stem cell transplantation.   Given the availability of very effective regimens, one consideration is whether patients should receive immediate stem cell transplantation or whether transplantation should be delayed until relapse. Other questions include the following: Is single transplantation better than tandem transplantation? What is the role of allogeneic and miniallogeneic transplantation in patients with myeloma? What should be done after transplantation? Should patients receive maintenance therapy?
  • IMiDs, immunomodulatory drugs.   Several new agents have been introduced to treat newly diagnosed patients with myeloma. These include the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitors bortezomib and carfilzomib. Carfilzomib is an irreversible proteasome inhibitor, whereas bortezomib is a reversible proteasome inhibitor.
  • The importance of all these new agents and why they are so successful in treating myeloma is that in addition to targeting the myeloma cells, they also target the microenvironment in the bone marrow, making it less hospitable to myeloma cells. These novel agents have effects on both the tumor and the tumor microenvironment. Kyle. N Engl J Med . 2004;351:1860.
  • TNF, tumor necrosis factor.   A number of mechanisms of action have been proposed for thalidomide. Thalidomide was originally evaluated in myeloma because of its antiangiogenic properties. The mechanisms of action of thalidomide are not fully understood but may relate to inhibition of tumor necrosis factor- α , cell-surface adhesion molecules, and interleukin 6. Thalidomide may also exhibit antiangiogenic properties through fibroblast growth factor and vascular endothelial growth factor inhibition. Kyle. N Engl J Med . 2004;351:1860; D’Amato. Proc NatlAcadSci USA . 1994;91:4082; Vacca. Blood . 1999;93:3064; Singhal. N Engl J Med . 1999;341:1565.
  • TNF, tumor necrosis factor.   Lenalidomide is a much more potent immunomodulatory agent that has been found to have multiple effects on myeloma cells and the tumor microenvironment. As with thalidomide, the mechanism of action of lenalidomide is not fully characterized, although the agent does exhibit antineoplastic, immunomodulatory, and antiangiogenic activity. Lenalidomide may also stimulate T-cell proliferation and inhibit T-regulatory cells. Lenalidomide has a more favorable toxicity profile than thalidomide.
  • CrCl, creatinine clearance; ESRD, end-stage renal disease; MM, multiple myeloma; QD, once daily.   When using lenalidomide with dexamethasone, it is important to remember that lenalidomide is cleared by the kidneys, so the lenalidomide dose must be reduced in patients with renal dysfunction. Lenalidomide can be used even in patients on dialysis, but the dose is reduced from the standard 25 mg/day for 21 days/month to as low as 5 mg/day following dialysis. In summary, lenalidomide is active in patients who have renal dysfunction and myeloma as well as patients with normal function, although one has to be very careful using it in patients with renal impairment.
  • ADP, adenosine diphosphate; ATP, adenosine triphosphate.   The proteasome inhibitors act on the proteasome, a key mechanism for the cell to degrade proteins that are no longer needed.   Proteasome inhibitors such as bortezomib bind to the proteasome, inhibit the degradative process, and block protein degradation. In particular, bortezomib affects the chymotryptic site on the proteasome. Other new proteasome inhibitors affect the chymotryptic site as well.
  • MM, multiple myeloma.   Although bortezomib is effective, care must be taken in patients with peripheral neuropathy. Peripheral neuropathy has been reported in 35% of patients with myeloma treated with bortezomib in phase II trials. The overwhelming majority of these patients had preexisting peripheral neuropathy. Only 3% of patients without baseline neuropathy developed significant peripheral neuropathy during treatment with bortezomib.
  • Len/dex, lenalidomide/dexamethasone; MM, multiple myeloma; MPT, melphalan, prednisone, and thalidomide ; MPV, melphalan/prednisone/bortezomib.   For patients who are not transplantation eligible, there are a number of treatment choices available. These include combination therapy with melphalan/prednisone/thalidomide (MPT), melphalan/prednisone/bortezomib (MPV), and lenalidomide and dexamethasone.  In addition, there is a clinical trial under way for newly diagnosed patients who are not eligible for transplantation, in which bortezomib is given at a different dose schedule and at a slightly higher dose than the standard regimen.
