Multiple Myeloma Multiple Myeloma Updates 2007northtexas.myeloma.org/MM07.pdf · Multiple Myeloma...

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Multiple MyelomaMultiple Myeloma Updates 2007

Brian Berryman, M.D.


Multiple Myeloma

Multiple Myeloma Updates 2007

Goals for today:

– Understand the staging systems for myeloma

– Understand prognostic factors in myeloma

– Review updates from ASH


Multiple Myeloma

Multiple Myeloma Staging History

1960 – Single prognostic factors

1970 – Durie Salmon tumor burden

1975 – Durie Salmon stage (in use today)

1980 – Beta 2 microglobulin and albumin

1990 – Other staging systems offered


Multiple Myeloma

Myeloma Staging Systems

Durie-Salmon. Cancer 1975.

Bataille (BSS). JCO 1986.

SWOG. Br. J. Haematology 2003.

Weber (WSS). Blood 2003.

International Staging System (ISS). JCO 2005.


Multiple Myeloma

Durie and Salmon. Cancer 1975.


Multiple Myeloma

Why a New Staging System to Replace Durie Salmon as the International

Standard?

Difficult to remember cutoffs for DS Stage

Subjective interpretation of bone lesions

Relative good survival for DS Stage 3 patients

β2M based risk groups appropriately being used by investigators in clinical trials, rather than DS Stage, but no consensus on β2M cutoffs


Multiple Myeloma

Griepp et al. JCO 2005.


Multiple Myeloma


Multiple Myeloma

Multiple Myeloma Staging

Proposed molecular staging systems

– Translocation and cyclin D or TCBergsagel and Kuehl. JCO 2005.

– Molecular classificationZhan et al. Blood 2006.


Multiple Myeloma


Multiple Myeloma

Multiple Myeloma Prognosis

Modern Staging Systems

Biochemical parameters

Karyotype or cytogenetics


Multiple Myeloma


Biochemical markers

– β2M, Albumin

– Plasma cell labeling index (PCLI)

– CRP, LDH

– Plasmablastic morphology


Multiple Myeloma


Cytogenetics

– P53 deletions (17)

– t(4;14)

– t(11;14)

– del 13

– 11q abnormalities

– Hypodiploidy

– 1q21 amplifications


Multiple Myeloma

First-Line Therapy and Issues in Transplantation


Multiple Myeloma

ASCT: standard of care for adults < 65 years of age with MM– Best response with initial therapy, followed by high-dose chemotherapy,

then ASCT

Patients > 65-70 years of age unlikely candidates for ASCT

Optimal induction regimen not determined– Some regimens (ie, VAD) associated with low response and significant

toxicity

In recent years, many new active agents incorporated into treatment regimens for MM– Studies presented at ASH 2006 evaluated various agents in front-line,

induction settingsChild JA, et al. N Engl J Med. 2003;348:1875-1883.Leger CS, et al. Biol Blood Marrow Transplant. 2000;6:204-210.

First-Line Therapy in MM: Introduction


Multiple Myeloma

Patients aged ≤ 65 years with newly diagnosed,

symptomatic MM

(N = 480)

DCEP (2 cycles)

Stratification by cytogenetics, β2-microglobulin level

VAD

Bort/Dex

Four 21-day cycles;Stem cell collection between cycles 3, 4

after G-CSF

VAD

Bort/Dex

*Second ASCT or reduced-intensity conditioning allogeneic transplantation if < VGPR.

Harousseau A, et al. ASH 2006. Abstract 56.

DCEP (2 cycles)

Melphalan + ASCT*

Melphalan + ASCT*

Melphalan + ASCT*

Melphalan + ASCT*

IFM 2005-01 Trial: Study Design


Multiple Myeloma

IFM 2005-01 Trial: Objectives and Interim Results

Primary objective: determine response (CR + nCR) with VAD vs bortezomib + dexamethasone

– Preliminary analysis in 161 patients

Higher CR/nCR with bortezomib + dexamethasone vs VAD


49CR1723VGPR6782CR + PR

920CR/nCR

VAD(n = 82)

Bortezomib + Dex(n = 79)

Postinduction Response, %


Multiple Myeloma

IFM 2005-01 Trial: Objectives and Interim Results (cont’d)

