MYELOMA 2015: WHERE HAVE WE BEEN..WHERE ARE WE GOING?

clinicaloptions.com/oncologyBest Practices in Multiple Myeloma

Multiple Myeloma

Plasma cell disorder: calcium elevation, renal dysfunction, anemia, and bone destruction

Estimated 24,050 cases and 11,090 deaths in 2014[1]

Median age at diagnosis: 69 yrs[2]

5-yr survival has improved substantially (45% in 2004-2010 vs 28% in 1987-1989[2]) due to novel agents

Sensitive to treatment, but not curable

– Progression inevitable

The future: risk-adapted therapy, individualized treatment

1. American Cancer Society. Cancer facts & figures. 2014. 2. SEER stat fact sheet: myeloma. 2013.

• NEW DEFINITIONS

NEW PARADIGMSUPFRONT TREATMENTMAINTENANCENEW AGENTSAUTO TRANSPLANT (CONSOLIDATION)

TYPICAL CASE

65 year old woman

Hb 108

Albumin 32

Total protein 102

Increased gammaglobulins May be polyclonal eg HCV,

rheumatoid

May be monoclonal product of clonal plasma cells in marrow

Antibody production by plasma cells

Kappa Lambda

BONE MARROW

MYELOMA: STAGING

CBC CMP FREE LIGHT CHAINS BETA MICROGLOBULIN SPEP, IMMUNOFIXATION., ?URINE STUDIES

BONE IMAGING (PLAIN XRAY PET OR MRI)

BONE MARROW EXAM, TO INCLUDE GENETIC STUDIES (CYTOGENETICS, FISH)


MRI and FDG-PET in Multiple Myeloma

> 3 focal lesions or SUV > 4.2 at diagnosis results in shorter PFS and OS[1]

65% of pts PET/CT negative 3 mos after ASCT with longer PFS and OS vs PET positive[1]

Complete FDG suppression associated with durable disease control and prolonged OS[1]

Skeletal survey (radiography, MRI, or CT) recommended in cases of plasmacytoma, extramedullary disease, suspected spinal cord compression as well as with new symptoms or suspected progression [2]

MRI and/or PET/CT indicated when symptomatic areas show no abnormality on radiograph[3]

1. Zamagni E, et al. Blood. 2011;118:5989-5995. 2. Ludwig H, et al. Leukemia. 2014;28:981-992. 3. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. 4. Boot M, et al. Novel prognostic modalities in multiple myeloma. 2013.

MRI FDG PET

Imaging Techniques[4]


MRI and FDG-PET in Multiple Myeloma

> 3 focal lesions or SUV > 4.2 at diagnosis results in shorter PFS and OS[1]

65% of pts PET/CT negative 3 mos after ASCT with longer PFS and OS vs PET positive[1]

Complete FDG suppression associated with durable disease control and prolonged OS[1]

Skeletal survey (radiography, MRI, or CT) recommended in cases of plasmacytoma, extramedullary disease, suspected spinal cord compression as well as with new symptoms or suspected progression [2]

MRI and/or PET/CT indicated when symptomatic areas show no abnormality on radiograph[3]

1. Zamagni E, et al. Blood. 2011;118:5989-5995. 2. Ludwig H, et al. Leukemia. 2014;28:981-992. 3. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2014. 4. Boot M, et al. Novel prognostic modalities in multiple myeloma. 2013.

MRI FDG PET

Imaging Techniques[4]

Prognosis (NEJM Sep 22,2011)

Treatment

Supportive

Chemotherapy

Transplant

Newer Agents

Depth of response

CURRENT TREATMENT SCHEME: FIT, YOUNGER PTS Thal/Dex triple induction

harvest stem cells

Velcade/Dex Auto

Revlimid

THE YIN/YANG OF MYELOMA

UNDERSTANDING MYELOMA GENOMICS HAS NOT YIELDED TREATMENT AS EFFECTIVE AS IMIDS AND PI, DRUGS WHOSE ACTIVITY WOULD NOT HAVE BEEN PREDICTED BY “RATIONAL” DEFINITION

IF GENOMICS DOES NOT PREDICT DRUG ACTIVITY, WHAT DOES?

