Multiple myeloma

MM

1. Multiple Myeloma Prem Mohan Jha 12/11/2019 1

2. Introduction Myeloma is a cancer of plasma cells. Plasma cells make antibodies that help to fight infections and play a key role in bone repair. Myeloma cells make too many copies of themselves. Myeloma cells make abnormal antibodies called M proteins that don’t help to fight germs. When myeloma cells spread throught the bone marrow, it is called multiple myeloma. 12/11/2019 2

3. Introduction 12/11/2019 3 Renal impairment is a common feature of symptomatic multiple myeloma (MM). It is not rare for a patient with myeloma to present to the nephrology clinic for evaluation of renal impairment, which is usually of recent onset, or to be hospitalized because of acute kidney injury (AKI). Conversely, in a patient with MM, development of RI may provide a clue to the diagnosis of the disease and may cause major management problems.

4. https://seer.cancer.gov 12/11/2019 4

5. https://seer.cancer.gov 12/11/2019 5

6. https://seer.cancer.gov 12/11/2019 6

7. https://seer.cancer.gov 12/11/2019 7

8. The Immune System In Myeloma 12/11/2019 8

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11. Who Classification Of Plasma Cell Neoplasms Monoclonal gammopathy of undetermined significance Multiple Myeloma Symptomatic Asymptomatic (Smoldering) Nonsecretory Plasma Cell Leukemia Plasmacytoma Solitary plasmacytoma of bone Extra medullary plasmacytoma Deposition Disease Primary Amyloidosis , Systemic Heavy and Light Chain Disease Osteosclerotic Myeloma (POEMS Syndrome) 12/11/2019 11

12. Natural History 12/11/2019 12 Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007

13. Progression to Symptomatic MM MGUS: up to 2 percent of persons 50 years of age or older and about 3 percent of those older than 70 years For SMM, maximum risk in the first 5 years Risk factors : Higher M spike, higher plasma cell burden, type of M protein, Abnormal free light chain ratio, circulating plasma cells . Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007 12/11/2019 13

14. Clinical Presentation 12/11/2019 14

15. Symptomatology Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78:21. 12/11/2019 15

16. Symptomatology 12/11/2019 16

17. Causes Of Anemia In Myeloma Bone marrow infiltration. Suppression by cytokines : TNF alfa , IL1. Erythroid apoptosis by fas ligand . Decreased erythropoietin production. Bleeding. Infections. 12/11/2019 17

18. Bone Pain Most common symptom. Aggravated on movement Sites : vertebral column> ribs > skull > pelvis > femur > clavicle > scapula. Persistent pain is s/o patjological fracture. Hypercalcemia Spinal cord compression Palpable mass lesion 12/11/2019 18

19. Renal disease 12/11/2019 19

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23. Renal disease Additional factors exacerbating renal failure in MM Volume depletion NSAIDS Hyperuricemia Nephrotoxic chemotherapeutic agents IV contrast Bisphosphonates Calcium 12/11/2019 23

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25. Diagnosis of Multiple Myeloma The diagnostic criteria that is currently accepted and followed is the International Myeloma Working Group Classification published in 2003. IMWG revised the diagnostic criteria in 2014. The International Myeloma Working Group recommends these criteria for routine practice and future clinical trials. 12/11/2019 25

26. Multiple Myeloma 12/11/2019 26 Criteria for the classification of monoclonal gammopathies , multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br. J. Haematol . 2003 Jun;121(5):749–57.

27. Smouldering Multiple Myeloma This is an intermediate stage during the transition from MGUS to frank symptomatic MM. The monoclonal plasmacytosis and gammopathy has increased to MM levels but the end organ damage that defines MM has not yet occurred. Serum monoclonal protein ( IgG or IgA ) ≥ 3gm/dl or 24 hr urinary monoclonal protein ≥500 mg and/or bone marrow plasma cells 10-60%. Absence of myeloma defining event or amyloidosis . 12/11/2019 27

28. Monoclonal Gammopathy of Undetermined Significance In almost all cases multiple myeloma is preceded by a premalignant asymptomatic stage termed as MGUS. In population over the age of 50 year MGUS is present in 3-4% cases. MGUS can progress to multiple myeloma at the rate of 1% per year. Diagnosis of MGUS requires the absence of end organ involvement. 12/11/2019 28

29. Monoclonal Gammopathy of Undetermined Significance All three criteria must be met: Serum monoclonal protein <3 gm/ dL Clonal bone marrow plasma cells <10%, Absence of end-organ damage Considering this high risk of plasma cell disorder, persons found to have MGUS should be monitored stringently lifelong. 12/11/2019 29

30. Solitary Plasmacytoma of Bone Occurs around a decade younger than MM. More common in males. The sites commonly affected are the axial skeleton more than the appendicular skeleton. Rate of progression to multiple myeloma is 10% in 3 years. 12/11/2019 30 Solitary plasmacytoma is diagnosed by: Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells Normal bone marrow with no evidence of clonal plasma cells Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) Absence of end-organ damage.

