Management of multiple myeloma

doctor à SKIMS hospital
9 Apr 2015

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Management of multiple myeloma

  3. Sarah Newbury, the first reported patient with multiple myeloma. A) Bone destruction in the sternum. (B) The patient with fractured femurs and right humerus. (C) Bone destrucion involving femur(reported by Dr William Macintyre in london 1845).Autopsy by dr John Dalrymple.) IN 1873 Rutizksy coined the term multiple myeloma.
  4. Epidemology The American Cancer Society has estimated 26,850 new cancer cases of MM in the United States in 2014, with an estimated 11,240 deaths representing 1% of all malignancies in whites and 2% in Afarican americans. Among hematological malignancies it constitutes 10% (2nd in number) in USA The mean age of affected individuals is 62 years for men (75% >70 years of age) and 61 years for women (79% >70 years of age). The 5-year survival rate reported in the SEER database has increased from 25% in 1975 to 34% in 2003 due to newer and more effective treatment options available.( survilance epidemology and end results programme). MALES more common than females(1.6:1) India..0.5 % of all malignancies. KASHMIR:-76/3940(0.02%) in 2014.
  5. ETIOLOGY • Radiation • Occupational (Ni,agricultural chemicals,benzene,petroleum,silicon ) • Mineral oil used as laxative • Heriditary and genetic. • HLA-cw2 over expression • Race (2:1) • Repeated infections(however no evident cause associated). • MGUS(premalignant condition).
  6. B cell differentiation
  7. Pathophysiology Indolent phase (MGUS , smoldering myeloma, myeloma IA ) 1-3 yr or longer Overt phase Increase in M pr Appearance of end organ damage 6 m0- 1 yr Plateau phase Aggressive terminal phase Dependent on BM stroma Treat effectively Temporarily can be controlled by chemo Responses short lived, survival poor
  8. Multiple Myeloma - Cytogenetics Deletion 17p and Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy
  9. radiation exposure Chr. Osteomyelitis, HHV8
  10. Bone marrow micro environment
  11. Clinical features Expansion of neoplastic cells Secretory proteins Host response
  12. Multiple myeloma Marrow infiltration Release of cytokines Bone destruction Bone pain Hypercalcemia IL-6 Il 1 β Anemia Monoclonal protein Immune deficiency Renal failure hyperviscosity Amylodosis Infection Neurological symptoms coagulopathy EMD
  13. Serum Protein Electrophoresis Serum Protein Electrophoresis : • 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. • Immunoglobulins ( IgG, IgM, IgA) usually migrate to gamma region but may sometimes extend to beta region. • SPEP should always be performed in combination with serum immunofixation in order to determine clonality
  14. SPEP SPEP showing Monoclonal Gammopathy • Shows a tall “narrow” band in gamma region – “M-Spike” • Also, note reduction in the normal polyclonal gamma band
  15. SPEP SPEP showing Polyclonal Gammopathy • Shows a broad based peak in gamma region . • Seen in chronic infections, inflammation, connective tissue disease, lymphoproliferative disease.
  16. Immunofixation • More sensitive than SPEP • Immunofixation is performed when SPEP shows a sharp “peak” or a plasma cell disorder is suspected despite a normal SPEP • 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)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.
  17. Bone marrow exaination
  18. Skeltal survey Skull – punched out lesions The bone lesions - proliferation of tumor cells, activation of osteoclasts and suppression of osteoblasts The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation. radioisotopic bone scanning is less useful in diagnosis than is plain radiography.
  19. MM & Skeletal Complications ~ 80% of patients with multiple myeloma will have evidence of skeletal involvement on skeletal survey • Vertebrae: 65% • Ribs: 45% • Skull: 40% • Shoulders: 40% • Pelvis: 30% • Long bones: 25% Dimopoulos M, et al. Leukemia. 2009:1-12.
  20. . MRI offers a sensitive means to document extent of bone marrow infiltration and cord or root compression in patients with pain syndromes.