Bortezomib + dexamethasone also associated with higher CR/nCR in patients with del13q, β2-microglobulin > 3 mg/L

Response also higher in patients receiving DCEP (n = 64) consolidation vs no DCEP (n = 78)– CR/nCR: 28% vs 11%

Grade 3/4 adverse events– Bortezomib + dexamethasone vs VAD: 30% vs 36%

Bortezomib + dexamethasone induction appears feasible– High postinduction CR/nCR may lessen probability for second ASCT



Multiple Myeloma

Tandem ASCT vs Delayed Second ASCT in MM

1. Attal M, et al. N Eng J Med. 2003;349:2495-2502.2. Attal M, et al. Blood. 2006;108:3289-3294.3. Abdelkefi A, et al. ASH 2006. Abstract 59.

Double ASCT established as option in first-line therapy of MM[1]

– Patients < 60 years of age with suboptimal response to first transplant

Maintenance thalidomide after double ASCT improves survival[2]

Abdelkefi and colleagues[3] investigated upfront tandem ASCT vs single ASCT + maintenance

– Late second ASCT in maintenance group


Multiple Myeloma

Tandem ASCT vs Delayed Second ASCT in MM: Study Design

First ASCT+ Melphalan 200 mg/m2

(n = 69)

First ASCT + Melphalan 200 mg/m2

(n = 71)

Patients with newly diagnosed, symptomatic MM< 60 years of age

(N = 140)

First-line Thalidomide +

Dexamethasone followed by

PBSC collection

Second ASCT+ Melphalan 200 mg/m2

(n = 69)

Maintenance Thalidomide

100 mg/d for 6 mos(n = 71)

Primary endpoint: OSSecondary endpoint: PFS

Abdelkefi A, et al. ASH 2006. Abstract 59.

Second ASCTupon

progression or relapse

Tandem ASCT Arm

Delayed Second ASCT Arm


Multiple Myeloma

Tandem ASCT vs Delayed Second ASCT in MM: Results

90% of patients in tandem ASCT group completed first transplant– 80% completed second transplant

86% of patients in delayed second ASCT group completed first transplant– 79% completed maintenance thalidomide


67

41

Delayed Second ASCT(n = 71)

.0451After second ASCT (tandem) or maintenance (delayed second)

NS39After first ASCT

P ValueTandem ASCT(n = 69)

CR/VGPR, %


Multiple Myeloma

No difference in OS between treatment arm

– PFS trend favors maintenance group

Delayed second ASCT possible global strategy for transplant-eligible MM patients

7775

Delayed Second ASCT(n = 71)

.08593-year PFS

.19873-year OS

P ValueTandem ASCT(n = 69)

Outcome, %


Tandem ASCT vs Delayed Second ASCT in MM: Results (cont’d)


Multiple Myeloma

Bortezomib ± Dexamethasone as Frontline Induction

Bortezomib1.3 mg/m2

Days 1, 4, 8, 11 3-week cycle

(N = 49)

If < PR after 2 cyclesor if < CR after4 cycles

Bortezomib +Dexamethasone

40 mg POday of and day after

bortezomib(n = 36)

Up to 6 cycles

Bortezomib ± dexamethasone effective induction regimen in MM– 88% response (median follow-up: 5.5 months)

Long-term follow-up of phase II study (N = 49)– Primary endpoint: ORR, safety/tolerability

Jagannath S, et al. Br J Haematol. 2005;129:776-783.Jagannath S, et al. ASH 2006. Abstract 796.


Multiple Myeloma

Bortezomib ± Dexamethasone as Frontline Induction: Results

181410CR/nCR2062VGPR 495737PR 8878 49ORR

Bortezomib + Dexamethasone

(6 Treatment Cycles)

Bortezomib + Dexamethasone

(4 Treatment Cycles)

Bortezomib Alone(2 Treatment Cycles)

Response, %

Jagannath S, et al. ASH 2006. Abstract 796.

Most patients responded within 4 cycles

– Median TTR: 1.9 months

36 patients received combination: 69% had improved response


Multiple Myeloma

Bortezomib ± Dexamethasone as Frontline Induction: Results (cont’d)

51% of patients (n = 25) went on to HDT-SCT

Estimated survival (median follow-up: 26.7 months)

– 1 year: 92%

– 2 year: 85%

– Posttransplant 2-year survival: 91%

No treatment-related mortality, DVT, PE

– Grade 2-3 sensory neuropathy, 36%; fatigue, 20% (N = 49)

Phase III study comparing bortezomib + dexamethasone with VAD as induction prior to HDT-SCT

Jagannath S, et al. ASH 2006. Abstract 796.