31. Extramedullary Plasmacytoma The common sites of involvement are the nasal cavity, nasopharynx , larynx and sinuses. It can happen in any location in the body and is commonly of the IgA subtype. Other evidence of systemic MM should not be present. The diagnostic criteria is: No M-protein in serum and/or urine Extramedullary tumour of clonal plasma cells Normal bone marrow Normal skeletal survey No end organ damage including bone lesions. 12/11/2019 31

32. Multiple Solitary Plasmacytomas This entity constitutes less than 5% of all PCDs. The diagnostic criteria for this entity are as follows: No M-protein in serum and/or urine More than one localized area of bone destruction or extramedullary tumour of clonal plasma cells which may be recurrent Normal bone marrow Normal skeletal survey and MRI of spine and pelvis if done No end organ damage other than the localized bone lesions. * Small elevation of M protein may be seen. 12/11/2019 32

33. Plasma Cell Leukaemia PCL occurs when there is more than 20% abnormal plasma cells in the differential WBC lineage or if there is an absolute number of more than 2x10^9/L of plasma cells. This might be primary or secondary. Primary (approx. 60%), if the patient presents with PCL and secondary is if the patients progresses to PCL from MM. 12/11/2019 33

34. Diagnostis 12/11/2019 34

35. Monoclonal Gammopathy The gold standard : SIFE & UIFE. In practice it is prudent to start with SPEP & UPEP As further follow ups require only a SPEP. 80% of MM patients will have a positive SPEP. With SIFE being added this increases to 93%. By adding UIFE the success rate of identifying a monoclonal gammopathy increased to 97%. 12/11/2019 35 Criteria for the classification of monoclonal gammopathies , multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br. J. Haematol . 2003 Jun;121(5):749–57.

36. Monoclonal Gammopathy 12/11/2019 36

37. Serum Free Light Chain Assay 12/11/2019 37

38. Serum Assays of Immunoglobulins 12/11/2019 38

39. Bone Marrow (BM) 12/11/2019 39

40. Test for Organ Involvement Anaemia is present at initial presentation in around two thirds of patients while during the course of the disease almost everyone will have this. The cut-off level of Hb for diagnosis of MM is <10gm% or 2gm% less than the normal. The anaemia is usually normocytic , normochromic in nature. Hypercalcemia is present in around 10-15% patients at presentation and is a major cause of reversible Renal insufficiency at presentation, usually responding to hydration and steroids. Serum Creatinine elevations above normal values are found in about one third of patients at presentation but requirement of dialysis is much lesser, most of them responding to correction of dehydration and hypercalcemia . Bone lesions. 12/11/2019 40

41. Imaging 12/11/2019 41

42. Imaging 12/11/2019 42

43. Imaging 12/11/2019 43

44. To summarize 12/11/2019 44

45. Other Investigations Required For Prognostication Serum β2 microglobulins : This is one of the back bones of the International Staging System (ISS) and is a marker of tumor burden. Serum LDH: Has an independent prognostic significance in various studies. ESR : Elevated in most cases of MM but the values correlate neither with tumor burden nor with treatment response. 12/11/2019 45

46. C-Reactive proteins : Elevated in MM and might be of value when infections are a presenting feature of MM. Molecular testing : Conventional cytogenetics and Fluorescent In situ Hybridisation (FISH) are being used recently. As per the available data researchers from Mayo Clinic have devised a stratification system based on cytogenetics which is as follows, 12/11/2019 46

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48. Minimum Baseline Diagnostic Workup 12/11/2019 48