The “YIN”: REPRESENTATIVE OF THE NORMAL ASPECTS OF PLASMA CELLS THAT IS RETAINED IN MYELOMA EVOLUTION

The “YANG”: CLASSIC GENETIC ABNORMALITIES OF MALIGNANT PLASMA CELLS

THE TAO OF MYELOMA

TWO BIOLOGIES EXIST WITHIN MALIGNANT PLASMA CELLS, BOTH REQUIRED FOR MYELOMA SURVIVAL

WHY ARE PIs MORE ACTIVE IN MYELOMA THAN OTHER CANCERS? IT MAY HAVE TO DO WITH NORMAL PLASMA CELL BIOLOGY; NOTE EFFECTIVENESS OF PI THERAPY IN DEPLETING NORMAL PLASMA CELL IN ANTIBODY MEDIATED REJECTION.

CONCLUSION: EFFECTIVE AGENTS MAY NEED TO TARGET BOTH PLASMA CELL BIOLOGIES: COMBINE SELECTIVE PLASMA CELL INHIBIITORS AND PROTEINS SELECTIVELY ACTIVATED IN MYELOMA

MYELOMA-REDEFINED

OLD CRITERIA PREVENTED THERAPY PRIOR TO INITIATING THERAPY

NEW CRITERIA: IF BIOMARKERS CONFIRM AN 80% CHANCE OF PROGRESSION TO MYELOMA IN 24 MONTHS, THEN MYELOMA CAN BE DIAGNOSED AND TREATED

NOW:

1. M PROTEIN NOT MANDATORY FOR DIAGNOSIS

2. BONE MARROW BIOPSY PREFERRED TO ESTABLISH BONE MARROW PLASMACYTOSIS

3. BONE LESIONS DEFINED BY CT/PET, MRI VS XRAY


Should Patients With High-Risk Smoldering Myeloma Be Treated? Previously, no benefit shown with alkylating agents,

bisphosphonates, interleukin-1β antagonists, and thalidomide[1]

Lenalidomide vs observation: phase III randomized trials

– PETHEMA (N = 119): Lenalidomide/dexamethasone delayed time to progression (median: not reached vs 21 mos, respectively; HR: 0.18; 95% CI: 0.09-0.32; P < .001) and improved OS vs observation[2]

– ECOG-E3A06: Ongoing phase II/III trial of lenalidomide vs observation in smoldering MM (planned N = 380)

– Initial phase II data: 33% ORR; grade 3 neutropenia and fatigue [4]

1. Landgren O, et al. Clin Cancer Res. 2011;17:1243-1252. 2. Mateos MV, et al. N Engl J Med. 2013;369:438-447. 3. ClinicalTrials.gov. NCT01169337. 4. Lonial S, et al. ASH 2013. Abstract 3174.

clinicaloptions.com/oncologyMultiple Myeloma and Other Plasma Cell Disorders

UPFRONT THERAPY 2015

FIT, YOUNGER PATIENTS

UNFIT, OLDER PATIENTS

WHAT IS THE GOAL? QUALITY OF LIFE? LENGTH OF SURVIVAL? PATHWAY TO TRANSPLANT? CR IS USUALLY OPTIMAL (BUT NOT ALWAYS)


FIRST: Lenalidomide/Dexamethasone vs MPT in NDMM SCT-Ineligible Pts

Ran

dom

ized

1:1

:1

Arm BRd18

Arm CMPT

Len + LoDex 18 cycles (72 wks) Lenalidomide 25 mg Days 1-21/28LoDex 40 mg Days 1, 8, 15, 22/28

Mel + Pred + Thal 12 cycles[2] (72 wks)Melphalan 0.25 mg/kg Days 1-4/42Prednisone 2 mg/kg Days 1-4/42Thalidomide 200 mg Days 1-42/42

PD

, OS

, and

subs

eque

nt a

nti-M

M T

x

PD

or

unac

cept

able

toxi

city

Active treatment + PFS follow-up phase

Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal 100 mg Days 1-42/42; Mel 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage.

