dr ayaskanta singh

8/14/2019 Dr AyASKANTA SINGH...

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Presented byDR . AYASKANTA SINGH

PG StudentPreceptor

DR . L . D . RAULAssociate Professor

P .G. Department ofmedicine


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Multiple myeloma represents malignant proliferation

of plasma cells derived from a single clone .1

It is a neoplastic plasma cell dyscrasia (PCD)characterized by a clinical pentad: (a) anemia(b) a monoclonal protein in the serum or urine or both

(c) abnormal bone radiographs and bone pain (d)hypercalcemia and (e) renal insufficiency .2

Multiple myeloma accounts for approximately 10% ofhematological cancers and 1 % of all cancers .2


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Incidence:

3 - 9 cases per 100000 population / year 2

more frequent in elderlymodest male predominance

The median age of diagnosis of 65-70 years . The diseaseis uncommon under age 40 .

The disease is uniformly fatal , with a median survival ofapproximately 3 years with conventional chemotherapy .


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Clinical symptoms:Bone pains, pathologicfractures

Weakness and fatigue anaemia

Serious infectionRenal failure

Bleeding diathesis

Neurologic symptoms

Nausea and vomiting

Laboratory tests:ESR > 100

Anaemia, thrombocytopeniaRouleaux in peripheral blood

smears

X ray- advanced lytic bonelesionsMarrow plasmacytosis > 10

-15%M protein in serum and/ or

urineHypercalcemiaProteinuriaAzotemia


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Almost all cases of multiple myeloma arisefrom an asymptomatic premalignantdisorder

characterized by proliferation in bonemarrow of monoclonal plasmacells ,derived from post germinal Bcells .

This is known as MGUS and the rate ofconversion to overt multiple myeloma is 1% per year.


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Multiple myeloma typically proceeds from a clonal proliferation of

plasma cells ,termed MGUS through intramedullary myeloma to extramedullary disease . These changes are accompanied by progressive

genetic changes (translocations , deletions and trisomy ) followed in the

later stage by oncogene mutations .3


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Monoclonal Gammopathy of Undetermined Significance (MGUS )Serum monoclonal protein (2 g/dl], anemia [hemoglobin 2 g/dl below lower limit of normal],bone lesions [ lytic lesions or osteoporosis with compression fracture] attributable to theplasma cell disorder).

bThe existence of immunoglobulin light-chain amyloidosis or another paraneoplasticdisorder attributable to the monoclonal gammopathy, such as a peripheral neuropathy.

Source: International Myeloma Working Group. Br J Haematol 2003; 121:749


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Patients with symptomatic and/orprogressive disease requires treatment .

Those with MGUS or smoldering

myeloma , who have no symptoms orspecific laboratory abnormalities should beobserved without therapy .

In general therapy is of two sorts :A)Systemic therapy to control the

progression of myeloma and B)Symptomatic supportive care to preventserious morbidity .


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The treatment of newly diagnosed multiple

myeloma patient depends on whether thepatient is transplant eligible or not .

Patients who are transplant candidates , i.e.

A) relatively young (


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A) Conventional chemotherapy.

Melphlan + Prednisone (MP)

VAD (Vincristine, Adriamycine,Dexamethasone)

Response rate 50-60% patients

Long term survival 5-10% patients

B) Combining THALIDOMIDE with MPimproves response rates and overall survivalthan MP alone. .

C) Combination ofBORTEZOMIB with MP isrecommended in patients of high risk groups.


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Multiple myeloma is relatively resistant to mostconventional chemo-therapeutic agent .

Since plasma cells are not dividing cells , cell cycledependant cytotoxic agents are of limited effectiveness .

Melphalan and cyclophosphamide and corticosteroids arethe most effective conventional agents for the treatmentof the disease.


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Drug resistance in myeloma is due to

1. Paucity of actively dividing cells.

2. Interleukin- 6 is a potent survival factor inmyeloma cells and induces resistance to druginduced apoptosis.

3. Interaction of myeloma cells with extracellularmatrix proteins and bone marrow stromal cells ,osteoblasts , osteoclast and endothelial cells.

4. The bone marrow micro-environment also

secretes anti apoptotic factors.


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To overcome drug resistance, high doses ofintravenous melphalan have been used to increasethe destruction of tumor cells. However this induces

severe and prolonged myelosuppression .

The morbidity and mortality of high dosechemotherapy are markedly reduced by infusion ofautologous hematopoietic stem cells.

Attal et al published the first prospectiverandomized control trial demonstrating an improvedsurvival for patients undergoing high dose of

therapy with autologous transplantation .5


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Autologous transplantation involves removal andstorage of the patients own cells with subsequentreinfusion after the patient receives high doses of

myeloablative therapy.

Homing of haematopoetic stem cells to bonemarrow microenvironment is poorly understood .

