VISHAL KUKRETI, M.D., FRCPC

PRINCESS MARGARET HOSPITAL

SEPTEMBER 24, 2011

Front Line Therapy for Newly Diagnosed Multiple Myeloma

Objectives

Overview of MyelomaTreatment options First Line Therapy

Transplant Eligible Non-Transplant Eligible

Incurable cancer of plasma cells Medullary and extra-medullary disease

Multiple Myeloma

Antibodies/Immunoglobulins

Plasma cells make antibodies (immunoglobulins, Igs) which consist of 2 heavy chains and 2 light chains

One type of antibody is made to bind with one foreign substance (virus, bacteria, etc.)

Patterns of Antibody Production

Normal SPEP Multiple Myeloma

Serum Protein Electropheresis

Types of Multiple Myeloma

Diagnostic Criteria

Diagnosis based on finding over 10% plasma cells (antibody forming cells) in bone marrow

Symptomatic myeloma characterized by “CRAB” Anemia (<100 or 20g/L below normal) Bone lesions - lytic Kidney damage (Creatinine 176 umol/L) Elevated blood calcium (>2.8mmol/L)

Anemia – 80%Renal dysfunction – 20%Hypercalcemia – 25%Bone destruction – 75%Hyperviscosity - <5%M-protein Identification

Serum – 80% Urine – 20% Neither (non-secretory) – 1-2%

Findings at diagnosis - MM

Age-specific incidence of MM

IneligibleTransplant candidates

http://info.cancerresearchuk.org/cancerstats/types/multiplemyeloma

Staging of Myeloma

International Staging System

Risk Category Characteristics1 2 M 3.5 mg/L + albumin 35 g/L2 2 M 3.5 mg/L+ albumin 35 g/L

or 2 M 3.5 – 5.5 mg/L

3 2 M 5.5 mg/L

Survival and ISS score

FISH Cytogenetics in Myeloma

t(4;14)=15% (dysregulation of FGFR3 and MMSET)

p53 deletion=10%(loss of tumor suppressor gene)

No t(4;14), no del17p, b2m£4 mg/L, no del13

No t(4;14), no del17p, b2m£4 mg/L, del13

No t(4;14), no del17p, b2m>4 mg/L, no del13

No t(4;14), no del17p, b2m>4 mg/L, del13

t(4;14) or del17p, b2m£4 mg/L

t(4;14) or del17p, b2m>4 mg/L

35%

50%

15%p=2.10-13

Avet-Loiseau H. Blood. 2007;109:3489-3495.

Combining Beta 2-Microglobulin and FISH Identifies 3 Prognostic Groups

Bisphosphonates◦ Osteonecrosis of the jaw – 1.8 to 12.8%◦ Duration of therapy

Vertebroplasty/Kyphoplasty Infections Induction Therapy – Transplant Eligible vs

Ineligible Autologous Stem Cell Transplant Maintenance therapy post-stem cell

transplantation

Treatment – Principles

Patient

Priming Therapy

FreezeCollect PBSCs

High-dose Chemotherapy

Reinfuse PBSCs

+/- Post-ASCT therapy

Autologous Stem Cell Transplant

Where We’ve Been with Initial Therapy

Preceded by VAD, Dex alone or Thal/Dex x 4 cycles

Melphalan 200 mg/m2

Overall response rate 80%CR/nCR rate 20%Median PFS 20-36 mosMedian OS 48-60 mos

Overall response rate 40-50%CR/nCR 5%Median PFS 12-15 mosMedian OS 30-36 mos

ASCT Melphalan + Prednisone

Novel Agents in Multiple Myeloma

Thalidomide Bortezomib Lenalidomide

Agent Class Effects ToxicityThalidomide(Thalomid®)

IMiD Immunomodulatory effects - inhibits TNFa, inhibits angiogenesis, stimulates T-cells (CD8), alters cytokine production, impedes binding to stromal cells

Teratogenicity, PN, sedation, rash, constipation, DVT

Bortezomib(VelcadeTM)

Proteasome inhibitor

Decreased adhesion, cytokine production, angiogenesis, NFkB, DNA repair

Fatigue, PN, GI toxicity

Decrease in neutrophils, platelets and lymphocytes

Lenalidomide

(CC-5013; Revlimid®)

