Second Primary Malignancies, Progression and Overall...

Second Primary Malignancies, Progression and Overall Survival during Lenalidomide

Maintenance Therapy for Multiple Myeloma patients

Philip McCarthy Roswell Park Cancer Institute Buffalo, NY April 2013

Disclosures

• Consulting/Speaker – Celgene – Janssen

• Off Label Therapy – Lenalidomide maintenance

• Monoclonal gammopathy of undetermined significance (MGUS) and Multiple Myeloma (MM) patients may be at risk for the development of second primary malignancies (SPM)

• MM therapies can increase the risk of SPM development

• The risk of SPM development should be evaluated within the context of the risk of disease progression and death due to MM

Mailankody et al Blood 2011

Risk of Second Primary Malignancy after MM and MGUS

Dimopoulos et al Blood 2012

K-M analysis of time to invasive SPM in MM-009 and MM-010

Incidence rate per 100 patient years

Second primary malignanciesSecond primary malignanciesAnalysis of NDMM patients enrolled in EMN trials1

* Most common: gastrointestinal, urinary, skin, AML, breast; # Most common: infection, cardiac event, thromboembolism, bleeding, respiratory dysfunction; § Most common: pneumonia, septic shock, sepsis, fever; SPM, second primary malignancy, NDMM, newly diagnosed multiple myeloma; IMID, immunomodulatory drug

*

#

§

0 0.5 1 1.5 2 2.5 3

Bortezomib + melphalan (1/511)

Lenalidomide + dexameth. (2/403)

IMIDs + melphalan (10/1375)

All hematol. SPMs (14/2749)

General populationhematol. tumors2

Cardiac (37/2463)

Infection (57/2463)

Toxic death (156/2463)

All SPMs (67/2463)

General populationall tumors2

1 Palumbo A, et al. EHA 2011;96(s1):s24 2 International Agency for Research on Cancer. World Health Organization 2008

0 0.05 0.1 0.15 0.2 0.25 0.3 0.350 0.05 0.1 0.15 0.2 0.25 0.3 0.35

Courtesy A Palumbo ASH 2012

• How do therapeutic agents interact with the MM plasma cells, hematopoietic cells and other tissues?

• Etiologies for SPM • Underlying disease • Types of induction, consolidation and

maintenance • Host genetic factors Reviewed in Thomas et al Second malignancies after multiple myeloma: from 1960s to 2010s. Blood 2012

IDO

Trp

L-kyn

EffectorT cells

Tregs

IL-6

myeloid APC

Bone marrow stroma

CD80/ CD86

CD28

Pro- survival

Myeloma

+

myeloid differentiation

IL-6R

Myeloid progenitor

STAT3

pkcβ irf8

- -

PKCβΙΙ

+

PKCβΙΙ

MDSC osteoclasts immature myeloid cells

Regeneration of the supportive

myeloid ME

CD14+DR-

CD80/CD83/ DC-SIGN+

IRF8:PU.1

PU.1

lenalidomide

mature myeloid

cells

AML

Courtesy K Lee and S Abrams

Potential Mechanisms for Myeloid Disorders with Lenalidomide Exposure

Melphalan-Prednisone-Lenalidomide N = 459, 82 centers in Europe, Australia, and Israel

MP M: 0.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 PBO: Days 1-21

MPR M: 0.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 R: 10 mg/day po Days 1-21

Placebo

Placebo

MPR-R M: 0.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 R: 10 mg/day po Days 1-21

RA

ND

OM

IZAT

ION

Double-Blind Treatment Phase

Disease Progression

Continuous lenalidomide treatment

Lenalidomide (25 mg/day)

± Dexamethasone

Open-Label Extension Phase

Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III)

10 mg/day days 1-21

Cycles (28-day) 1-9 Cycles 10+

M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System. Courtesy A Pallumbo from Palumbo A, et al. EHA 2010. Abstract 0566.