  21. PET SCAN
  23. Prognostic factors
  25. Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder i.e; Undetermined Significance Monoclonal Gammopathy of Undetermined Significance ( MGUS)
  26. • Incidence of MGUS increases with age : • 1% of adults in US • 3% of adults over age 70 years • 11% of adults over age 80 years • 14% of adults over age 90 years • Significance : Can progress to monoclonal Disease IgG or IgA MGUS IgM MGUS Monoclonal Gammopathy of Undetermined Significance ( MGUS)
  27. • Predictors of Progression : • Size of the M-protein at the time of recognition of MGUS - most important predictor of progression • IgM & IgA monoclonal proteins have a greater risk of progression than an IgG M-protein. • Risk of progression does not go away with time! • Risk of progression 1% per year • CUMULATIVE RISK • 10% at 10 years, 25% at 25 years from diagnosis • So, Management : MGUS - Progression
  28. • Both criteria should be met : • Serum monoclonal protein ≥3 g/dL and/or bone marrow plasma cells ≥10 percent • No end organ damage related to plasma cell dyscrasia (see CRAB) • Management : • Does not require any intervention • 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) Smoldering Myeloma
  29. • Rare variant : About 1% of Myelomas • May present with Bone lesions ( most common presenting symptom bone pain) • No serum or urine monoclonal protein ( diagnosis can be missed if one is not aware of this entity, NSMM). • Renal failure and hypercalcemia are generally lacking • Anemia may be present • 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. • Must rule out IgD and IgE myeloma Non-Secretory Myeloma
  30. 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
  31. • Plasma cell tumors that arise outside the bone marrow and no features of Multiple Myeloma • Most Common Primary Sites - Head and Neck region: Upper air passages and oropharynx (May involve draining lymph nodes. • Less Common Sites – Lymph nodes (primary), salivary glands, spleen, liver, etc. • 25% have small monoclonal spike • Rare dissemination, rarer evolution to myeloma • Management : • If completely resected during biopsy, no further therapy • If incompletely resected, radiation therapy locally Extramedullary Plasmacytoma
  32. All three criteria must be met • Presence of a serum or urinary monoclonal protein • Presence of 10 percent or more clonal plasma cells in the bone marrow or a plasmacytoma • Presence of end organ damage felt related to the plasma cell dyscrasia, such as: CRAB : Hypercalcemia (calcium > 11.5gm%), Renal Insufficiency, Anemia (hgb < 10gm%) or Lytic bone lesions Multiple Myeloma
  33. Multiple Myeloma Spinal Cord Compression : oncological Emergency Spinal cord compression occurs in 5 % of patients with multiple myeloma ( plasmacytoma or pathological fracture related) Managed with urgent: 1. Corticosteroids 2.Neurosurgical intervention (laminectomy or anterior decompression in pathological #) + radiation therapy to preserve neurological function 3. Radiation therapy alone ( plasmacytoma)
  34. *Thal/dex or dex are additional options especially if immediate response is needed. Clearly not transplantation candidate based on age, performance score, and comorbidity BD/MPT, MPB, Len/dex or clinical trial* Potential transplantation candidate Nonalkylator-based induction x 2 cycles (BD/BDD/BTD/LD/BCD) Stem cell harvest Initial Approach to Treatment of MM
  35. Novel Frontline Options Immunomodulatory drugs (IMiDs) • Thalidomide • Lenalidomide Proteasome inhibitors • Bortezomib • Carfilzomib
  36. Thalidomide: Proposed Mechanism of Action 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.
  37. Lenalidomide Immunomodulatory derivative of thalidomide More potent than thalidomide in preclinical models • Dose-dependent decrease in TNF-α and interleukin-6 • Directly induces apoptosis, G1 growth arrest • Enhances activity of dexamethasone More favorable toxicity profile than thalidomide Difficult to use in renal insufficiency ( dose adjust) Richardson P, et al. Blood. 2003;100:3063. Hideshima T, et al. Blood. 2000;96:2943-2950.
  38. Bortezomib: A Reversible Proteasome Inhibitor Chymo- tryptic Site Post- Glutamyl Site Tryptic Site b1 b2 b3 b4 b5 b6 b7 Cross section of b ring Bortezomib Adams J, et al. Invest New Drugs. 2000;18:109-121. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338. H N B N H O O OH N N OH Interferes with intracellular pathway that degrades proteins regulating cell cycle, apoptosis,angiogenesis
  39. Transplant candidates Induction chemotherapy Stem cell transplant Maintenance
  40. Induction cemotherapy
  41. Who is not a candidate for transplant ? • Age >65 yrs • Myeloma related organ or tissue impairment (end organ damage) ( ROTI) Hb 2 g /dl below the lower limit of normal or, <10 g /dl s. Ca - 25 mmol/l above the upper limit of normal or, >75 mmol/ l bone lesions- lytic lesions or osteoporosis with compression fractures s creat - >173 µmol/ l symptomatic hyperviscosity, amyloidosis, reccurent bac infections (>2 episodes in 12 months) Hence majority of patients are not candidates
  42. Non transplant candidates
  43. Rationale of SCT
  44. Myeloablation with stem cell support • 1.TBI (12 Gy in 8 #) and cyclophosphamide • 2. TBI (8 Gy ) +high dose melphalan +/- Cyclo • 3. high dose melphalan alone (140-200 mg/m2) • High dose carboplatin /etopside /cyclo.