  • CR, complete response; MM, multiple myeloma; MP, melphalan/prednisone; MPT, melphalan/prednisone/thalidomide; ORR, overall response rate; VMP, bortezomib/melphalan/prednisone.   For elderly patients who are not candidates for transplantation, MP has been the standard therapy. MP is associated with an overall response rate of approximately 60%, but with an extremely low complete remission rate (< 5%). Both MPT and bortezomib/melphalan/prednisone (VMP) have been used successfully to treat elderly patients with myeloma.
  • DVT, deep vein thrombosis; IMiD , immunomodulatory drug; MP, melphalan/prednisone; ORR, overall response rate; PE, pulmonary embolism; MPR, melphalan/prednisone/lenalidomide; VMP, melphalan/prednisone/bortezomib.   In elderly patients with myeloma, we see very good response rates with melphalan/prednisone/lenalidomide and melphalan/prednisone/bortezomib. Remember that immunomodulatory agents are associated with an increased risk of DVT or pulmonary embolus. In addition, bortezomib-containing regimens are associated with reactivation of herpes zoster, so patients who are undergoing treatment with bortezomib-based therapy must receive herpes zoster prophylaxis.    
  • Approximately 80% of patients with multiple myeloma have some evidence of skeletal involvement. Most lesions are typically found within the axial skeleton and are all osteolytic. Although the majority of this skeletal involvement will be observed on skeletal survey, further diagnostic testing can look for areas of focal lesions. Some of the areas that may also reveal lytic lesions include the vertebrae (65%), the ribs (45%), the skull (40%), the shoulders (40%), the pelvis (30%), and the long bones (25%). The picture on the slide illustrates a pathologic fracture associated with 2 significant lytic lesions.
  • Roodman GD. Mechanisms of bone metastasis. N Engl J Med . 2004;350:1655-1664.
  • OPG, osteoprotegerin; RANKL, receptor activator for nuclear factor-κB ligand.   Bisphosphonates are often concentrated under the site of osteoclasts within the bone. After the initiation of bone resorption, the osteoclasts take up the bisphosphonates within the cell. This uptake inhibits osteoclast activity and, as a result, leads to a decrease in the number of osteoclasts by inhibiting their recruitment and activating apoptosis. Bisphosphonates may also modulate some of the signaling from osteoblasts to osteoclasts; the receptor activator for nuclear factor-κB ligand (RANKL) binds to the RANK receptor on the osteoclast precursor allowing for the formation and suppression of apoptosis. Bisphosphonates may actually decrease osteoclast formation and increase apoptosis by increasing the osteoprotegerin production of the osteoblast.   References: 1. Reszka AA, Rodan GA. Bisphosphonate mechanism of action. Curr Rheumatol Rep . 2003;5:65-74. 2. Viereck V, Emons G, Lauck V, et al. Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegrin production by primary human osteoblasts. Biochem Biophys Res Commun . 2002;291:680-686. 3. Pan B, Farrugia AN, To LB, et al. The nitrogen-containing bisphosphonate, zoledronic acid, influences RANKL expression in human osteoblast-like cells by activating TNF-alpha converting enzyme (TACE). J Bone Miner Res . 2004;19:147-154.
  • CrCl, creatinine clearance.   When managing patients with multiple myeloma for the prevention of skeletal-related events, intravenous bisphosphonates are generally used instead of oral bisphosphonates because of their significantly higher potency and bioavailability. In the United States, there are 2 intravenous bisphosphonate options—pamidronate and zoledronic acid—for the prevention of skeletal-related events in patients with multiple myeloma. Recommended doses and infusion times are provided to avoid some of the adverse events that are associated with their use. Because these drugs undergo renal clearance, the estimated creatinine clearance is preferred to determine the dosing and the time. The duration of infusion is extended and the dose is reduced with decreasing creatinine clearance. Package inserts for zoledronic acid recommend dose reduction depending on the degree of renal impairment; zoledronic acid is not recommended in patients with a creatinine clearance < 30 mL/min.