Multiple Myeloma

Lenalidomide + Dexamethasone in Patients With Newly Diagnosed MM

Phase II study investigated lenalidomide + dexamethasone in newly diagnosed MM (N = 34)

– Lenalidomide: 25 mg PO, Days 1-21

– Dexamethasone: 40 mg PO, Days 1-4, 9-12, 17-20

– DVT prophylaxis: daily aspirin

SCT allowed for responders

Patients with PD taken off treatment

Response and survival with combination assessed

Lacy M, et al. ASH 2006. Abstract 798.


Multiple Myeloma

Lenalidomide + Dexamethasone in Patients With Newly Diagnosed MM

Aspirin effective as DVT prophylaxis; most events mild/moderate

Adverse events– Grade 3/4 fatigue, neutropenia (21% for each)

– 2 infection-related deaths

92902-year OS

3948CR/VGPR (4 month)

83592-year PFS

10090ORR (4 month)

Lenalidomide + Dexamethasone With SCT

(n = 13)

Lenalidomide + Dexamethasone (n = 21)

Outcome, %

Lacy M, et al. ASH 2006. Abstract 798.


Multiple Myeloma

Thalidomide + Dexamethasone

x 4 cycles

Lenalidomide + High- or Low-Dose Dexamethasone in MM*

Newly diagnosed

MM patients

(N = 445)Low-Dose Arm†

Lenalidomide 25 mg PO Days 1-21

Dexamethasone 40 mg PO Days 1, 8, 15, 22

(n = 222)

CR/PR

< PR

SCT at 4 months

CR, PR, or SD

High-Dose Arm†Lenalidomide

25 mg PO Days 1-21Dexamethasone 40 mg

PO Days 1-4, 9-12, 17-20(n = 223)

*DVT prophylaxis with aspirin initially recommended; required after September 2005.†Treatment given for 4 cycles, every 28 days.

Primary endpoint: best response at 4 months (ITT)Safety analysis performed

Rajkumar SV, et al. ASH 2006. Abstract 799.


Multiple Myeloma

Lenalidomide + High- or Low-Dose Dexamethasone: Results

NeuropathyHyperglycemiaFatigueInfection/pneumoniaDVT/PEDeath (grade 5)Any toxicity (≥ grade 4)Any nonhematologic

Grade 3/4 Adverse Events, %

.3721.40.4

.0902.35.8

.0044.111.7

.0319.016.1< .0016.318.4.0060.54.9.02511.319.3.00239.654.3

P ValueLow-Dose Arm (n = 222)

High-Dose Arm (n = 223)


Increased nonhematologic toxicity in high-dose vs low-dose arm


Multiple Myeloma

Lenalidomide + High- or Low-Dose Dexamethasone: Results (cont’d)

No differences in rate of hematologic toxicity between arms

– Grade ≥ 3 neutropenia: ~ 3% in each arm

Response assessment ongoing

Conclusions

– Lenalidomide + high-dose dexamethasone associated with greater toxicity

– Increased thrombotic events

– DVT prophylaxis recommended for all patients receiving lenalidomide + dexamethasone



Multiple Myeloma

Lenalidomide, Melphalan, and Prednisone in Untreated MM

Thalidomide combined with MP: standard regimen for elderly MM patients

Phase I/II study: lenalidomide + MP

– 53 MM patients > 65 years of age

– 4 dosing cohorts (prednisone dose: 2 mg/kg/d)

Palumbo A, et al. ASH 2006. Abstract 800.

0.25 mg/kg + 10 mg/d0.18 mg/kg + 10 mg/d0.25 mg/kg + 10 mg/d0.18 mg/kg + 5 mg/d

Lenalidomide + Melphalan Dose

Cohort 4 (6 + 15)Cohort 3 (6 + 15)Cohort 2 (6)Cohort 1 (6)Dosing Group (n)


Multiple Myeloma

Lenalidomide, Melphalan, and Prednisone in Untreated MM (cont’d)

No DLT in cohorts 1 and 2

DLTs observed in cohorts 3 and 4

MTD determined: 0.18 mg/kg + 10 mg/d (cohort 3)

Grade 3 neutropenic fever, cutaneous eventsGrade 4 thrombosis

NeutropeniaGrade 3 metabolic events

DLT

Cohort 4

Cohort 3Dosing Group

Palumbo A, et al. ASH 2006. Abstract 800.