Palumbo et al NEJM 2012

Lenalidomide Maintenance in the Non-Transplant Eligible MM population (MM015)

Second Primary Malignancies All Patients (MM015) NEJM 2012

SPM, n (IR per 100 per year) MPR-R (n = 150)

MPR (n = 152)

MP (n = 153)

Total Invasive SPMs 12 (3.04) 10 (2.57) 4 (0.98)

Hematologic 7 (1.75) 6 (1.54) 1 (0.24)

Solid tumors 5 (1.26) 5 (1.28) 3 (0.74)

Non-melanoma skin cancer 2 (0.50) 5 (1.29) 6 (1.50)

Patie

nts

(%)

100

75

50

25

0

100

75

50

25

0

100

75

50

25

0 0 20 40 60 0 20 40 60 0 20 40 60

Time (Months) Time (Months) Time (Months)

MPR-R MPR MP PD/Death Hematologic SPM Solid Tumor

IR, incidence rate; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with lenalidomide maintenance; PD, progressive disease; PY, person-year; SPM, second primary malignancy.

Courtesy A Palumbo

IFM 2005-02: Study design

Arm A= Placebo (N=307)

until relapse

Patients < 65 years, with non-progressive disease, ≤ 6 months after ASCT in first line

Arm B= Lenalidomide

(N=307) 10-15 mg/d until

relapse Primary end-point: PFS. Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide….

Phase III randomized, placebo-controlled trial N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008

Courtesy M Attal NEJM 2012 SCT = autologous stem cell transplant. IFM = Intergroupe Francophone du Myelome.

Consolidation: Lenalidomide alone 25 mg/day p.o.

days 1-21 of every 28 days for 2 months

Randomization: stratified according to Beta-2m, del13, VGPR

Attal et al N Engl J Med 2012

IFM 2005-02: PFS from randomization (Study unblinding 1/2010)

Courtesy M Attal, Median follow-up 45 months

IFM 2005-02: OS (10/2011)

Courtesy M Attal Attal et al N Engl J Med 2012

IFM 2005 02: Patients with at least one SPM (10/2011) Lenalidomide

(N= 306)

Placebo

(N= 302)

Total

(N= 608)

Hematologic malignancies (%) 13 (4.2) 5 (1.7) 18 (3.0)

AML/MDS 5 4

ALL 3 0

Hodgkin lymphoma / Non-HL 4 / 1 0 / 1

Solid tumours (%) 10 (3.3) 4 (1.3) 14 (2.3)

Esophageal / Colon 4 0

Breast 2 0

Lung / Sinus 1 1

Kidney / Prostate 3 2

Melanoma 0 1

Non-Melanoma skin cancers (%) 5 (1.6) 3 (1.0) 8 (1.3)

Total (%) 26 (8.5) 11 (3.6) 37 (6.1) . Courtesy M Attal; Attal et al N Engl J Med 2012

IFM 2005-02: SPM (10/2011)

P = 0 .01

0

10

20

30

40

50P

ati

en

ts (

%)

3 0 2 30 1 28 8 285 2 75 26 4 22 4 14 7 78 37 6 0P la cebo30 6 30 2 29 6 286 2 67 24 7 21 2 15 3 86 33 6 0Le na lido m ide

N a t r isk

0 6 12 18 24 3 0 3 6 42 48 54 60 66

M o n th s o f fo l lo w -u p

Le na lido m ide

P lace bo

. Attal et al N Engl J Med 2012

D-S Stage 1-3, < 70 years > 2 cycles of induction Attained SD or better ≤ 1 yr from start of therapy > 2 x 106 CD34 cells/kg

Placebo

Lenalidomide* 10 mg/d with

↑↓ (5–15 mg)

Restaging Days 90–100

Registration

CALGB 100104 Schema

CR PR SD

Stratification based on registration β-2M level and prior thalidomide and lenalidomide use during Induction. Primary Endpoint: powered to determine a prolongation of TTP from 24 months to 33.6 months (9.6 months)

Mel 200

ASCT

* provided by Celgene Corp, Summit, NJ

Randomization

ITT Analysis with a median follow-up from transplant of 34 months p<0.001 Estimated HR=0.48 (95% CI = 0.36 to 0.63), Median TTP: 46 months versus 27 months.