  • The incidence of ONJ associated with bisphosphonate support is not well characterized in the literature, and much of the evidence is based on case studies or patient surveys. It is an uncommon complication that causes avascular necrosis within the maxilla or mandible. Visualization of exposed bone, evidence of infection, or pain may be the presenting factor. It is not known whether the duration of therapy or the dosing of therapy is associated with the development of ONJ.
  • Hyperviscosity features : Blurred vision, headaches, dizziness, paresthesias, retinal vein engorgement and flame-shaped hemorrhages, papilledema, stupor and com
  • Plasma cell disorders ppt

    1. 1. <ul><li>Hematology-High Yield Topics </li></ul><ul><li>For Internal Medicine Boards and Hematology Boards </li></ul><ul><li>Target Audience : Internal Medicine Residents, Family Medicine Residents, Hematology Fellows, Medical Students, IM Board Recertification exam aspirants </li></ul><ul><ul><li>Archer Internal Medicine Board Review </li></ul></ul><ul><ul><li> </li></ul></ul>
    2. 2. <ul><li>Definition: </li></ul><ul><li>Group of lymphoid neoplasms of terminally differentiated B - cells that have in common the expansion of a single clone of immunoglobulin (Ig) - secreting plasma cells and a resultant increase in serum levels of a single homogeneous (monoclonal) Ig or it’s fragments. </li></ul>Plasma Cell Dyscrasias
    3. 3. Plasma Cell <ul><li>Plasma cells : </li></ul><ul><li>Terminally differentiated B-cells </li></ul><ul><li>Not normally found in peripheral blood . </li></ul><ul><li>Account for less than 3.5% of nucleated cells in the bone marrow </li></ul><ul><li>Oval cells with low N:C ratio. Cytoplasm is basophilic blue. Nucleus (30-40% of the cell) is oval or round and typically placed eccentrically (to one side) of the cell. </li></ul><ul><li>A clear, colorless area adjacent to the nucleus contains Golgi apparatus </li></ul><ul><li>Russell bodies : Globules (2-3 μm) of accumulated immunoglobulins in the cytoplasm of plasma cells. Usually round. Russell bodies may be found in normal bone marrow. </li></ul>
    4. 4. Plasma Cell <ul><li>Mott cells </li></ul><ul><li>Plasma cells crowded with Russell bodies. An obstruction blocks the release of Golgi secretions. These cells can be found in any case of chronic plasmacytosis. </li></ul>
    5. 5. Plasma Cell <ul><li>Flame Cells </li></ul><ul><li>Large, multinucleated plasma cells seen in Multiple myeloma. The cytoplasm resembles a red flame . </li></ul>
    6. 6. Plasma Cell Dyscrasias Synonyms
    7. 7. Plasma Cell Dyscrasias
    8. 8. <ul><li>Investigations in any suspected Monoclonal Gammopathy should include to accurately classify the disorder: </li></ul><ul><li>Complete Blood Count ( look for anemia) </li></ul><ul><li>Comprehensive Metabolic panel </li></ul><ul><ul><li>Look for renal insufficiency, hypercalcemia and subtle clues like decreased anion gap </li></ul></ul><ul><ul><li>Total protein and albumin level. Determine Globulin component. Too low globulin ( < 2gm%) or Elevated Globulin ( > 3.5gm%) is concerning : Determine if Polyclonal vs. Monoclonal. Evaluate further with : </li></ul></ul><ul><ul><ul><ul><ul><li>Quantitative Immunoglobulins : Increase in all components usually, polyclonal. Increase in single component with reciprocal decrease of uninvolved globulin usually, may suggest monoclonal . </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>24HR-Urine protein electrophoresis with urine immunofixation ( Serum Free Light Chain assay ( κ / λ ratio) may be used in place of UPEP} </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Bone marrow biopsy to evaluate % plasma cells if there is monoclonal protein or abnormal UPEP or Light chain assay or if strong clinical picture of myeloma. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Skeletal survey if monoclonal gammopathy has been established ( Bone scans are usually, negative in MM) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Beta-2 microglobulin and Albumin for staging and prognosis in MM ( once diagnosis is made). </li></ul></ul></ul></ul></ul>Investigations