Multiple Myeloma

Lenalidomide, Melphalan, and Prednisone in Untreated MM (cont’d)

Response in cohort 3 and 4[1]

– PR: 39%; VGPR: 44%

Cohort 3 EFS compared favorably with thalidomide + MP historic control

No difference in outcome for patients with unfavorable cytogenetics

– Data suggest no benefit with higher melphalan doses in MM patients with abnormal cytogenetics[2]

International, intergroup study will compare L-MP with MP 1. Palumbo A, et al. ASH 2006. Abstract 800.2. Palumbo A, et al. ASH 2006. Abstract 55.


Multiple Myeloma

International, Intergroup MM-015 Trial: Study Design

*Expected enrollment; study not yet recruiting.

Patients with newly diagnosed

MM

(N = 450*)

L-MP9 courses

MP9 courses

MaintenanceLenalidomide

No treatment

No treatment

L-MP9 courses

Relapsed/Refractory Disease


Multiple Myeloma

Rationale for Bortezomib + PLD in Relapsed/Refractory MM

Synergy between bortezomib, anthracyclines

– May reduce resistance, augment anticancer effect[1]

Phase I studies[2,3]

– Bortezomib + PLD well tolerated

– Associated with improved TTP

– Enhanced response rate

Phase III study assessed bortezomib + PLD vs bortezomib alone in relapsed/refractory MM

1. Ma MH, et al. Clin Cancer Res. 2003;9:1136-1144. 2. Orlowski RZ, et al. Blood. 2005;105:3058-3065. 3. Biehn SE, et al. Ann Hematol. In press.


Multiple Myeloma

Bortezomib-naive patients with

relapsed/refractory MM;all patients received ≥ 1 prior therapy

(N = 646)

Bortezomib MonotherapyBortezomib 1.3 mg/m2,

Days 1, 4, 8, and 11, every 21 days

(n = 322)

Bortezomib + PLDBortezomib 1.3 mg/m2,

Days 1, 4, 8, and 11 PLD at 30 mg/m2 given on

Day 4 of every 21 days(n = 324)

Continued treatment for 8 cycles

or until CR, PD, or unacceptable toxicity

Bortezomib + PLD vs Bortezomib Alone in Relapsed/Refractory MM

Orlowski RZ, et al. ASH 2006. Abstract 404.

Primary endpoint: TTPSecondary endpoints: ORR, OS, safety


Multiple Myeloma

Longer TTP With Bortezomib + PLD vs Bortezomib Alone


Bortezomib + PLDMedian TTP: 9.3 months

BortezomibMedian TTP: 6.5 months

HR: 1.82 (95% CI: 1.41-2.35; P = .000004)

Days

Prog

ress

ion

Free

(%)

0 100 200 300 400 5000

20

40

60

80

100


Multiple Myeloma

Bortezomib + PLD vs Bortezomib Alone: Clinical Outcomes

Trend for improved OS with combination

No difference in response

– Longer duration of response with bortezomib + PLD

--3234PR, %--1114CR + nCR, %

.00087.010.2Response duration, mos

.2514348Total response (CR/PR/nCR), %

.1138891OS, %

P ValueBortezomib (n = 310)

Bortezomib + PLD (n = 303)

Outcome



Multiple Myeloma

Bortezomib + PLD vs Bortezomib Alone: Clinical Outcomes (cont’d)

No additional benefit with PLD for del13q patients

Manageable toxicity

Most common serious adverse events in both arms

– Thrombocytopenia: 22% with combination vs 15% for bortezomib

– Neutropenia: 30% with combination vs 14% for bortezomib

No increase in peripheral neuropathy with combination

Cardiac events

– 2% for combination vs 3% for monotherapyOrlowski RZ, et al. ASH 2006. Abstract 404.

Multiple Myeloma Multiple Myeloma Updates 2007northtexas.myeloma.org/MM07.pdf · Multiple Myeloma...

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