CALGB 100104, NEJM 2012 follow up to 10/31/2011

86 of 128 placebo patients not progressing, crossed over to lenalidomide at unblinding In Jan 2010

CALGB 100104: Time to Progression

CALGB 100104, NEJM 2012 follow up to 10/31/2011

ITT Analysis: 35 deaths in the lenalidomide arm and 53 deaths in the placebo arm p=0.028, 3 yr OS 88 vs 80%, HR 0.62 or a 38% reduction in death with the cross over

Median follow-up of 34 months

CALGB 100104: Overall Survival

CALGB 100104, NEJM 2012 follow up to 10/31/2011 4 of 8 Heme malignancies received an anthracycline

CALGB 100104: Second Primary Malignancies

SPM Len Arm Placebo Arm

Placebo Crossover to Len

Cross over Time on len in months

ALL 1 0 1 32 mo AML 5 + 1 0 0 HL 1 0 0 MDS 1 0 1 6 mo NHL 0 1 0 Total Heme 8 + 1 = 9 1 2 Breast 3 0 0 Carcinoid 0 1 0 Brain 1 0 0 GI 2 1 0 Gyn 1 1 0 Melanoma 1 2 0 Prostate 1 0 0 Thyroid 1 0 0 Renal 0 0 1 14 mo Total Solid Tumors 10 5 1 Basal Cell Ca 2 + 3 1 0 Squamous Cell Ca 2 2 1 4 mo Total Skin Cancers 4 + 3 = 7 3 1

CALGB 100104: SPMs before PD, follow-up to Jan 7, 2013, new SPM cases since 10/31/2011 are in Red IMW 2013

ITT Analysis with a median follow-up from transplant of ~48 months p<0.001 Median TTP: 50 months versus 27 months.

Time to Progression CALGB 100104 IMW 2013 follow up to January 7, 2013

146 events on placebo 104 events on lenalidomide

CALGB 100104: Updated TTP

Estimated HR=0.51 (95% CI = 0.39 to 0.66),

Overall Survival CALGB 100104 IMW 2013 follow up to January 7, 2013

ITT Analysis with a median follow-up from transplant of ~48 months. p= 0.008, Median OS: not reached versus 73 months

69/229 (30%) deaths on placebo 47/231 (20%) deaths on lenalidomide

CALGB 100104: Updated OS

Estimated HR=0.61 (95% CI = 0.41 to 0.87)

Analysis including placebo patients crossing over within 6 months of randomization on the lenalidomide arm with a median follow-up of ~48 months. p= 0.003



CALGB 100104: Updated OS, 6 mo crossover

Estimated HR=0.57 (95% CI = 0.39 to 0.82)

Analysis including placebo patients crossing over within 12 months of randomization on lenalidomide arm with a median follow-up of ~48 months. p= 0.003




CALGB 100104: Updated OS, 12 mo crossover


The cumulative incidence risk of second primary cancers was greater in the lenalidomide group (P=0.0008). The cumulative incidence risks of progressive disease (P<0.001) and death (P=0.002) were greater in the placebo group

CALGB 100104 NEJM 2012 follow up to Oct 31, 2011

CALGB 100104: Cumulative Incidence Risk of SPM, PD, Death

The cumulative incidence risk of second primary cancers was greater in the lenalidomide group (p=0.034). The cumulative incidence risks of progressive disease (p=0.004)and death (p<0.001) were greater in the placebo group

CALGB 100104 IMW 2013 follow up to January 7, 2013

CALGB 100104: Cumulative Incidence Risk of SPM, PD, Death Updated

Event Free Survival CALGB 100104 IMW 2013 follow up to January 7, 2013

ITT Analysis: Events are Progressions, Deaths and SPM. 151/229 (66%) placebo patients and 113/231 (49%) lenalidomide patients have experienced events. Median EFS 27 and 47 months respectively p <0.001

CALGB 100104: Event-Free Survival, Updated


CALGB 100104, January 2013 Subset analysis, ITT IMW 2013

Median TTP Stratified by Prior Lenalidomide Use Placebo No Prior Len, 27 mo; Placebo Prior Len, 28 mo; Len No Prior Len, 46 mo, Len Prior Len, Not reached

CALGB 100104 Lenalidomide Stratification

CALGB 100104, January 2013, Subset analysis, ITT IMW 2013

Median OS Stratified by Prior Lenalidomide Use Placebo No Prior Len, 73 mo; Placebo Prior Len, Not reached; Len No Prior Len, Not reached; Len Prior Len, Not reached

CALGB 100104 Lenalidomide Stratification

Comparisons CALGB 100104 IFM 2005-02 Induction Thal- and Len-containing

regimens (74%) VAD (~52%) and VD (~44%)