Len + LoDex ContinuouslyLenalidomide 25 mg Days 1-21/28LoDex 40 mg Days 1, 8, 15, 22/28

Arm AContinuous Rd

1. Hulin C, et al. ASH 2014. Abstract 81. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al. J Clin Oncol. 2009;27:3664-3670. 4. Benboubker L, et al. N Engl J Med. 2014;371:906-917

Phase III(N = 1623)

FIRST Trial: OS by Age Stratification

Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.

Aged 75 Yrs or Younger100

80

60

40

20

0

Pts

(%

)

0 6 12 18 24 30 36 42 48 54 60

OS (Mos)

HR (95% CI)Rd vs MPT: 0.77 (0.59-1.01)Rd vs Rd18: 0.88 (0.67-1.16)Rd18 vs MPT: 0.88 (0.68-1.14)

Rd Rd18MPT

3-Yr OS, %747067

Aged Older Than 75 Yrs100

80

60

40

20

0

Pts

(%

)

0 6 12 18 24 30 36 42 48 54 60

OS (Mos)

HR (95% CI)Rd vs MPT: 0.80 (0.59-1.09)Rd vs Rd18: 0.94 (0.69-1.29)Rd18 vs MPT: 0.85 (0.63-1.15)

Rd Rd18MPT

3-Yr OS, %635854

FIRST Trial: Grade 3/4 Adverse Events

Grade 3/4 Treatment-Emergent AE, %

Dose for Pts Aged ≤ 75 Yrs Dose for Pts Aged > 75 Yrs

Continuous Rd

(n = 347)

Rd18(n = 348)

MPT(n = 357)

Continuous Rd

(n = 185)

Rd18(n = 192)

MPT(n = 184)

Hematologic in ≥ 10% of pts

Neutropenia 28 25 47 28 29 40

Anemia 18 12 20 19 23 17

Thrombocytopenia 8 9 13 9 7 7

Leukopenia 5 6 11 4 5 8

Nonhematologic

Infection 29 21 16 29 23 20

Cardiac disorders 12 6 6 12 9 13

Fatigue 6 8 5 9 10 8

Peripheral sensory neuropathy

1 1 10 1 0 8

Cataracts 7 3 < 1 3 2 1

DVT and/or PE 8 5 6 7 6 4

Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.

FIRST Trial: Conclusions

Continuous Rd improved PFS vs MPT or 18 cycles of Rd for newly diagnosed MM regardless of age Median and 3-yr PFS both extended with

continuous Rd vs MPT or Rd18 whether pts were younger or older than 75 yrs of age

3-yr OS extended with continuous Rd vs MPT whether pts were younger or older than 75 yrs of age

Analysis of FIRST results based on age consistent with overall trial results

Toxicity profile of Rd similar among pts 75 yrs of age or younger and older than 75 yrs of age

Hulin C, et al. ASH 2014. Abstract 81.

FIT, YOUNGER PATIENTS

3 DRUG COMBINATIONS GIVE VERY HIGH RESPONSE RATES, INCLUDING ~30% CR. 2 DRUG REGIMENS NOT QUITE AS HIGH A RESPONSE, BUT NO CLEAR DECREASE IN OS VS 3 DRUG REGIMEN

OPTIONS ARE RVD, CYBORD, VPT

LENALIDOMIDE: SIDE EFFECTS ARE HEMATOLOGIC, CONSTITUTIONAL, GI, FETAL

VELCADE: LESS TOXICITY WITH SC THERAPY. NEUROLOGIC, HEMATOLOGIC TOXICITY MOST LIKELY


RELAPSED, REFRACTORY PATIENTS


Pomalidomide/Bortezomib/Dexamethasone for Lenalidomide Refractory MM Phase I/II trial to determine MTD; assess safety and efficacy of

pomalidomide/bortezomib/dexamethasone

– Included pts with relapsed MM who had 1-4 previous lines of therapy and were resistant/refractory to lenalidomide

– Accrual: 50 pts (phase I: 3 at dose level 1, 6 at dose level 2; phase II: 41)

Current analysis: 47 pts treated at MTD (dose level 2 + phase II)

Lacy MQ, et al. ASH 2014. Abstract 304.