IMiD Stimulate T-cell proliferation, upregulate IL-2 and IFN-g, inhibit TNFa and IL-6Decreased adhesion, alter synthesis of cytokines, induce growth arrest and caspase dependent apoptosis

NK cell cytotoxicity

Myelosuppression, DVT

Strategies to Improve ASCT Results

Improved induction therapyRisk Stratification – t(4;14)Improved dose intensive therapy

Tandem ASCT New regimens (“Vel-Mel,” Bu-Mel, busulfex + bortezomib)

Post-ASCT therapy Consolidation Maintenance

Induction Trials before ASCT

Many phase I-II trials of 3- and 4-drug regimens May allow option to continue regimen without ASCT

Phase III trials that include ASCT 3 compare novel regimen with VAD 2 compare novel regimen with thalidomide + dex 1 compares novel regimen with bortezomib + dex

Novel Induction Regimens before ASCT

VAD or Dex

THALIDOMIDE

ThalDex*TAD*CTD*

THALIDOMIDE

ThalDex*TAD*CTD*

BORTEZOMIB(VELCADE)

Bortez+Dex* VTD* PAD*VCD

Cybor-DRVDD

BORTEZOMIB(VELCADE)

Bortez+Dex* VTD* PAD*VCD

Cybor-DRVDD

LENALIDOMIDE(REVLIMID)

RDRd

RVD

LENALIDOMIDE(REVLIMID)

RDRd

RVD

Stem cell harvestHigh-dose melphalan +

ASCTRD: Lenalidomide + high-dose dexRd: Lenalidomide + low-dose dex

*Studied in phase III transplant trials

Study/Author N Induction regimen

# ASC

T

Consolidation

Maintenance

MAG/Macro 204 Thal + dexVAD

1 - -

HOVON-50/Lokhorst

536 TADVAD

1 - ThalInterferon

IFM 2005-02/Harousseau

482 BDVAD

1 or 2 +/- len +/- len

HOVON 65/GMMG-HD4/ Sonneveld

613 VADPAD

1 or 2 --

Thal 50 mg/dB 1.3 mg/m

(q 2 weeks)

GIMEMA MMY-3006/Cavo

447 VTDThal + dex

2 VTDThal + dex

DexDex

PETHEMA/GEM05MEN0S65/Rosinol

306 Thal + dexVTD

VBMCP/VBAD/Vel

1 - --

IFM 2007-02/Moreau

199 Vel/dexvTD

1 or 2 --

--

Study/Author Induction

regimen

# ASCT + Post-Rx

Post-ASCTResponse (%)VGPRc(CR+n

CR)

Median PFS

(mos)

Median OverallSurvival(mos)

MAG/Macro TD 1 44 --

--

HOVON-50/Lokhorst

TAD 1+Thal 66 (31) 34 73

IFM 2005-02/Harousseau

BD 1 or 2+/- Len

54 (35) 36 81% (3 yrs)

HOVON 65/GMMG-HD4/ Sonneveld

PAD 1 or 2 + bortez

75 (50) 42% (3 yrs)

78% (3 yrs)

GIMEMA MMY-3006/Cavo

VTD 2 + VTD+ Dex

87 (55*) 85%(2 yrs)

96% (2 yrs)

PETHEMA/Rosinol

VTD 1 (46*) NYR 76% (4 yrs)

IFM 2007-02/Moreau

Vel/dexvTD

1 or 2 73 (61) --

--

“CYBOR-D”: Phase II Trial Newly Diagnosed Myeloma

Schedule

Bortezomib Cyclophosphamide Dex

Dose (mg/m2)

Day Days (300 mg/m2) Days (40 mg)

Biweekly

1.3 1,4,8,11 1,8,15,22 1-4, 9-12, 17-20

Weekly 1.5 1,8,15,22

1,8,15,22 Same x 2 cycles, then decreased to

1,8,15,22

Reeder C, et al. Leukemia 2009; 23: 1337-1341; Reeder CB, et al. Blood 2010; 115: 3416-3417.