    9. 9. Serum Protein Electrophoresis <ul><li>Serum Protein Electrophoresis : </li></ul><ul><li>Serum is placed on special paper treated with agarose gel and exposed to an electric current. This separates the serum protein components into five classifications by size and electrical charge : serum albumin, alpha-1 globulins, alpha-2 globulins, beta globulins, and gamma globulins. </li></ul><ul><li>Immunoglobulins ( IgG, IgM, IgA) usually migrate to gamma region but may sometimes extend to beta region. </li></ul><ul><li>SPEP should always be performed in combination with serum immunofixation in order to determine clonality </li></ul>
    10. 10. SPEP <ul><li>SPEP showing Monoclonal Gammopathy </li></ul><ul><li>Shows a tall “narrow” band in gamma region – “M-Spike” </li></ul><ul><li>Also, note reduction in the normal polyclonal gamma band </li></ul>
    11. 11. SPEP <ul><li>SPEP showing Polyclonal Gammopathy </li></ul><ul><li>Shows a broad based peak in gamma region . </li></ul><ul><li>Seen in chronic infections, inflammation, connective tissue disease, lymphoproliferative disease. </li></ul>
    12. 12. Immunofixation <ul><li>More sensitive than SPEP </li></ul><ul><li>Immunofixation is performed when SPEP shows a sharp “peak” or a plasma cell disorder is suspected despite a normal SPEP </li></ul><ul><li>Immunofixation always done to confirm the presence of M-Protein and to determine the type (IgM or IgG etc and the light chain restriction : k or λ ) </li></ul><ul><li>Why do both SPEP and IF ? Why not just IF in initial diagnosis ? </li></ul><ul><ul><li>Unlike SPEP, immunofixation does not give an estimate of the size of the M protein (ie, its serum concentration), and thus should be done in conjunction with electrophoresis. </li></ul></ul>
    13. 13. Constitute Several Disorders Examples :
    14. 14. <ul><li>Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder i.e; Undetermined Significance </li></ul>Monoclonal Gammopathy of Undetermined Significance ( MGUS)
    15. 15. <ul><li>Incidence of MGUS increases with age : </li></ul><ul><ul><ul><li>1% of adults in US </li></ul></ul></ul><ul><ul><ul><li>3% of adults over age 70 years </li></ul></ul></ul><ul><ul><ul><li>11% of adults over age 80 years </li></ul></ul></ul><ul><ul><ul><li>14% of adults over age 90 years </li></ul></ul></ul><ul><li>Significance : Can progress to monoclonal Disease </li></ul><ul><li>IgG or IgA MGUS IgM MGUS </li></ul>Monoclonal Gammopathy of Undetermined Significance ( MGUS)
    16. 16. MGUS - Progression
    17. 17. And it’s Variants
    18. 18. <ul><li>Both criteria should be met : </li></ul><ul><ul><li>Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent </li></ul></ul><ul><ul><li>No end organ damage related to plasma cell dyscrasia (see CRAB) </li></ul></ul><ul><li>Management : </li></ul><ul><ul><li>Does not require any intervention </li></ul></ul><ul><ul><li>Close surveillanace is necessary to ensure stability of the disease ( SPEP, CBC, Creatinine and calcium every 3 to 4 month and Skeletal Survey annually to pick up asymptomatic bone lesions) </li></ul></ul>Smoldering Myeloma
    19. 19. <ul><li>Rare variant : About 1% of Myelomas </li></ul><ul><li>May present with Bone lesions ( most common presenting symptom bone pain) </li></ul><ul><li>No serum or urine monoclonal protein ( diagnosis can be missed if one is not aware of this entity, NSMM). </li></ul><ul><li>Renal failure and hypercalcemia are generally lacking </li></ul><ul><li>Anemia may be present </li></ul><ul><li>Bone marrow biopsy must be performed in suspected cases: Immunostaining for a monoclonal protein on bone marrow sections may establish the diagnosis, Clonal plasma cell population in marrow. </li></ul><ul><li>Must rule out IgD and IgE myeloma </li></ul>Non-Secretory Myeloma