49. Investigations For Monitoring 12/11/2019 49

50. Detection of Clonal Plasma Cells Bone marrow Plasmacytoma Peripheral blood 12/11/2019 50

51. Demonstrating Monoclonal Protein 12/11/2019 51 10 1 100 1000 10000 100000 0.1 1000 10000 100000 1 10 100 Serum Kappa (mg/L) Serum Lambda (mg/L) Normal sera Kappa LCMM Lambda LCMM Renal impairment Serum or Urine Protein Electrophoresis Serum or Urine I mm uno f i xat io n 0.1 Serum Free Light Chain Assay FLC reference range:  3.3 – 19.4 mg/L  5.7 – 26.3 mg/L    ratio 0.26 - 1.65 FLC reference range : In Renal Impairement    ratio : 0. 37 – 3.1

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53. Skeletal Surveys 12/11/2019 53

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55. When Should A Renal Biopsy Be Performed In A Patient With Multiple Myeloma? 12/11/2019 55

56. Why A Renal Biopsy May Be Helpful Even When MCN Seems Certain 12/11/2019 56 Significant portion of patients had secondary renal pathologies. Eight cases of coexisting MIDD, three cases of AL amyloidosis and nine cases of focal segmental glomerulosclerosis , which occurred at a rate much higher than previously thought. Renal biopsy had prognostic importance. The benefits must be balanced by the cost, the risk and the added benefits. Ecotière et al. Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients. Nephrol Dial Transplant 2016; 31: 64–72.)

57. Histologic Features of Myeloma Kidney 12/11/2019 57

58. Myeloma Cast Nephropathy 12/11/2019 58

59. Treatment 12/11/2019 59

60. Supportive Care Adequate hydration is a key component. Treatment of anemia Prompt treatment of infections. Management of hypercalcaemia is crucial. Avoidance of agents that contribute to renal damage, such as NSAIDS, aminoglycoside antibiotics, and contrast dyes . 12/11/2019 60

61. Anemia 12/11/2019 61

62. Infections 12/11/2019 62

63. Thrombosis 12/11/2019 63

64. Pain WHO ladder that can be used are 1. Paracetomol (Max 1 gm QID) 2. Tramadol (max 50mg QID or BD sustained release forms) 3. Fentanyl patches (25-50 mcg patch/ 48 hrs) 4. Morphine can be used for severe pain (patients on palliative care for advanced myeloma may be given max morphine upto 120 mg/day) 5. Neuropathic pain: Gabapentin / Pregabalin / Amitryptyline All patients receiving opioid analgesics to be given laxatives. Avoid using NSAIDS 12/11/2019 64

65. Peripheral Neuropathy PN can be due to myeloma disease per se (M-protein associated), POEMS, AL- amyloidosis , chemotherapy induced (CIPN) or associated with comorbidities e.g. type2 diabetes mellitus, CIDP, CKD or nutritional deficiency. The prevalence of PN in newly diagnosed MM is to the tune of 62%. NCS is not always necessary in the diagnosis as they do not co-relate with the clinical findings. 12/11/2019 65

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68. 12/11/2019 68 Clin J Am Soc Nephrol 7: 1722–1729, 2012. doi : 10.2215/CJN.02470312

69. Bisphosphonates 12/11/2019 69

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71. 12/11/2019 71 Clin J Am Soc Nephrol 7: 1722–1729, 2012. doi : 10.2215/CJN.02470312

72. 12/11/2019 72 Future Oncol. (2015) 11(21), 2865–2871

73. Denosumab Denosumab is a fully human monoclonal antibody that binds to RANKL and inhibits osteoclast maturation, activation, and function. Denosumab is well tolerated, with arthralgias as the most common side effect. The FDA has reported only a slightly increased incidence of serious infections (4.1% for denosumab and 3.3% for placebo), with no increase in opportunistic infections. 12/11/2019 73

74. Denosumab Denosumab has been associated with a similar incidence of osteonecrosis of the jaw as zoledronic acid. The median response time is 9 days with duration of response sustained for up to 104 days. Phase III multicenter randomized double-blinded trial comparing efficacy of denosumab with zoledronic acid showed a statistically significant delay in time with first on-study HCM, and recurrence of HCM in patients treated with denosumab compared with zoledronic acid. 12/11/2019 74

75. Denosumab 12/11/2019 75

76. Denosumab 12/11/2019 76 Cost Around 28000/-

77. Gallium Nitrate Approved for the treatment of malignancy related hypercalcemia . Reduction in osteoclast activity and bone remodeling . Administered by a continuous infusion at a dosage of 200 mg/m2 per day over 5 consecutive days. Reports comparing gallium to bisphosphonates and calcitonin have shown equal or perhaps even superior efficacy in decreasing calcium levels. Adverse effects: Hypocalcemia & Hypophosphatemia . The latter being observed in nearly 80% of patients. 12/11/2019 77

