multiple myeloma

I.P.G.M.E.&R.S.S.K.M. HOSPITAL

Plasma Cell Neoplasm

Dr Soumen MukherjeeDr Dharmendra Singh

HISTORY of Plasma Cell Neoplasm1850 : 1st Clinical description reported in England by Dr. William Macintrye

a patient named Thomas Alexander presented to him with fatigue , diffuse bone pain and increased frequency of urination.

1873 : The term Multiple Myeloma by Rustizky (1873) by independent observation with similar complaints.

1899 : Ellinger described increased serum protein & E.S.R in MM.

1900 : Wright described involvement of Plasma cells in MM & for the 1st time He used Xray to described patient’s C/F.

1929 : Development of BM aspiration technique.

1937 : Serum protein electrophoresis .

1953 : Graber described heavy & light chain monoclonal protein.

1958 : 1st use of chemotherapeutic agent (d & l mixture of phenylalanine mustard) by Blokin.

1962 : Bergsagel , reported remission in MM by using Melphalan.

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.


Origin of Plasma cells

Pleuripotent Stem Cells

GEMMPrecursor

Lymphoid Progenitor

RBCPlatelet

GranulocyteMonocyte

Eosinophil

ThymusB-

Lymphocytes

T Cells

Process Ag & forms MHC-Ag Complex

Helper T-Cells Recognise The Complex

& transformed to…

APC

TH1TH2Plasma

CellsIL-4,IL6,IL10

B-Lymphocyt

esIg

AB SECRET

INGPLASMA CELL

FIGHTING CURRENT INFECTION

IgG IgG

AGACTIVATED

B-CELL

IgM

SECRETE IgISOTYPE

IgG

MATURE

B-CELL

ENTERS CIRCULATION & BINDS TO SPECIFIC ANTIGEN

IgMIgD

IMMATURE

B-CELL

GAINS ACCESS TOPRIMARY LYMPHOIDFOLLICLE & MATURES

IgMIgD

IMMATURE

B-CELL

SMALL PRE

B-CELL

LARGE PRE

B-CELL

LATE PRO

B-CELL

EARLY PRO

B-CELL

STEM CELL

BONE MARROW

IMMATURE

B-CELL

LEAVES BM & ENTERSPERIPHERAL CIRCULATION

IgM

SECONDARY LYMPHOID ORGANS & CIRCULATION

• Terminally differentiated B-cells• Not normally found in peripheral

blood • Account for less than 3.5% of

nucleated cells in the bone marrow

• 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.

• A clear, colorless area adjacent to the nucleus contains Golgi apparatus

• 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.

Plasma Cell

Plasma Cells

There is increased production of immunoglobulin(Ig)These immunoglobulins are monoclonal in nature.

Immunoglobulin secreted may be heavy chain or light chain.


Epidemiology

As per most recent data of SEER (Surveillance epidemiology & End Result Programme )

Males are affected more than Females1% of all Malignancy10% of all Haematological malignancy2nd common after NHL among haematological malignancyMedian age of diagnosis -70 yrsMedian age of death -75 yrsBlacks are affected more than Whites.

Classification of Plasma Cell Neoplasm

Monoclonal Gammopathy of Undetermined Significance (MGUS) ( 62%)• Multiple Myeloma (18%)• Variants : Smoldering Myeloma (3%) , Non Secretory Multiple Myeloma, Light Chain Myeloma

• Plasmacytoma (2.5%) : Solitary Plasmacytoma of the bone, Extramedullary Plasmacytoma • Plasma cell leukemia • IgD myeloma • POEMS syndrome ( Osteosclerotic Myeloma)• Waldenstrom’s Macroglobulinemia (Lymphoplasmacytic Lymphoma )Malignant Monoclonal Gammopathies

Malignant Lymphoproliferative disorders

Heavy Chain disease ( Gamma HCD, Mu HCD, Alpha HCD)

Immunoglobulin Deposition diseases : Primary Amyloidosis, Systemic light chain and Heavy chain deposition diseases

Investigations

• Complete Blood Count ( look for anemia)• Comprehensive Metabolic panel

• Look for renal insufficiency(RFT), hypercalcemia and subtle clues like decreased anion gap

• 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 : • Quantitative Immunoglobulins :

Increase in all components usually, polyclonal. Increase in single component with reciprocal decrease of uninvolved globulin usually, may suggest monoclonal .

• Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected.

• 24HR-Urine protein electrophoresis with urine immunofixation ( Serum Free Light Chain assay (κ/λ ratio) may be used in place of UPEP}

• 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.

• Skeletal survey if monoclonal gammopathy has been established ( Bone scans are usually, negative in MM)

• Beta-2 microglobulin and Albumin for staging and prognosis in MM ( once diagnosis is made).

Investigations in any

suspected Monoclonal

Gammopathy should

include, to accurately classify the disorder:

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.

Serum Protein Electrophoresis(SPEP)

SPEP showing Monoclonal Gammopathy

• Shows a tall “narrow” band in gamma region – “M-Spike”

• Also, note reduction in the normal polyclonal gamma band

SPEP

SPEP showing Polyclonal Gammopathy

• Shows a broad based peak in gamma region . • Seen in chronic infections, inflammation,

connective tissue disease, lymphoproliferative disease.

SPEP

More sensitive than SPEP

• 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.

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)

Why do both SPEP and IF ? Why not just IF in initial diagnosis ?

Immunofixation

18F-Fluoro-DeoxyglucosePositron Emission Tomography (FDG-PET)• Advantages– Higher sensitivity vsconventional radiography– Detects 46% to 63% morelesions than WBXR– Normalization of scans aftertreatment corresponds with a ≥90% decrease in M-protein

• Disadvantages– Less sensitive than MRI• Especially for diffuse diseaseMRI

BASELINE POST TREATMENT

Monoclonal GammopathiesConstitute Several Disorders Examples

Monoclonal Gammopathy of Undetermined Significance ( MGUS)

Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder i.e; Undetermined Significance

M-protein <3 g/dL<10% Plasma cells in Bone MarrowNo or small amount of M-protein in urineAbsence of lytic bony lesions , anaemia , hypercalcemia or renal insuffciency.No evidence of lymphoproliferative disorderStability of M-protein over time.

Monoclonal Gammopathy of Undetermined Significance ( MGUS)Incidence of MGUS increases with age :

1% of adults in US3% of adults over age 70 years11% of adults over age 80 years14% of adults over age 90 years

Significance : Can progress to monoclonal Disease

IgG or IgA MGUS Ig M MGUS

Multiple MyelomaPrimary AmyloidosisRelated Plasma cell disorder

NHLCLLWaldenstrom’s Macroglobulinemia

MGUS - ProgressionPredictors 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 : Periodic monitoring of serum protein electrophoresis

Interval of monitoring based on initial M-Protein level

Monitoring should be at least annually LIFELONG

PathogenesisNormally human B-cells expresses TLRs

These are essential for B-cells to recogniseInfectious agent & PAMP(Pathogen Associated Molecular Pattern)

Then initiates host defence (Ig production)

B ce

lls




B ce

lls

B ce

lls




B ce

lls

B ce

lls

B ce

lls




B ce

lls

B ce

lls

B ce

lls IL-6IgCk

Pathogenesis Aberrent Expression of TLR by Plasma cells

TLR + Specific ligand = Abnormal reaction toInfection

Increased expression of IL-6

MGUS(abnormal plasma cells) contains CD126(IL-6 receptor α chain)In compare to normal plasma cells

Increased production of Ig due to activation or proliferation of MGUS

Proliferation may acquire Cytogenetic abnormality

Normally human B-cells expresses TLRs



B ce

lls

MM Cell in the BM Microenvironment

Multiple Myelomaand its variations :

Smoldering Myeloma• 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)

Non-Secretory Myeloma• 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

Solitary Plasmacytoma• No M protein in serum / urine• Single area of bone destruction due to clonal plasma cell .• Bone marrow not consistent with M.M. • Normal skeletal survey.• No end organ damage(other than solitary bone lesion)