    20. 20. Solitary Plasmacytoma Localized plasma cell tumor • Absence of a plasma cell infiltrate in random marrow biopsies • No evidence of other bone lesions by radiographic examination • Absence of renal failure, hypercalcemia or anemia
    21. 21. <ul><li>Plasma cell tumors that arise outside the bone marrow and no features of Multiple Myeloma </li></ul><ul><li>Most Common Primary Sites - Head and Neck region: Upper air passages and oropharynx (May involve draining lymph nodes. </li></ul><ul><li>Less Common Sites – Lymph nodes (primary), salivary glands, spleen, liver, etc. </li></ul><ul><li>25% have small monoclonal spike </li></ul><ul><li>Rare dissemination, rarer evolution to myeloma </li></ul><ul><li>Management : </li></ul><ul><ul><ul><li>If completely resected during biopsy, no further therapy </li></ul></ul></ul><ul><ul><ul><li>If incompletely resected, radiation therapy locally </li></ul></ul></ul>Extramedullary Plasmacytoma
    22. 22. <ul><li>All three criteria must be met </li></ul><ul><li>Presence of a serum or urinary monoclonal protein </li></ul><ul><li>Presence of 10 percent or more clonal plasma cells in the bone marrow or a plasmacytoma </li></ul><ul><li>Presence of end organ damage felt related to the plasma cell dyscrasia, such as: CRAB : Hyper c alcemia (calcium > 11.5gm%), R enal Insufficiency, A nemia (hgb < 10gm%) or Lytic b one lesions </li></ul>Multiple Myeloma
    23. 23. Multiple Myeloma Bone Lesions : Conventional radiographs (Skeletal Survey) abnormal in 80% of patients who present with multiple myeloma
    24. 24. Multiple Myeloma Anemia: Normochromic /normocytic anemia occurs in 75% patients at diagnosis Defined as less than 10gm% in MM
    25. 25. Multiple Myeloma <ul><li>Major Causes : </li></ul><ul><ul><li>Myeloma cast nephropathy </li></ul></ul><ul><ul><li>Hypercalcemia </li></ul></ul><ul><ul><li>Amyloidosis </li></ul></ul><ul><ul><li>Radiocontrast dye in a patient with myeloma </li></ul></ul>Renal Insufficiency : Serum creatinine increased in > 50% at diagnosis Creatinine >2g/dL in 20% of patients Renal failure may be presenting manifestation
    26. 26. Multiple Myeloma <ul><li>Managed with urgent: </li></ul><ul><li>1. Corticosteroids </li></ul><ul><li>2.Neurosurgical intervention (laminectomy or anterior decompression in pathological #) + radiation therapy to preserve neurological function </li></ul><ul><li>3. Radiation therapy alone ( plasmacytoma) </li></ul>Spinal Cord Compression : An Oncological Emergency Spinal cord compression occurs in 5 % of patients with multiple myeloma ( plasmacytoma or pathological fracture related)
    27. 27. Multiple Myeloma - Cytogenetics Deletion 17p and Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy
    28. 28. Multiple Myeloma Staging : International Staging System : Stage I — B2M <3.5 mg/L and serum albumin ≥3.5 g/dL Stage II — neither stage I nor stage III Stage III — B2M ≥5.5 mg/L Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months
    29. 29. Multiple Myeloma <ul><li>Treatment Decisions : </li></ul><ul><li>Indications for treatment : presence of any of CRAB ( bone lesions can be diffuse osteopenia alone) </li></ul><ul><li>Risk Stratification : </li></ul><ul><ul><li>FISH for detection of t(4;14), t(14;16), and del17p13 </li></ul></ul><ul><ul><li>Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy </li></ul></ul><ul><ul><li>The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment </li></ul></ul>
    30. 30. Current Frontline Options <ul><li>Conventional chemotherapy </li></ul><ul><ul><li>Survival ≤ 3 yrs </li></ul></ul><ul><li>Transplantation </li></ul><ul><ul><li>Prolongs survival 4-5 yrs </li></ul></ul><ul><li>Novel agents targeting stromal interactions and associated signaling pathways have shown promise and improved survival. </li></ul>Chng WJ, et al. Cancer Control. 2005;12:91-104.