28 day cycle 28 day cycle

•Rapid onset •Responses after 4 cycles of weekly dosing:

•ORR 98%•≥VGPR 68% •CR/nCR 43%

•No issues with SC collection

Induction Therapy before ASCT - Summary

Advantages of bortezomib-containing induction Rapid induction of remission Effective in renal failure Effective in high-risk cytogenetic subgroups

Some evidence that 3- and 4-drug regimens produce higher remissions, and convey better PFS Combinations of bortezomib and IMiDs very costly

Weekly bortezomib carries much lower risk of PNPMH approach is to use CYBOR-D x 4 cycles

Randomized Tandem ASCT Trials

N Post-ASCTRx

CR/VGPR rate (%)

Single Tandem

Median PFS(months)

Single Tandem

Median OS(months)

Single Tandem

Attal, 2003

399 α IFN 42 50 25 30* 48 58*

Fermand, 2003

277 None 39 37 31 33 49 73

Goldschmidt, 2005

268 α IFN -- -- 22 NYR* 23 NYR

Sonneveld, 2004

303 α IFN 13 28 20 22* 55 50

Cavo, 2007

321 α IFN 38 48 23 35* 65 71

* p< 0.05

Newer Post-ASCT Strategies

Consolidation VTD (GIMEMA trial) Lenalidomide + dexamethasone (IFM 2005 02) Bortezomib (Nordic Myeloma Study Group trial) RVD (CTN trial)

Maintenance Lenalidomide (CALGB trial, IFM 2005 02)

IFM/Dana Farber 2009 Trial

VRD x 3

SC collectionCY + G-CSF

Melphalan 200 mg/m2

+ ASCT

VRD x 2

Rev maintenance x 1 yr

VRD x 5

Rev maintenance x 1 yr

HDM + ASCT recommended at

relapseASCT will be considered pertinent if EFS is prolonged by ≥ 9 months

ASCT in MyelomaSummary and Conclusions

Several approaches integrating novel agents with ASCT improve outcome Difficult to dissect contribution of induction, consolidation,

maintenance Improved response rates with newer strategies

≥ VGPR rates 60-75%; CR/nCR rates 30-50%Median PFS has improved from 2 to 3 years

3 ½ years with lenalidomide maintenanceOverall survival results are improved in some studies

Where We Are Now

Preceded by novel induction regimens

Melphalan 200 mg/m2

+/- second ASCT +/-thalidomide maintenance

Overall response rate 80-90%CR/nCR rate 35-50%Median PFS 36 mos2 year OS 90-93%

Overall response rate 65-75%CR/nCR 20-25%Median PFS 24-30 mosMedian OS 48-50 mos2 year OS 70-93%

ASCTMPT or MPV

or Lenalidomide + Dex

Transplant-Ineligible Patients –

Balancing the Toxicities and Efficacy of Novel Agents

How do we choose initial therapy in non-transplant patients?

Drug availability Practical considerations Patient-related features

Co-morbidities (diabetes, peripheral neuropathy) Marrow reserve Renal function

Disease-related features Aggressive biology, such as t(4;14) Light chain nephropathy

Treatment related features Rapidity of response Toxicity profile (VTE, peripheral neuropathy)

New Treatment Options for Newly Diagnosed Myeloma Patients

Non-transplant Candidates

Add novel agent to melphalan + prednisoneContinuous suppressive therapy with IMiD +

dexamethasone (lenalidomide + weekly dex) Combination therapy with 3-4 drug regimens +/-

maintenance CTD1 • VDC4 • VMPT6

RVD2 • VDCR4

CyborD3 • Thal + dex + PLD5

1Morgan G, et al. Blood 2007;110: abstract 3593 2Richardson PG, et al. Blood 2008;112: abstract 92; 3Reeder CB, et al. Leukemia 2009;23: 1337-1341; Kumar S et al. Blood 2009; 114: abstract 127; 5Offandini M, et al. Br J Haematol 2009;144: 653-659.; 6Palumbo A, et al. Blood 2009; 114: abstract 128.