However, there is evidence that the binding ofchemokine SDF-1(stromal derived factor 1) toCXCR4 (CXC chemokine receptor 4) expressed onhematopoietic stem cells has a role. 4


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Homing of Autologous Hematopoietic Stem Cells to Bone Marrow

Homing of Autologous Hematopoietic Stem Cells to Bone Marrow. Hematopoietic stem cells express the chemokine receptor CXCR4,

whereas bone marrow stromal cells express chemokine stromal cell-derived factor 1 (SDF-1). After stem cells are infused into a recipient,

SDF-1 activates CXCR4-positive stem cells, stimulating adhesion to endothelial cells through interaction between intercellularadhesion molecule 1 (ICAM-1) and leukocyte-function-associated antigen 1 (LFA-1) and between very late antigen 4 (VLA-4) and

vascular-cell adhesion molecule 1 (VCAM-1). These stem cells then extravasate into the bone marrow stroma and adhere to stromal cells

through similar adhesion interactions between cells. Data are from Peled et al.14

Harousseau J and Moreau P. N Engl J Med 2009;360:2645-2654


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Autologous stem cell transplantation has no anti-tumor effect by itself and is a form of supportivemanagement after high dose therapy.

By restoring a functioning bone marrow soon aftertreatment, autologous stem cell therapy makes itpossible to deliver a very high dose of melphalanthat would have been fatal .


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Total duration of treatment is 4 6 months


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3 to 6 cycles of chemotherapy is given toreduce the tumor burden and plasma cellinfiltration in the bone marrow .

As a general rule , induction regimenshould be containing non alkylatingagents or if alkylating containing,number of cycles should be restricted to

four prior to stem cell mobilization .

Melphalan is not used in induction as it istoxic for hematopoietic stem cells .


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Induction treatment is dexamethasonebased , either used alone or in combination

with VAD chemotherapy .The dose of single agent dexamethasone is40 mg for 4 days every 2 week .

The dose of combination VADchemotherapy is-

VINCRISTINE 0.4 mg/d in a 4 daycontinous infusion

DOXORUBICIN-9 mg /m2 per day in a 4 daycontinuous infusion

DEXAMETHASONE-40 mg for 4 days perweek for 3 weeks


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The response rate of single agent high dosedexamethasone is 43% which is only 15 % lower

than VAD combination therapy .

Thus single agent dexamethasone is used in lieu ofVAD for induction . It has the advantage ofavoidance of immediate placement of a long-termcentral venous catheter .

However this approach is being replaced with theadvent of novel agents like thalidomide ,

bortezomib and lenalidomide .


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Reference Regimen phase N CR (%) VGPR(%)

PR (%) OR(%)

Raj kumar et al2006 DEX 3 104 0 0 41 41

THAL-DEX 3 99 4 0 59 63

Weber et al

2003

THAL-DEX 2 40 16 0 56 72

Demopolos et al2003

VAD 3 127 13 0 49 62

Goldshmidt et al2006

VAD 3 406 3 0 60 63

aganath et al2005 BORTEZ 2 32 3 9 28 40

BORTEZ+ DEX 2 32 6 19 63 88

Popat et al 2005 LD - PAD 2 19 11 28 50 89

Wintrobes clinical hematology


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According to European group for Blood and BoneMarrow Transplant (EBMT ) criteria :-

CR-COMPLETE RESPONSE : bone marrowplasma cells(BMPC) < 5% ; 100 % decrease in

serum and urine M protein within 6 months .

VGPR- Very Good Partial Response : BMPC 90% reduction in serum and urine M

protein .

PR Partial Response : BMPC < 5% ; 50-90 %reduction in serum and urine M protein


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1. Thalidomide

2. Bortezomib

3. Lenalidomide


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Thalidomide is an immune modulatory drug (IMiD) . Itinhibit angiogenesis , modulate adhesion molecules ofmyeloma cells and their surrounding stroma, modulatecytokines and affect natural killer cells, induces apoptosisand G1 growth arrest in myeloma cells .

As a single agent, response rates occur in about onethird of patients . The combination of thalidomide and

dexamethasone results in response rates of 63 to 72 % .6

Major adverse effects are deep vein thrombosis and

thromboembolic complications.


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Bortezomib is a reversible and selective

proteasome inhibitor. Myeloma cells, are heavilydependent on proteasome-regulated proteins fortheir growth and interaction with stromal cells.

Bortezomib cause growth arrest, to induce

apoptosis, and to inhibit angiogenesis .

The side effects of bortezomib are

Peripheral neuropathy .

Myelosuppression .Gastrointestinal nausea and vomiting .


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* Modified EBMT criteria Harousseau JL,et al ASCO 2008


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Lenalidomide (thalidomide derivative) is morepotent than thalidomide.

Rajkumar et al. treated 34 patients withlenalidomide 25 mg orally on days 1 to 21 anddexamethasone 40 mg on days 1 to 4, 9 to 12,and 17 to 20, both repeated every 28 days.Aspirin was given as DVT prophylaxis. Theoverall response rate was 91%, with 6%achieving a complete response and 32% a verygood partial response .

Adverse effects included thrombo-embolism ,peripheral neuropathy, neutropenia andthrombocytopenia


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Peripheral blood progenitors have replaced bone

marrow (aspirated from iliac crest ) as the source ofstem cells because of (1) Easier availability. (2)faster haematopoetic recovery aftertransplantation .(3) Reduced contamination by tumorcells .7

Cells (CD-34+ cells) are collected during aphaeresisprocedures after stem cell mobilization with the useof G-CSF or GM-CSF.