Younger median Age at Presentation (55yrs)50-60% will convert to Multiple Myeloma within 10 yrsTreatment : Radiation(40-50Gy) to the site of Solitary Plasmacytoma

Extramedullary Plasmacytoma

•No M protein in serum / urine•Extramedullary tumor of clonal plasma cells•Normal bone marrow •Normal skeletal survey•No end organ damage(including bone lesions)

Extramedullary Plasmacytoma

• 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(40-50Gy)

All three criteria must be met Presence of a serum or urinary monoclonal

proteinPresence 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 (Hb < 10gm%) or Lytic bone lesions

Multiple Myeloma

PRESENTING FEATURES OF MYELOMA

Multiple Myeloma - Cytogenetics

Deletion 17p and Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy

Recurring Chromosomal Translocations in Multiple Myeloma

Cyclin D Induces GrowthMMSET Growth factorC-Maf Transcription factorC-Myc Growth/apoptosisMum Transcription factor

•Complete Blood Count ( look for anemia)•Comprehensive Metabolic panel • Look for renal insufficiency(RFT), hypercalcemia and subtle clues like decreased anion

gap • 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 :

• Quantitative Immunoglobulins : Increase in all components usually, polyclonal. Increase in single component with reciprocal decrease of uninvolved globulin usually, may suggest monoclonal .

• Serum Protein Electrophoresis with immunofixation if monoclonal gammopathy is suspected.

• 24HR-Urine protein electrophoresis with urine immunofixation ( Serum Free Light Chain assay (κ/λ ratio) may be used in place of UPEP}

• 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.

• Skeletal survey if monoclonal gammopathy has been established ( Bone scans are usually, negative in MM)

• Beta-2 microglobulin and Albumin for staging and prognosis in MM ( once diagnosis is made).

Investigations:

Salmon-Durie Staging System

STAGE SURVIVAL

Ì 61 months

ÌÌ 55 months

ÌÌÌ 30 months

Multiple Myeloma

STAGE PARAMETER MEDIAN SURVIVAL

Stage Í Serum β2-microglobulin<3.5mg/L 62 months

Stage ÍÍ Not fitting stage Í & ÍÍ 44 months

Stage ÍÍÍ Serum β2-microglobulin>5.5mg/L 29 months

INTERNATIONAL STAGGING SYSTEM

*High lactate dehydrogenase and plasma cell leukemia are also considered high-risk myeloma.

RISK STRTIFICATION OF MULTIPLE MYELOMA (MYO CLINIC)

Standard Risk• Hyperdiploidy• t(11;14)• t(6;14)

Intermediate Risk• t(4;14)

High Risk*• 17p deletion

• t(14;16)• t(14;20)

More effective, less toxic mechanism-based TXs

Paradigm Shift in Oncology

1960-1990 2000

EMPERICAL APPROACH

NON SPECIFIC CYTOTOXIC

AGENT

MOLECULAR BASED

APPROACH

TARGETED ANDSELECTED

BIOLOGICAL APPROACH

Clearly not transplantation candidate based on age, performance

score, and comorbidity

MPT, MPV, Len/dexor clinical trial*

Potential transplantation candidate

Nonalkylator-based induction x 4 cycles

Stem cell harvest*Thal/dex or dex are additional options especially if immediate response is needed.

Initial Approach to Treatment of MM

ELIGIBILITY FOR STEM CELL TRANSPLANTATION

Autologous Hematopoietic Stem Cell Transplantation

1. Age ≤ 70 years2. Cardiac Function: ejection fraction ≥ 45%3. Pulmonary Function: DLCO ≥ 60% predicted4. Serologies: Patients cannot be HIV + or have active Hepatitis B, Hepatitis C or HTLV-15. Renal Function : creatinine clearance ≥ 50 ml/min6. Liver Function: Bilirubin ≤ 2.0 mg/dl and transaminases ≤ 2x normal,7. Karnofsky performance status >: 80%8. No significant co-morbid medical or psychiatric illness which would significantly

compromise the patient's clinical care and chances of survival.