Pomalidomide 4 mg/day on Days 1-21

Bortezomib 1.3 mg/m2 (IV or SC) and dexamethasone 40 mg

Day 1 Day 8 Day 15 Day 22

8 cycles

Pomalidomide 4 mg/day until PD


AnxietyGeneralized muscle

weaknessEdema limbsConstipation

DyspneaInsomniaDizziness

Thromboembolicevent

Lung infectionVomitingNausea

DiarrheaPeripheral

neuropathyFatigue

Pomalidomide/Bortezomib/Dexamethasone: Summary of Adverse Events

Lacy MQ, et al. ASH 2014. Abstract 304. Reproduced with permission.

Hematologic Toxicity

Grade 3+ All grades

AnemiaThrombocytopeniaNeutropenia

2%70%

2%81%

89%68%

Pts (n)

0 10 20 30 40 50

Pts (n)

0 5 10 15 20 3525 30

Nonhematologic Toxicity

45%

64%

70%


Pomalidomide/Bortezomib/Dexamethasone: Conclusions Pomalidomide/bortezomib/dexamethasone associated

with high response rate (85%) in pts with relapsed MM who are resistant/refractory to lenalidomide

Weekly administration of bortezomib and dexamethasone enhanced tolerability and convenience of treatment

Pomalidomide/bortezomib/dexamethasone associated with manageable AEs, consisting primarily of mild cytopenias

Lacy MQ, et al. ASH 2014. Abstract 304.


ASPIRE: Phase III Trial Comparing Len/ Dexamethasone ± Carfilzomib in R/R MM Randomized, open-label, multicenter phase III trial

KRd* (n = 396)Carfilzomib 27 mg/m2 IV

Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only) Lenalidomide 25 mg Days 1-21

Dexamethasone 40 mg Days 1, 8, 15, 22

Rd (n = 396)Lenalidomide 25 mg Days 1-21

Dexamethasone 40 mg Days 1, 8, 15, 22

Stratified by β2-microglobulin, prior bortezomib, and prior lenalidomide

*After cycle 12, carfilzomib given on Days 1, 2, 15, 16. After cycle 18, carfilzomib discontinued.

Stewart AK, et al. ASH 2014. Abstract 79.

Pts with symptomatic R/R MM after 1-3 prior treatments with ≥ PR to ≥ 1 prior regimen

(N = 792)


ASPIRE: PFS in ITT Population (Primary Endpoint)

KRd Rd(n = 396) (n =

396)

Median PFS, mos 26.3 17.6HR (KRd/Rd) (95% CI) 0.69 (0.57-0.83)P value (1 sided) < .0001

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion

Sur

vivi

ngW

ithou

t P

rogr

essi

on

KRdRd

0 6 12 18 24 30 36 42 48Mos Since Randomization

Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.

Risk Group by FISH

KRd (n = 396) Rd (n = 396) HR P Value

n Median PFS, Mos n Median PFS, Mos

High 48 23.1 52 13.9 0.70 .083

Standard 147 29.6 170 19.5 0.66 .004


ASPIRE: Interim OS Analysis

Median follow-up: 32 mos

Median OS was not reached; results did not meet prespecified statistical boundary (P = .005) at interim analysis

KRd Rd(n = 396) (n = 396)

Median OS, mos NR NRHR (KRd/Rd) (95% CI) 0.79 (0.63-0.99)P value (1 sided) .018

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion

Sur

vivi

ng

KRdRd

0 6 12 18 24 30 36 42 48Mos Since Randomization



ASPIRE: Response Rates and PFS by Response

Per

cent

age

of P

ts

1.0

0.8

0.6

0.4

0.2

0.0S

urvi

val P

roba

bilit

y

0 10 20 30 40 50

Mos From Randomization

sCRCRVGPRPRMRSDPD


PFS by Response With KRd Tx

AEs consistent with previous studies; no unexpected toxicities observed

100

80

60

40

20

0≥ CR ≥ VGPR ORR

(≥ PR)