Best Reported Outcomes with Newer Non-ASCT Regimens in Phase III Trials

Author Rx Duration of therapy (wks)

Overall response rate (CR+nCR) (%)

Median PFS

(mos)

Median OS

(mos)

2 year OS(%)

Facon1 MPT 72 76 (18) 27.5* 51.6* 78

Palumbo2 MPT+ T 24+ 76 (28) 21.8* 45 82

Hulin3 MPT 72 61 (7) 24* 45* 70

San Miguel4 VMP 54 71 (35) 24* NYR* 83

Palumbo5 MPR+ R 40+ 77 (18) NYR* NYR ~70

Rajkumar6 Len+dex Until prog 70 (14 CR) 25.3 NYR 87

1Facon T, et al. Lancet 2007:370; 1209-1218; 2Palumbo A , et al. Blood 2008;112: 3107-3114; 3 Hulin C, et al. Blood 2007; 110: abstract 75;4San Miguel JF, et al. N Engl J Med 2008; 359: 906-917; 5 Palumbo A, et al. Blood 2009; 114: abstract 613; 6Rajkumar SV, et al. Lancet Oncol 2010; 11: 29-37.

*Significant benefit over MP alone

IFM 99/06: MPT vs MP vs Mel10065-75yo

PFS

OS

MP plus thal 200-400 mg/d (with no maintenance thalidomide phase)

Facon et al, IFM 99/06, Lancet 2007

MP

MPT M

P

MPT

MP

MEL100MEL100

MPT

Melphalan 0.25mg/kg and Prednisone 2mg/kg, days 1-4, for 12 cycles, q 6 weeks

VADx2 + MEL100x2 + ASCTx2

Study ORR

(%)

CR

(%)

PFS Median (mos)

OS Median (mos)

OS

p-value

IFM 99/06Facon1

76 v 35 13 v 2 28 v 18 52 v 33 0.0006

IFM 01/01Hulin3

61 v 31 7 v 1 24 v 19 44 v 29 0.03

HOVONWijermans5

62 v 47 2 v 2 15 v 11 40 v 31 0.05

GIMEMAPalumbo2

76 v 48 16 v 4 22 v 15 45 v 48 NS

NordicWaage 4

57 v 38 13 v 4 15 v 14 29 v 33 NS

1Facon T, et al. Lancet 2007;370:1209-18; 2Palumbo A, et al. 2008; 112: 3107-3114; 3Hulin C, et al. J Clin Oncol 2009 May 18 [Epub¸ahead of print]; 4Waage A, et al. Blood 2007;110:abstract # 76; 5Wijermans P, et al. Blood 2008; 112: abstract #649; 6San Miguel J, et al. 2008; New Engl J Med 2008; 359: 906-917.

MPT vs MP studies

Select toxicities: MPT vs MP (Grade3-4)Facon et al., IFM 99–06: 65-75yo

MP (N=193)

MPT(N=124)

P-value

Neutropenia 26% 48% <0.0001

Thrombosis/embolism 4% 12% 0.0008

Peripheral neuropathy 0 6% 0.001

Solmolence/fatigue/dizziness

0 8% <0.0001

Cardiac (arthymia, CHF) 0.5% 2% Rate too low

constipation 0 10% <0.0001

VMPCycles 1-4Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

Cycles 5-9Bortezomib 1.3 mg/m2 IV: days 1,8,22,29Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

VMPCycles 1-4Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

Cycles 5-9Bortezomib 1.3 mg/m2 IV: days 1,8,22,29Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

MPCycles 1-9Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

MPCycles 1-9Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

RANDOMISE

9 x 6-week cycles (54 weeks) in both arms

San Miguel et al. N Engl J Med 2008; 359: 906-917

VISTA: VELCADE as Initial Standard Therapy in multiple myeloma:

Assessment with melphalan and prednisone

Conducted at 151 centres in 22 countries in Europe, North and South America, and Asia.

Patients with newly diagnosed MM not transplant eligible due to age (≥65 years) or coexisting conditions

VISTA: Select patient demographics and disease characteristics

VMP MP

Median age 71 71

≥75yo 31 30

KPS ≤70%, (~ECOG 2+) % 35 33

ISS Stage I / II / III, % 19 / 47 / 35 19 / 47 / 34

Lytic bone lesions, % 65 66

Serum creatinine, median (mg/dL) 1.1 1.1

CrCl ≤30 / >30-60 / >60 ml/min, % 6 / 48 / 46 5 / 50 / 46

History of neurological conditions, % 18 20

History of cardiac conditions, % 35 31

San Miguel et al. N Engl J Med 2008; 359: 906-917

VISTA: VMP vs MP (9 cycles)

TTP OS

San Miguel et al. (VISTA). N Engl J Med 2008;359:906-17.