After collection, stem cells are cryopreserved indimethyl sulfoxide until transplantation .


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The standard preparative regimenbefore ASCT is high dose melphalan (200 mg per square meter of body

surface area ) .

It is administered as a single

intravenous infusion lasting 30 to 60minutes or as two infusions of 100mg per meter square during a twoday period .


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The hematopoietic stem cells are infused 48hours after melphalan administration throughcentral venous catheter .

The patient is pre-medicated with an antihistamine, an anti emetic, an anti pyretic andcorticosteroids to mitigate transfusionreactions.

Patients are discharged after resolution ofany adverse effects and when the neutrophilcount is greater than 5,000/dl . The duration ofhospital stay is 2 to 3 weeks.


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The autologous stem cell product can becontaminated with tumor cells that could lead torelapse .

A varieties of techniques have developed to purge

autologous products of tumor cells .

In vitro incubation with cyclophosphamidederivatives or monoclonal antibodies have shown todiminish tumor cell numbers in stem cell products.

Another technique is positive selection of stem cellsusing antibodies to CD 34+, leaving tumor cellbehind.


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Related to high dose melphalan chemotherapy-

Severe and prolonged myelosuppression .

Gastrointestinal toxic effects like mucosities.

Transient alopecia

Gonadal toxic effects

Rarely Atrial fibrillation and veno-occlusive hepatic disease

Related to infusion of autologous stem cells .

Nausea and vomiting , headache , chills and fever .8

Anaphylaxis and cardiac arrest may rarely occur


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Conventional Chemotherapy (CC) versus AutologousHematopoietic Stem Cell Transplantation (ASCT),

IFM 90 Trial.

HDT+ASC

T

CC


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Allogenic transplant has the following advantages Eliminates stem cell contamination by tumor cells.Graft versus myeloma effect.

However allogenic transplantation is not preferred in MMpatients because

Toxicity is excessivelyhigh, with a transplant-related mortalityin excess of50% in studies due to GVH disease .Chances of graft rejection.Only a small minorities of patients had HLA identical siblings.Could not be given in patients more than 60-65 years .

Hematology 2007


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Two planned autologous SCTs within 6months .

-stem cell is collected before initial

transplant.-half of the stem cell is used for each

procedure.

Second transplant may benefit :-patients who do not respond or

respond marginally to 1st transplant.


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Hypercalcemia - bisphosphonates.

-adequate hydration.

-glucocorticoid therapy.

-calcitonin.Bone lesions analgesics and chemo therapy.

Anaemia erythropoetin and hematinics.

Renal failure dialysis.

Hyperviscosity plasmapheresis.

-


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High dose chemotherapy and ASCT should be part ofinitial therapy in patients with newly diagnosed multiplemyeloma who are 65 years of age or younger .

Conditioning with a high dose of melphalan ( 200 mgper m 2 ) is recommended .

There is no consensus regarding doubletransplantation .

The addition of novel agents before and aftertransplantation improves the results , but use of suchdrugs have not been approved in any country .9


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1. Nikhil C. Munshi , Dan L.Longo kenneth C. Anderson ,HarrisonsPrinciples of Internal Medicine 17 th;2007 ;106: 700-706

2. Angela Dispenzieri,Martha Q. Lacy,Philip R. Greipp ,multiplemyeloma . Wintrobes Clinical Hematology 12th;2009 ;99 :

3. Harousseau J-L, Moreau P. Autologous hematopoietic stem-celltransplantation for multiple myeloma. N Engl J Med 2009;360:2645-2654.

4. Peled A, Kollet O, Ponomaryov T, et al. The chemokine SDF-1activates the integrins LFA-1, VLA-4, and VLA-5 on immature humanCD34(+) cells: role in transendothelial/stromal migration andengraftment of NOD/SCID mice. Blood 2000;95:3289-3296 .

5. Attal M, Harousseau J-L, Stoppa A-M, et al. A prospective,randomized trial of autologous bone marrow transplantation andchemotherapy in multiple myeloma. N Engl J Med 1996;335:91-97

6 Rajkumar SV Blood E Vesole D Fonseca R Greipp PR


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6. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR.Phase III clinical trial of thalidomide plusdexamethasone compared with dexamethasone alonein newly diagnosed multiple myeloma: a clinical trialcoordinated by the Eastern Cooperative OncologyGroup. J Clin Oncol 2006;24:431-436

7.Harousseau JL. Optimizing peripheral blood progenitorcell autologous transplantation in multiple myeloma.

Haematologica 1999;84:548-5538. Sauer-Heilborn A, Kadidlo D, McCullough J. Patient care

during infusion of hematopoietic progenitor cells.Transfusion 2004;44:907-916

9. San-Miguel J, Harousseau JL, Joshua D, Anderson KC.

Individualizing treatment of patients with myeloma inthe era of novel agents. J Clin Oncol 2008;26:2761-

2766.


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