  45. Total body irradiation  Goal – as palliation in radiation sensitive disease to eradiacte residual cancer  Used along with stem cell support  Technique – 1. using large field size to encompass entire body – stationary beam Extended SSD – 200-600cmStandard SSD LINAC
  46. 2. use less than whole body FS - Moving beam / couch
  47.  Rigorous dosimetry  Use of compensators at head neck region  Dose variation acceptible- 10 % of prescribed dose  Supine postion , at extended SSD, using AP/PA – most desirable  Back up must be available Presciption – midpoint at level of umbilicus Dose / fractionation  8- 10 Gy/ SF at dose rate  12-15 Gy @ 1-5 -2 Gy / # twice or thrice daily Complications  Pneumonitis fractionated regimes tolerated better
  48. Role of maintenance therapy? Why the question? • Despite ↑remission rates, -no clear plateau in the survival curves following conventional or HDT. • Although the proportion of patients achieving CR has increased, all patients eventually relapse. • Various maintenance therapies have been evaluated in MM in an effort to sustain remission.
  49. Maintenance therapy  Depends on type , length of induction therapy  If steroids used- depends on type, dose, schedule  No standard therapy to prolong TTP.  modest increase in only EFS not OS Agents tried–  low dose (50 mg )alt day prednisolone Berenson et al. Blood 2002;99:3163. Lenalidomide(25 mg) Br J Haematol 2013;112:1020-34  thalidomide 200 mg OD Attal et al. Blood 2006;108:3289.
  50. Role of radiation  Mainstay of treatment prior to availability of chemotherapy  Present day role Definitive  solitary bone / extradural plasmacytoma  Dose – 40-50 Gy @ 2 Gy / # Palliative  impending bone fracture- vertebra, humerus, femur, pelvis  spinal cord compression For irradiation hemipelvis, monitor hemogram
  51. Portal  8 cm wide  Centered on spine  Extends one to two vertebral bodies above and below
  52. • Dose- 30 Gy/ 10 #,/20 Gy/ 5 #,(30 Gy dose better than 20gy ) Radies D et al:J cli oncology:2005 • Energy- 1.25 Mv/ • Prone • Supine- treat through table, after raising table ht to max • Cervical spine- direct posterior field. Thoracic spine- single post field. • Lumbar spine/pelvis- AP – PA field / single post field
  53. • Fractures of long bone - fixation - post op RT • Symptomatic vertebral compression fractures- vertebroplasty/ kyphoplasty - post op RT • 50 % of nonambulatory cases regain ambulation after RT • 67 % cases improve sphincter function • 89 % - relief of back pain . • Median duration of response 12 months LECOVET ET AL:BR J HEMATOLOGY:1997 • For analgesia, however, avoid NSAID • use lumbar corsets, braces for stabilising spine
  54. Bisphosphonates • Bisphosphonates are structural analogues of pyrophosphates that bind to hydroxyapatite crystals in bone & inhibit osteoclast induced bone resorption drug IV/oral dose pamindronate Iv 60 – 90 mg 4wkly zoledronate iv 4 mg 4 wkly clodronate PO 1600 mg / d ibandronate PO 50 mg/d Oral formulations less tolerated because of GI toxicity Overall bisphosphonates results in 44 % relief in bone pain, 28 - 56 % decrease in bony complications , including hypercalcemia, decrease need for EBRT. Relatively safe & inexpensive, at least 1 yr therapy reqd for any significant response Zoledronic acid more effective than pamidronate Combining CCT well tolerated & also improves PFS
  55. • However , these agents can cause • Renal dysfunction – Pamindronate – glomerular lesion , with proteinuria (nephrotic levels ) zolendronic acid – tubular dysfunction • Ostenecrosis of jaw – before starting – all patients should have dental examination • Monitor s. calcium- if s. calcium reduced oral calcium 1000 mg daily and Vitamin D (800 IU ) can be given • Ensure adequate hydration – 2-3 l of liquids to promote excretion of light chains, Ca , UA
  56. Special clinical problems and other supportive measures Hypercalcemia Nausea, fatigue, confusion, polyuria, constipation Best approach- admit, check RFT,SE,Alb, Ca IV fluids, dexam, bisphosphonate Renal failure Hydrate, treat hypercalcemia, reduce s .UA, consider hemodialysis if reasonable evidence of good prognosis and have not failed initial therapy Infections Foremost cause of death Prophylactic use of IVIg, antibiotics not required Hyper viscosity Bleeding, retinopathy,malaise, stroke,coma Serum M protein > 3-4 g/dl plasmapheresis Anemia Normocytic, normochromic Erythropoetin- improves Hb by >2 g/dl
  57. • ULTRA HIGH RISK MM. • 25 % of MM patients are now are classfied in to UHRM. • They include the following • ISS 3 with clinical presentation as EMD OR Plasma cell leukemia • LDH high,FISH shows 17q deletion with PCLI >1%. • SURVIVAL <2YRS • POMALIDOMIDE(3rd generation im is used /currently recommended)
  58. Future therapies • t(4,14) >>>> FGGR3 gene>>>>>dovatinib • t(11,14)>>>cyclin d>>>>>>seleciclib,dinaciclib • Braf mutation>>>>>>tipifaranib
  59. THANKU