Allogeneic Hematopoietic Stem Cell/Bone Marrow Transplantation

9. Age ≤ 50 years10.Availability of an HLA-matched sibling donor (six of six or five of six HLA-match).11.Normal LFT's (unless related to disease).12.Cardiac function: ejection fraction ≥ 45%.

CLINICAL FOLLOW UP

Active TherapyPre Transplant Disease Assessment

Post Transplant Disease Assessment

Surveillance

•quantitativeparaprotein•CBC•calcium•albumin•creatinine monthly

•paraprotein assessment(serum, urine)•skeletal survey•CBC•calcium•albumin•creatinine•B2 microglobulin

•see pre transplant diseaseassessment•bone marrow investigationif absence of monoclonalprotein to determinecomplete remission status

•Q3 monthly assessment withquantitative paraprotein measurementCBC, calcium, albumin, creatinine•skeletal survey annually•bone marrow examination as clinicallyindicatedBCSH

Primary therapy (transplant candidates)

Relapse after transplant:*A second (tandem) autologous stem cell transplant is recommended for patients who relapse more than 12months after the first transplant.*Patients who relapse within 12 months of the initial transplant are best treated with agents they have not received before*Patients who relapse after the second autologous transplant may be candidates for allogeneic transplant or salvage chemotherapy

Main Component 3 Drug regimen 2 Drug regimen 4 Drug regimen

Bortezomib based PAD, VCD VD

Bortezomib+IMiD based VRD, VTD VRDC, VDTC

Lenalidomide based LD, Ld

Thalidomide based TAD, CTD TD

If none of Novel drug available

VAD

Progressive Improvement in response to combination Therapy

Disease category Response criteria7

sCR, stringent complete response *Normal free light chain (FLC) and absence of clonal cells in bone marrow by immunohistochemistry / immunofluorescence

CR, complete response *Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow

VGPR, very good partial response *Serum and urine M-protein detectable by immunofixation but not on electrophoresis

PR, partial response *≥50% reduction of serum M-protein AND reduction 24h urinary M-protein by ≥90% OR to <200mg per 24hour

SD, stable disease *Not meeting criteria for CR, VGPR, PR or progressive disease

Primary treatment (non-transplant candidates)

Once the best remission has been achieved, maintenance therapy with lenalidomide or thalidomide, with orwithout steroids, can prolong remission, although not survival

Main Component 3 Drug regimen 2 Drug regimen

4 Drug regimen

Thalidomide MPT, CTD TD

Bortezomib MPV, VCD VD, vD VMPT

Thalidomide +Bortezomib VTD

Lenalidomide LD, lD

If none of Novel drugs available MP, BP

Treatment recommendations for salvage therapy

Salvage therapy is used in patients who have relapse following allogeneic or autologous stem cell transplant or in patients with primary progressive disease following initial autologous or allogeneic stem cell transplant

Salvage therapy can also be used in patients who are ineligible for stem cell transplant with progressive or relapsing disease after initial induction therapy

Salvage therapy includes the regimens, that were not previously selected

Therapy for relapse / refractory myelomaThalidomide*Lenalidomide*Bortezomib*Liposomal doxorubicin*

*All of the drugs mentioned above can be used with or without Dexamethasone

Newer agents •Pomalidomide(Thalidomde analogue) •Carfilzomib(2nd generation Proteosome inhibitor)•Vorinostat , Panobinostat (HDAC Inhibitor)•Perifosine (AKT Inhibitor)•Elotozumab(Anti CS-1 cell surface molecule)

Comparative trials of high-dose therapy (HDT) versus standard-dose chemotherapy (SDT). IFM-90 (Intergroupe Francais de Myelome) randomized trial with 100 patients accrued to each arm comparing SDT with VMCP-VBAP and HDT with melphalan 140 mg/m2 plus total-body irradiation (8 Gy). Higher complete remission rates and significantly longer event-free and overall survival were noted with HDT