    31. 31. MM: INITIAL THERAPY <ul><li>The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation </li></ul>
    32. 32. Initial Approach to Treatment of MM *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 4 cycles Stem cell harvest
    33. 33. DETERMINING TRANSPLANT ELIGIBILITY <ul><li>Autologous hematopoietic cell transplantation (HCT) results in superior event-free and overall survival rates when compared with combination chemotherapy </li></ul><ul><li>All patients should be evaluated at diagnosis for transplant eligibility so that the risks and benefits of autologous HCT can be reviewed with those eligible </li></ul><ul><li>A minority of patients will be eligible for allogeneic HCT, but the value of allogeneic approaches in myeloma remain investigational </li></ul>
    34. 34. NOT Eligible for Autologous HCT <ul><li>Age >77 years </li></ul><ul><li>Direct bilirubin>2.0 mg/dL (34.2 µmol/liter) </li></ul><ul><li>Serum creatinine>2.5 mg/dL (221 µmol/liter) unless on chronic stable dialysis </li></ul><ul><li>Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain </li></ul><ul><li>New York Heart Association functional status Class III or IV </li></ul>
    35. 35. Transplantation vs Conventional Chemotherapy 54 42 Attal M, et al. N Engl J Med. 1996;335:91-97. Child JA, et al. N Engl J Med. 2003;348:1875-1883. 15 30 45 60 25 50 75 100 OS (%) 0 0 High dose Conventional dose Mos 20 40 60 80 25 50 75 100 Survival (%) 0 0 Intensive therapy Standard therapy Mos P = .03 by Wilcoxon test P = .04 by log-rank test
    36. 36. Autologous Stem Cell Transplantation <ul><ul><li>Mel 200 mg/m 2 standard conditioning regimen </li></ul></ul><ul><ul><li>Sufficient performance score, and adequate liver, pulmonary, cardiac function needed </li></ul></ul><ul><ul><li>Higher PR and CR rates than conventional chemotherapy </li></ul></ul><ul><ul><li>Higher OS and EFS than conventional Rx </li></ul></ul><ul><ul><li>Advanced age and impaired renal function are, by themselves, not contraindications </li></ul></ul>Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010.
    37. 37. Stem Cell Transplantation <ul><li>Key issues </li></ul><ul><li>Efficacy compared with conventional chemotherapy </li></ul><ul><li>Timing: early vs delayed </li></ul><ul><li>Single vs tandem </li></ul><ul><li>Role of allogeneic and miniallogeneic transplantations </li></ul><ul><li>Maintenance post-SCT </li></ul>
    38. 38. Novel Frontline Options <ul><li>Immunomodulatory drugs (IMiDs) </li></ul><ul><ul><li>Thalidomide </li></ul></ul><ul><ul><li>Lenalidomide </li></ul></ul><ul><li>Proteasome inhibitors </li></ul><ul><ul><li>Bortezomib </li></ul></ul><ul><ul><li>Carfilzomib </li></ul></ul>
    39. 39. Proposed Mechanism of Action for Multiple Myeloma Therapies Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Copyright ©2004. Massachusetts Medical Society. All rights reserved.
    40. 40. Thalidomide: Proposed Mechanism of Action <ul><li>Proposed mechanisms </li></ul><ul><ul><li>Inhibition of TNF-  </li></ul></ul><ul><ul><li>Suppression of angiogenesis </li></ul></ul><ul><ul><li>Increase in cell-mediated cytotoxic effects </li></ul></ul><ul><ul><li>Modulation of adhesion molecule expression </li></ul></ul>Kyle RA, et al. N Engl J Med. 2004;351:1860-1873. Rajkumar SV, et al. Leukemia. 2003;17:775-779. D’Amato RJ, et al.Proc Natl Acad Sci U S A. 1994;91:4082-4085.