78. Gallium Nitrate Renal impairment has been reported. Not recommended for use when the serum creatinine concentration > 2.5 mg/dl. Adequate fluid resuscitation is essential before initiation of treatmentwith gallium. BUN and creatinine must be followed closely during treatment. Patients receiving gallium have reported nausea, vomiting, lethargy, altered mental status, and both diarrhea and constipation. 12/11/2019 78

79. Calcitonin Inhibits osteoclast bone resorption and increases urinary calcium excretion. Synthetic calcitonin (derived from salmon) is administered as 4–8 U/kg intramuscularly or subcutaneously every 6–8 hours. Rapid onset of effect, leading to reductions in serum calcium within 2–6 hours after dosing. Effect is modest and transient, with a mean duration of effect of 2–4 days. Repeated administration : Tachyphylaxis . 12/11/2019 79

80. Calcitonin Overall, its efficacy is poor, inducing normocalcemia in just one third of patients. Calcitonin’s major role may be as an adjunctive agent with bisphosphonates in the treatment of severe, symptomatic hypercalcemia when calcium levels must be reduced rapidly. Side effects are minimal; nausea, vomiting, and injection site pain are the most common. Davidson TG: Conventional treatment of hypercalcemia of malignancy Am J Health Syst Pharm 58[ Suppl 3]: S8–S15, 2001. 12/11/2019 80

81. Corticosteroids Inhibiting 1a-hydroxylase conversion of 25-hydroxyvitamin D to calcitriol . The efficacy of corticosteroids is based on case reports and thus the dosing guidelines are uncertain; Reasonable regimen is IV hydrocortisone, 200–300 mg/d, for 3–5 days. Typically, calcium levels are slow to decrease with corticosteroid treatment alone. 12/11/2019 81 Mathur M, Sykes JA, Saxena VR, et al: Treatment of acute lymphoblastic leukemia-induced extreme hypercalcemia with pamidronate and calcitonin . Pediatr Crit Care Med 4: 252–255, 2003

82. Hemodialysis 12/11/2019 82 For patients with acute hypercalcemia and AKI (especially in the setting of oliguria ), SALINE-INDUCED DIURESIS may not be feasible and may lead to volume overload. In these circumstances, hemodialysis using a very-low-calcium dialysate (#1 mmol /L) is an option. Argile´s A, Kerr PG, Canaud B, Flavier JL, Mion C: Calcium kinetic and the long-term effects of lowering dialysate calcium concentration. Kidney Int 43: 630–640, 1993. For refractory cases of hypercalcemia , several case reports describe the use of citrate anticoagulation to chelate calcium along with CVVHDF . Kindgen -Milles D, KramR , KleinekofortW , Morgera S: Treatment of severe hypercalcemia using continuous renal replacement therapy with regional citrate anticoagulation. ASAIO J 54: 442–444, 2008.

83. Plasma Exchange Two studies suggested that plasma exchange was beneficial. ( Pozzi et al., 1987; Zucchelli et al., 1988). Blade and Rosinol (2005) supported that patients with renal failure severe enough to require dialysis do not benefit from plasma exchange. In a recent report from the Mayo Clinic, plasma exchange in combination with bortezomib -based chemotherapy, in a limited number of patients, was associated with high rates of renal recovery . ( Burnette et al., 2011). 12/11/2019 83

84. Plasma Exchange In some patients with non- oliguric AKI, early initiation of a plasma exchange programme and effective chemotherapy may be of some benefit , but these patients should be carefully selected ( Dimopoulos et al., 2010c; Burnette et al., 2011). 12/11/2019 84

85. Specific Antimyeloma Therapy 12/11/2019 85

86. 12/11/2019 86 MPT , melphalan , prednisone, thalidomide; VMP , bortezomib , melphalan , prednisone; CTD , cyclophosphamide , thalidomide,dexamethasone ; MP , melphalan , prednisone; VTD , bortezomib , thalidomide,dexamethasone ; VCD , bortezomib , cyclophosphamide , dexamethasone ; PAD , bortezomib , doxorubicin, dexamethasone ; RVD , lenalidomide , bortezomib , dexamethasone , BP , bendamustin , prednisolone ]

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89. Two Drug Combinations Thalidomide- Dexamethasone (TD ): Thalidomide : 100-200 mg daily Dexamethasone : 40 mg on days : 1-4, 9-12, 17-20. Repeat every 4 weeks Overall response rate : 60-70% Progression free survival : 22 months. 12/11/2019 89 P Gupta. A twelve year study of multiple myeloma at the all india institute of medical sciences, new delhi , india . Indian Journal of Medical and Paediatric Oncology. 1995 Jun;16(2):108–14.