High dose with TBI Vs Standard Dose

HDT versus conventional therapy also showed a superior CR rate in the HDT arm, with a trend for prolonged EFS and OS in the HDT arm

Novel Biologically Based Agents

Immunomodulatory drugs (IMiDs)ThalidomideLenalidomide

Proteasome inhibitorsBortezomibCarfilzomib

Thalidomide: Proposed Mechanism of Action

Inhibition of TNF- synthesis.Suppression of angiogenesis(inhibition of

FGF,VEGF,IL-6)Increase in cell-mediated cytotoxic effectsModulation of cell surface adhesion

molecule expressionDose : 50 – 400 mg/day orally

Toxicity : Somnolence , Constipation , Neuropathy , DVT, SJS , Teratogenic

Lenalidomide

Immunomodulatory derivative of thalidomide More potent than thalidomide .

Dose-dependent decrease in TNF-α and interleukin-6 Directly induces apoptosis, G1 growth arrestEnhances activity of dexamethasone

More favorable toxicity profile than thalidomideDifficult to use in renal insufficiency ( dose adjust)

Dose : 25 mg /day oral D1-D21 . 28 day cycle.

Renal Impairment (CrCl)Moderate (30 to < 60 mL/min)Severe (< 30 mL/min, not requiring dialysis)ESRD (< 30 mL/min, requiring dialysis)

Lenalidomide Dosage10 mg QD

15 mg Q 48 hrs

5 mg QDOn dialysis days, administer

following dialysis

Lenalidomide Dosing for MM and Impaired Renal Function

Bortezomib:A Reversible Proteasome Inhibitor

Chymo-tryptic

Site

Post-Glutamyl

SiteTryptic

Site

β1 β2

b3

b4

β5

b6

b7

Cross section of b ring

Bortezomib

H N B

N H

O

O

OHN

N

OH

Interferes with intracellular pathway that degrades proteins regulating cell cycle, apoptosis,angiogenesis

Mechanism of Action

•Blockade of NFkB activation and related pracrine IL-6 production by BMScs•Acts directly on MM cells to induce apoptosis through Caspases 8,9 activation •Reversible inhibitor of 26s proteosome •Adds to antiMM effects of dexamethasone.•It inhibits the secretion of Growth Promoting cytokines.

It has been shown to overcome the adverse outcome associated with chromosome 13 abnormality

Dose : 1.3 mg/m2 I.V. twice weekly for 2 weeks (1,4,8,11 days)Followed by a 10 day rest period (day 12 to 21 )

Toxicity : fatigue, diarrhoea, impaired LFT , orthostatic hypotension, reversible thrombocytopenia, peripheral neuoropathy

Peripheral Neuropathy Following Bortezomib Therapy in Advanced MM

Peripheral neuropathy was reported in 90/256 (35%) patients with MM treated with bortezomib in phase II trials

80% of patients entered these trials with preexisting peripheral neuropathy

3% patients without vs 16% with baseline peripheral neuropathy developed grade 3 peripheral neuropathy

Treatment of complications:Anaemia : blood transfusion , supportive management ,

inj. Erythropoietin 40000U/week

Nephropathy : correction of hypercalcaemia , dose reduction of chemotherapeutic agents . e.g. Lenalidomide.

Hyperviscocity : plasmapheresis.

Infections : antibiotics , IVIG for recurrent life threatnening infections

Prophylaxis :Herpes zooster prophylaxis Before bortezomib therapy , antipneumococcal / anti influenza vaccine prophylaxis.

Pain : NSAIDS , Spinal braces

Bone pain & Skeletal complications : Bisphophonates , fixation of fracture of bone , +/- RT.

Pal RT for impending pathological fracture or to treat spinal cord compression,Dose 8 Gy in single fraction / 20 Gy in 5 fractions.