    41. 41. Lenalidomide <ul><li>Immunomodulatory derivative of thalidomide </li></ul><ul><li>More potent than thalidomide in preclinical models </li></ul><ul><ul><li>Dose-dependent decrease in TNF- α and interleukin-6 </li></ul></ul><ul><ul><li>Directly induces apoptosis, G1 growth arrest </li></ul></ul><ul><ul><li>Enhances activity of dexamethasone </li></ul></ul><ul><li>More favorable toxicity profile than thalidomide </li></ul><ul><li>Difficult to use in renal insufficiency ( dose adjust) </li></ul>Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.
    42. 42. Lenalidomide Dosing for MM and Impaired Renal Function Lenalidomide [package insert]. Renal Impairment (CrCl) Lenalidomide Dosage Moderate (30 to < 60 mL/min) 10 mg QD Severe (< 30 mL/min, not requiring dialysis) 15 mg Q 48 hrs ESRD (< 30 mL/min, requiring dialysis) 5 mg QD On dialysis days, administer following dialysis
    43. 43. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2  3  4 b5  6  7 Cross section of  ring Bortezomib <ul><ul><li>Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. </li></ul></ul>B O O OH N N OH Interferes with intracellular pathway that degrades proteins regulating cell cycle, apoptosis,angiogenesis H N N H
    44. 44. Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM <ul><li>Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials </li></ul><ul><li>80% of patients entered these trials with preexisting peripheral neuropathy </li></ul><ul><li>3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy </li></ul>Richardson PG, et al. ASH 2003. Abstract 512.
    45. 45. Initial Approach to Treatment of MM Clearly not a transplantation candidate MPT, MPV, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction Stem cell harvest
    46. 46. Frontline Therapy in Elderly MM Patients <ul><li>For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment </li></ul><ul><ul><li>ORR: 60% </li></ul></ul><ul><ul><li>Long-term CR: < 5% </li></ul></ul><ul><li>Trials with MP-based combinations reported improved response rates and time to progression </li></ul><ul><ul><li>MPT </li></ul></ul><ul><ul><li>VMP </li></ul></ul>NCCN Practice Guidelines. Myeloma. V.3.2010.
    47. 47. Conclusions <ul><li>In elderly patients, the addition of novel agents to standard MP has provided improved response rates </li></ul><ul><ul><li>MP alone (ORR: 50%; CR: 5%) </li></ul></ul><ul><ul><li>MPR (50% to 95% reduction in myeloma protein in 55.6%) </li></ul></ul><ul><ul><li>VMP (ORR: 86%) </li></ul></ul><ul><li>Care should be taken with IMiD-based therapy to include aspirin prophylaxis for DVT/PE </li></ul><ul><li>Care should be taken with bortezomib-based regimens to include herpes zoster prophylaxis </li></ul>
    48. 48. MM & Skeletal Complications <ul><li>~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey </li></ul><ul><ul><li>Vertebrae: 65% </li></ul></ul><ul><ul><li>Ribs: 45% </li></ul></ul><ul><ul><li>Skull: 40% </li></ul></ul><ul><ul><li>Shoulders: 40% </li></ul></ul><ul><ul><li>Pelvis: 30% </li></ul></ul><ul><ul><li>Long bones: 25% </li></ul></ul>Dimopoulos M, et al. Leukemia. 2009:1-12.
    49. 49. The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.
    50. 50. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis [1] Bisphosphonates are released locally during bone resorption [1] Bisphosphonates are concentrated under osteoclasts [1] Bisphosphonates may modulate signaling from osteoblasts to osteoclasts New bone X Bone <ul><li>Increased OPG production [2] </li></ul><ul><li>Decreased RANKL expression [3] </li></ul>1. Reszka AA, et al. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V, et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B, et al. J Bone Miner Res. 2004;19:147-154.