Pre-AHSCT Consolidation None DCEP (~25%) Number of AHSCT One One (79%), Two (21%) Post-AHSCT Consolidation before randomization

None Lenalidomide: 25 mg daily, 3 of 4 wks x 2 pre day ~100

Median F/U at un-blinding ~18 months ~33 months Median F/U from randomization 31 months 45 months

Dosing schedule 10 mg (between 5 to 15 mg) 10 mg (between 5 to 15 mg) Time from first patient enrolled 78 months 62 months Placebo patients crossed over to lenalidomide at un-blinding

Yes (86 of 128 eligible patients)

No

Second primary malignancies ~3 fold increase ~2.6 fold increase Increase in AML/MDS Yes No Increase in ALL/HL No Yes Maintenance Stopped No Yes at a median of ~32 months

JNCCN 2013

Conclusions • Lenalidomide maintenance therapy after single ASCT improves TTP,

OS and EFS when compared to placebo • There is an increased risk of SPMs with len maintenance that may

be related to prior melphalan and/or anthracycline therapies • SPM occurrence has not increased over time • Further study is necessary to understand the SPM differences in the

IFM 2005 02 and CALGB 100104 studies • The cumulative incidence risk for SPM is higher in the len arm and

the cumulative incidence risk for progression and death is higher in the placebo arm

• The risk of SPM development should be evaluated within the context of the risk of disease progression and death due to MM

• Future plans for CALGB 100104 analyses include: – dose confirmation and outcomes (TTP, OS, Adverse events including SPMs) – Genetic studies to correlate genetic polymorphisms with toxicity and

outcome – Evaluating risk factors for SPM

Participating Centers • CALGB: Dana Farber Cancer Inst, Illinois Onc Res Assoc, Memorial Sloan

Kettering Cancer Ctr, Mt Sinai School of Med, North Shore Univ Hosp, Roswell Park Cancer Inst, State Univ NY, Upstate Med Univ, Ohio State Univ Med Ctr, Univ California San Diego, Univ California San Francisco, Univ Chicago, Univ Illinois Chicago, Univ Minnesota, Univ Nebraska, Univ North Carolina Chapel Hill, BMT Group Georgia, Virginia Commonwealth Univ, Univ of Vermont, Wake Forest Univ School Medicine, Walter Reed Army Med Ctr, Washington Univ School Medicine, Weill Med College Cornell Univ, Western Pennyslvania Hosp

• ECOG: Cancer Inst of New Jersey, Case Western Metro Health Med Ctr, Columbia Presbyterian, St Lukes Hsp, Univ of Florida Gainesville, Fox Chase Cancer Ctr, Geisinger Med Ctr, Indiana Univ Medical Ctr, Jewish Hospital, Marshfield Clinic, Med College Georgia, Univ Miami, Univ Pennsylvania, Univ Pittsburgh, Scottsdale, Univ Hospital Cleveland, Vanderbilt Univ, Med College of Wisconscin, Univ of Wisconsin

• BMT-CTN: City of Hope, LDS Hosp, MD Anderson, Oregon Health Sciences Univ, Univ of Mississippi Med Ctr

CALGB 100104 Cooperative Effort

Patients, Caregivers and the Clinical Teams CALGB: C Linker, K Anderson, K Owzar, R Larson, R Schilsky, M

Bertagnolli, V Hars, C Jiang, M Kelly, M Seiler, L Bressler, J Postiglione, S Sutherland, C Hofmeister, H Hassoun, D Hurd, P Richardson, D Weisdorf, R Vij, T Gentile, K van Besien, T Shea, A Bashey, L Isola, S Devine

ECOG: E Stadtmauer, J Wingard, N Callandar BMT-CTN: S Giralt, M Horowitz, M Pasquini, J Ferrara, J Antin, R

Maziarz, A Krishnan, G Somlo, S Carter, N Poland, A Foley, C Gurgol This study was supported in part by grants from the NCI to

CALGB (M Bertagnolli, MD, Chair), to the CALGB Statistical Center (S George, PhD), to ECOG and NHLBI/NCI funding to BMT-CTN. The content of this presentation is solely the responsibility of the authors and does not necessarily represent the official views of the NCI

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