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%

The Central Role of the Osteoclast in Osteolytic Bone Destruction

Growthfactors

Osteoclast differentiation

Osteolysis

Direct effects on osteoclast differentiation

Tumor cells

Bone loss

Activeosteoclast

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

Increased OPG production[2]

Decreased RANKL expression[3]

Recommended Doses and Infusion Times

Drug Dose/Infusion Time Interval

Estimated CrCl > 60 mL/min

PamidronateZoledronic acid

90 mg over 2-3 hrs4 mg over 15 mins

3-4 wks3-4 wks

Estimated CrCl 30 to < 60 mL/min

Pamidronate

Zoledronic acid

90 mg over 2-3 hrs*Reduced dosage†

3-4 wks3-4 wks

Estimated CrCl < 30 mL/min

Pamidronate

Zoledronic acid

90 mg over 4-6 hrs*Not recommended

3-4 wks

*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.

Bisphosphonates and Osteonecrosis

Uncommon complication causing avascular necrosis of maxilla or mandible Suspect with tooth or jaw pain or exposed bone May be related to duration of therapyTrue incidence unknownAlways enquire recent dental therapy or tooth related problems before starting bisphosphonates

• Transplant-eligible patients–Bortezomib/Thalidomide/Dexamethasone (VTD) vs Thalidomide/Dexamethasone (TD)–Bortezomib/dexamethasone– Lenalidomide/low-dose Dexamethasone (Rd)

• Transplant-ineligible patients–VISTA: Bortezomib/Melphalan/Prednisone (VMP) vs Melphalan/Prednisone (MP)– Lenalidomide/low-dose Dexamethasone (Rd)

• New combinations and early studies–Transplant-eligible patients• Bortezomib/Lenalidomide/Dexamethasone• Bortezomib/Lenalidomide/Dexamethasone vs Bortezomib/Dexamethasone

–Transplant-ineligible patients• MTP vs MPR (Phase III)• VMP vs Bortezomib/Thalidomide/Prednisone (VTP) (Phase III)

–Early studies• Bortezomib/Vorinostat (Phase I)

Recent and Ongoing Clinical Studies

VTD vs. TD in Patients Who Are Transplant Eligible

• Study objective– VTD vs TD in preparation for autologous stem cell

transplantation (ASCT)• Study design– Randomized trial– Three cycles of induction therapy

• Methods– Pts. randomized to either VDT (n=199) or TD (n=200).– Stem cells were collected.– Consolidation therapy with same treatment to pts. – Results drawn from a final analysis of 399 patients.

Phase III Bortezomib-Thalidomide-Dexamethasone (VTD) vs Thalidomide-Dexamethasone (TD) Prior to Stem Cell Transplantation (SCT)

Cavo et al. Blood 2008 112: Abstract 158

• Prophylaxis– Acyclovir prophylaxis against reactivation of VZV.– TEE prophylaxis with low molecular weight heparin, aspirin, or

warfarin; fixed low-dose warfarin is effective.

• Conclusions:– In comparison with TD, 3 21-d cycles of VTD as primary therapy

significantly increased CR+nCR rates.– These response rates translated into significantly higher CR+nCR

after first ASCT in the VTD arm.– Combinations of novel induction agents, such as VTD, can have a

remarkable impact on both pre- and post-ASCT clinical outcome.

Conclusions From VTD vs. TD

Cavo et al. Blood 2008 112: Abstract 158

Bortezomib and Dexamethasone Prior to ASCT in Transplant-Eligible Patients

• Phase III, active control, multicenter, open label, randomized– Objective: compare the CR rate with vincristine/adriamycin/dexamethasone

(VAD) and bortezomib/dexamethasone combinations as induction therapy.• Number of severe AE was similar between the arms:

Post Induction Post ASCT

CR/nCR ≥VGPR ≥PR CR/nCR ≥VGPR ≥PR

VAD 9% 24% 71% 28% 50% 88%

Bortezomib/Dexamethasone 22% 50% 89% 38% 66% 87%

P-value 0.0085 0.0001 NS 0.127 0.021 NS

Harousseau et al, Blood 2007 110: Abstract 450.

• Post-induction complete remission (CR) was increased by VD compared to VAD.