VMP: Consistent efficacy in patients with poor prognostic characteristics

Median follow up: 36.7 months

TTP 1 OS 2

High-risk vs. standard-risk cytogenetics

Median follow up: 25.9 months

highstandar

d high

standard

Time (months) Time (months)

1. San Miguel et al. N Engl J Med 2008; 359: 906-917 (Suppl)2. Mateos et al. J Clin Oncol 2010; 28: 2259-2266

Select Grade 3-4 Adverse events: VISTA Updated data

VMP (N=340) MP (N=337)

Neutropenia 40 38

Thrombocytopenia 38 31

Anemia 19 28

Leukopenia 24 20

Lymphopenia 20 11

Pneumonia 7 5

Peripheral sensory neuropathy 14 0

Fatigue 8 2

Diarrhoea 8 1

Minimizing Neuropathy:once- vs. twice-weekly bortezomib –

GIMEMA study

VMP(Twice weekly)

VMP(Once weekly)

CR 27% 23%

PFS @ 3years 32% 35%

OS @ 3 years 86% 85%

Sensory peripheral neuropathy

Any grade 43% 21%

Grade 3-4 14% 2%

PN discontinuation 16% 4%

Total planned dose 67.6 mg/m2 46.8 mg/m2

Total delivered dose 41 mg/m2 40 mg/m2

Palumbo et al; ASH 2010, Abstract #620

Once weekly bortezomib is new standard schedule!

Vesole DH et al. ASH 2010; Abstract 308.

E4A03: Phase III trial of LD vs Ld in newly diagnosed MM

Lenalidomide: 25 mg daily, days 1-21 of 28-day cycle; D: High-dose Dex: total 480 mg/28-day cycle; d: Low-dose Dex: total 160 mg/28-day cycle

Salvage therapyThalidomide 200 mg/d po,

days 1-28High-dose (Arm III) vs Low-

dose (Arm IV)

DSMB mandated crossoverto Low-dose dex (Ld)

March 27, 2007N = 79 patients on study at

time of crossover

DSMB mandated crossoverto Low-dose dex (Ld)

March 27, 2007N = 79 patients on study at

time of crossover

Newly

Diagnosed

Myeloma

N = 445

Lenalidomide + High-Dose Dexamethasone

(LD)[40 mg, d 1-4, 9-12, 17-20]

Lenalidomide + Low-Dose Dexamethasone

(Ld)[40 mg, d 1, 8, 15, 22]

If PD within 4 mo

LD vs Ld: Overall Survival by age

Len plus low-dose dex is safe and effective for both older and younger patients

Age > 65 Age > 75

Vesole et al; ASH 2010, Abstract 308

LD versus Ld: Toxicities

LD

n=223

Ld

n=220

P-value

Response at 4 cycles 79% 68% 0.008

VGPR 42% 24% <0.008

Blood clots 26% 12% <0.001

Infection 16% 9% 0.043

Severe toxicity 53% 31% <.001

Early deaths 5% 0.5% 0.003

RD in comparison to Rd is slightly more effective but significantly more toxic.Once weekly DEX is now widely used and is generalized to the relapsed setting and to use with other novel agents

Rajkumar et al Lancet Oncol 2010;11:29-37

Conclusions

Not all elderly are the same. Not all myeloma is the same

Bortezomib-based induction (e.g. VMP) is reasonably well tolerated and associated with enhanced OS in most patients >65yo and >75yo (and is funded in Ontario)

Oral induction regimens (e.g. MPT, MP or len/dex) may be appropriate in some non high-risk patients

In patients with renal impairment or t(4;14), -17p a velcade-based induction regimen is preferred (e.g. VMP)

Higher intensity regimens less beneficial and may be adverse in frail patients

Weekly bortezomib is a new standard of administration

Low dose dex is the standard of care in lenalidomide

Niesvizky et al. Haematologica 2011; 96 (s1): S98 (Abstract P-228); poster presentation at IMW 2011

PMH Approach to Front Line Therapy

Ages 65-70

Transplant Eligible (<65)

Non-Transplant Eligible (>70)

Cybor D Induction (clinical trials)

ASCT(Tandem if high risk)

VMPMPTMP

(Clinical trials)

Maintenance Lenalidomide