    51. 51. Recommended Doses and Infusion Times *Consider dose reduction . † 3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39 mL/min). Kyle R, et al. J Clin Oncol. 2007;25:2464-2472. Drug Dose/Infusion Time Interval Estimated CrCl > 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs 4 mg over 15 mins 3-4 wks 3-4 wks Estimated CrCl 30 to < 60 mL/min Pamidronate Zoledronic acid 90 mg over 2-3 hrs* Reduced dosage † 3-4 wks 3-4 wks Estimated CrCl < 30 mL/min Pamidronate Zoledronic acid 90 mg over 4-6 hrs* Not recommended 3-4 wks
    52. 52. Bisphosphonates and Osteonecrosis <ul><li>Uncommon complication causing avascular necrosis of maxilla or mandible </li></ul><ul><li>Suspect with tooth or jaw pain or exposed bone </li></ul><ul><li>May be related to duration of therapy </li></ul><ul><li>True incidence unknown </li></ul><ul><li>Always enquire recent dental therapy or tooth related problems before starting bisphosphonates </li></ul>Papapetrou PD. Hormones (Athens). 2009;8:96-110.
    53. 53. POEMS (Osteosclerotic myeloma)
    54. 54. POEMS (Osteosclerotic myeloma)
    55. 55. Plasma Cell Leukemia <ul><li>>2 X 109/L plasma cells in blood ( seen on peripheral smear) </li></ul><ul><li>Younger age </li></ul><ul><li>Higher incidence of organomegaly and lymphadenopathy </li></ul><ul><li>More extensive bone marrow infiltration </li></ul><ul><li>Renal failure more common </li></ul><ul><li>Less bone pain, fewer lytic lesions </li></ul><ul><li>Poor response to therapy </li></ul><ul><li>Peripheral smear showing Plasma cells </li></ul>
    56. 56. <ul><li>Monoclonal gammopathy - IgM type </li></ul><ul><li>Plasmacytoid lymphoma </li></ul><ul><li>Median age at diagnosis - 60 yrs </li></ul><ul><li>Presentation : </li></ul><ul><ul><ul><li>Hyperviscosity syndrome (15%) : visual impairment, neurologic manifestations </li></ul></ul></ul><ul><ul><ul><li>Bleeding ( Acquired VWD) </li></ul></ul></ul><ul><ul><ul><li>Cryoglobulinaemia </li></ul></ul></ul><ul><ul><ul><li>Organomegaly, lymphadenopathy + (20%-40%) </li></ul></ul></ul><ul><ul><ul><li>Autoimmune hemolysis - common </li></ul></ul></ul><ul><ul><ul><li>Bone marrow involvement 90% </li></ul></ul></ul><ul><ul><ul><li>Lytic bone lesions 2% </li></ul></ul></ul><ul><ul><ul><li>Hypercalcemia 4% </li></ul></ul></ul><ul><li>Management : </li></ul><ul><ul><li>Asymptomatic patients not treated until symptoms develop </li></ul></ul><ul><ul><li>If Hyperviscocity features  urgent Plasmapheresis </li></ul></ul><ul><ul><li>Symptomatic WM : Rituximab based therapy </li></ul></ul>Waldenstrom’s Macroglobulinemia
    57. 57. Amyloidosis
    58. 58. <ul><li>Evaluate for amyloidosis in patients with a monoclonal protein in serum or urine plus : </li></ul><ul><ul><ul><li>Nephrotic syndrome or renal insufficiency </li></ul></ul></ul><ul><ul><ul><li>Congestive heart failure </li></ul></ul></ul><ul><ul><ul><li>Peripheral neuropathy </li></ul></ul></ul><ul><ul><ul><li>Carpal tunnel syndrome </li></ul></ul></ul><ul><ul><ul><li>Hepatomegaly </li></ul></ul></ul><ul><ul><ul><li>Idiopathic malabsorption </li></ul></ul></ul><ul><ul><li>Diagnostic Criteria: </li></ul></ul><ul><ul><ul><ul><li>Tissue biopsy showing typical morphology </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Apple green birefringence under polarized light after Congo Red staining </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Typical fibrillar ultrastructure </li></ul></ul></ul></ul><ul><ul><li>Diagnostic methods and Sensitivity </li></ul></ul><ul><ul><ul><ul><ul><li>Bone marrow examination 56% </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Abdominal fat aspiration 80% </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Combined BM & fat aspirate 89% </li></ul></ul></ul></ul></ul>Amyloidosis
    59. 59. Questions?