• One-year PFS and OS rates were 93% and 97% with VD and 90% and 95% with VAD, respectively.

Conclusions From Bortezomib and Dexamethasone Prior to ASCT

Harousseau et al, Blood 2007 110: Abstract 450.

VISTA Trial: VMP vs MP in Transplant-Ineligible Patients

A Phase 3 Study Comparing Bortezomib/Melphalan/Prednisone (VMP) With Melphalan/Prednisone (MP)

•Study objective:–Define the differences in efficacy and outcome between VMP vs MP

•Study design and method:–VMP arm (IV Bortezomib in combination with oral prednisone and oral melphalan) vs

MP arm (oral melphalan and prednisone)

•Primary endpoint:–Time to progression (TTP)

•Secondary endpoints:–Progression-free survival (PFS), overall survival (OS), overall response rate (ORR),

time to progression (TTP) and duration of response (DOR), and safety

San Miguel et al Blood 2007 110: Abstract 76; San Miguel et al Blood 2008 112: Abstract 650; Harousseau et al Blood 2008 112: Abstract 650 Mateous et al. Haematologica 2008; 93(4), 560-565

VISTA Trial: VMP vs. MP Most Common Adverse Events (in ≥30% Patients) receiving VMP (n=60)

Adverse Event % Toxicities All Grades % Toxicities Grades 3/4

Anemia 86 10

Thrombocytopenia 93 51

Infection 75 16

Neutropenia 85 43

Asthenia 63 5

Nausea 55 2

Diarrhea 55 16

Peripheral Neuropathy 55 17

Constipation 52 8

Anorexia 38 2

Vomiting 30 2

Mateos, et al. Haematologica 2008; 93(4) 560-565

Conclusions• Adverse events

–46% with VMP–36% with MP

• Patients remained on therapy longer with VMP:–46 weeks with VMP–39 weeks with MP

• Patients had a longer time to next therapy.• Patients also had longer treatment-free survival.

VISTA Trial: VMP vs. MP

These results establish VMP as another option for patients not eligible for SCT.

San Miguel et al Blood 2007 110: Abstract 76; San Miguel et al. Blood 2008 112: Abstract 650.

• Randomized multicenter Phase III ECOG E4A03 study–RD arm (223 patients)• Lenalidomide 25 mg (days 1-21)• Dexamethasone 40 mg (days 1-4,9-12,17-20)

–Rd arm (222 patients)• Lenalidomide 25 mg (days 1-21)• Dexamethasone 40 mg (days 1,8,15,22)

–Primary endpoint: response rate at 4 months

Lenalidomide/Dexamethasone (RD) vs Lenalidomide/Low-Dose

Dexamethasone (Rd) in Transplant-Ineligible Patients

Rajkumar et al, Blood 2007 110: Abstract 74

Rajkumar et al, Blood 2007 110: Abstract 74; Jacobus et al., Blood 2008 112: Abstract 1740

Results From Lenalidomide/Dexamethasone (RD) vs Lenalidomide/Low-Dose

Dexamethasone (Rd)Toxicity (Grade >3) RD (N=223) Rd (N=222)

Neutropenia 2.7% 3.2%Thrombocytopenia 1.8% 1.4%DVT/PE 25.6% 11.4%Atrial Fibrillation/Flutter 3.1% 0.0%Infection/Pneumonia 16.1% 9.0%Fatigue 11.7% 4.1%Hyperglycemia 5.8% 2.3%Neuropathy 0.4% 1.4%

Efficacy RD Rd1-year Survival 88% 96%2-year Survival 75% 87%OS in Pts<65 (1 year) 92% 97%OS in Pts>65 (1 year) 83% 94%

Deaths 42 16

Results From RD vs Rd• Rd is associated with superior OS compared to

RD in NDMM patients.• Increased mortality in RD arm is due to

disease progression as well as increased toxicity.– Prevention of venous thrombotic events is a

priority for both combinations.

Rajkumar et al, Blood 2007 110: Abstract 74; Jacobus et al., Blood 2008 112: Abstract 1740

multiple myeloma

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