90. Lenalidomide - Dexamethasone (LD) : Lenalidomide : 25 mg daily from D1 to D21 Dexamethasone : 40 mg on D1, D8, D15, D21 Repeat every 4 weeks Overall response rate : 70 – 80 % Progression free survival : 25 months 12/11/2019 90 Philippe Moreau, Michel Attal , Thierry Facon : Frontline therapy of multiple myeloma. Blood. 2015; 125(20): 3076-3084 .

91. Bortezomib-Dexamethasone : (VD) Better response rates with VD(38% vs. 15% VGPR) and a modest improvement (36 vs. 30months). Grade 3 or 4 adverse events were similar in both groups (38% vs. 40%). There were more deaths during treatment in VAD arm, (0.8% vs. 2.9%). Neuropathy was more with VD arm (35% vs. 22% and Grade 3 or 4 in 10% vs. 3%). But to summarise this study showed that VD was superior to VAD regimen. 12/11/2019 91

92. The major drawback of Bortezomib -containing regimens is the risk of neurotoxicity early in the disease course. The neuropathy with Bortezomib can occur abruptly and can be significantly painful and debilitating in a subset of patients. Recent studies show that the neurotoxicity of Bortezomib can be greatly diminished by administering Bortezomib using a once-weekly schedule and by administering the drug subcutaneously. Bortezomib , unlike Lenalidomide , does not affect stem cell mobilisation . 12/11/2019 92

93. Multi Drug Combinations Bortezomib : 2 Mg Bolus IV Or SC On D1, D8, D15, D22. Thalidomide : 100 – 200 MG on days D1-D21. Dexamethasone : 40 mg on D1,D8,D15,D22. 4 cycles every 4 weeks Overall response rate : 95% 12/11/2019 93

94. Bortezomib–Cyclophosphamide–Dexamethasone ( VCD ) Cyclophosphamide : 300 mg/m2 orally on : D1,D8,D15,D22 Bortezomib : 2 mg iv on : D1, D8, D15, D22 Dexamethasone : 40 mg on : D1, D8, D15, D22 Repeat every 4 weeks Overall response rate : 90 % 12/11/2019 94

95. Bortezomib+Lenalidomide+Dexamethasone ( VRD) Bortezomib : 2 MG IV ON D1, D8, D15 Lenalidomide : 25 MG ORAL, ON D1-D14 Dexamethasone : 40 MG ON D1,D8,D15,D22 Overall Response Rate : 100% 12/11/2019 95

96. Bone Marrow Transplantation Autologous stem cell transplantation Allogeneic stem cell transplantation Stem cell Mobilization Plerixafor Cyclophosphamide 12/11/2019 96

97. Radiation therapy Indications Pre-transplantation Palliation of symptoms (i.e.: pain) Plasmacytoma 12/11/2019 97

98. Surgery Indications Plasmacytoma Pathological fractures Compression fractures 12/11/2019 98

99. Prognosis Stage of disease Proliferation rates LDH levels Treatment availability: Conventional therapy / Targeted Therapy / High-dose chemotherapy M protein concentration Age Treatment response Plasmablastic histology 12/11/2019 99

100. Poor Prognosticators High LDH levels Hypercalcemia Renal impairment Large tumor burden Bence -Jones proteinuria Low hemoglobin value 12/11/2019 100

101. Renal Transplant In Pts With Myeloma Related ESRD Rare due to the nature of the disease: Patients with MM die due to their underlying malignancy in a median of 3–5 years after the diagnosis. Furthermore, patients with MM are at high risk for infections, may experience several relapses in which the allograft is exposed to toxic light chains, and the use of immunosuppression may be problematic. (De Lima et al., 1981; Walker and Bear, 1983; van Bommel, 1996). 12/11/2019 101

102. Renal Transplant In Pts With Myeloma Related ESRD 12/11/2019 102

103. Thank You 12/11/2019 103