KRdRd

31.8

9.3

69.9

40.4

87.1

66.7


ASPIRE: Conclusions

PFS significantly improved by 8.7 mos in pts treated with KRd vs Rd relapsed/refractory MM (HR: 0.69; P < .0001)

– Median PFS of 26.3 mos with triplet combination unprecedented in this setting

Interim OS analysis reveals trend favoring KRd

Increased ORR with KRd vs Rd: 87.1% vs 66.7%

– More pts achieved CR or better with triplet: 31.8% with KRd vs 9.3% with Rd

Acceptable safety profile observed with KRd

KRd potentially new standard of care for treatment of relapsed MM

Stewart AK, et al. ASH 2014. Abstract 79.


Combination Therapy With Carfilzomib and Panobinostat Multiple Myeloma Research Consortium multicenter

phase I trial to determine MTD; assess safety and efficacy of panobinostat and carfilzomib

Kaufman JL, et al. ASH 2014. Abstract 32.

Cohort Panobinostat(TIW 3 of 4 wks)

Carfilzomib(Days 1/2, 8/9, 15/16

q4w)

Dexamethasone (Prior to Carfilzomib Dose)

1 15 mg 20 mg/m2 lead-in followed by 27 mg/m2 4 mg cycle 1, then optional




MTD


Combination Therapy With Carfilzomib and Panobinostat: Conclusions Combination carfilzomib/panobinostat appears safe and

effective in pts with relapsed/refractory MM

– MTD of the combination: carfilzomib 36 mg/m2 + panobinostat 20 mg TIW for 3 of 4 wks

Promising response rate, DoR, PFS, and OS

Manageable adverse events in pts with no unexpected toxicities


DOES DEFINING MINIMAL RESIDUAL DISEASE INFORM TREATMENT?


MRD by High-Throughput Sequencing Predicts Prognosis in Patients With CR Quantitative; with amplification and sequencing of immunoglobulin gene

segments using consensus primers for: immunoglobulin heavy-chain locus complete (IGH-VDJH), IGH incomplete (IGH-DJH), and immunoglobulin κ locus (IGK)

MRD stratifies the CR population into 2 groups with strikingly different prognosis

Martinez-Lopez, et al. Blood. 2014;123:3073-3079.

TT

P (

%)

100

80

60

40

20

0100 1500 50

Mos

P = .0009

n = 26

n = 36

TTP (CR Patients)MRD negativeMRD positiveThreshold: 10-5


ASO-PCR Flow Cytometry Next Generation Sequencing (HTS)

Sensitivity Limited by cell number and sometimes background: > 10-5

Limited by technical applicability of antibodies 4-color assay (> 10-4),Higher sensitivity with 8 colors and new bioinformatical tools

Limited by cell number: > 10-6

Very low intrinsic background

Intraclonal variability

Hypersomatic mutations can affect target identification and assay sensitivity

Clones expressing aberrant phenotypes can emerge

May affect subclone identification in mature lymphoid malignancies and hamper MRD assessment

Bioinformatical algorithms needed

Labor intensity Needs 5-7 working days for assay establishment

Fast, experienced investigators needed

Dependent on HTS device

Bioinformatical expertise is crucial

Standardization Easily adaptable to MM

Ongoing process Performed only on a service basis (EUROCLONALITY, EUROMRD initiative on NGS ongoing)

Comparing Flow Cytometry and RQ-PCR: Different Point of View and Novel Incumbent

NEW AGENTS


Phase Ib/II: Single-Agent Oprozomibin Relapsed/Refractory MM Open-label phase Ib/II dose escalation study of oprozomib

– Oprozomib is a selective, irreversible oral epoxyketone proteasome inhibitor with promising antitumor activity

– In pts who relapsed after ≥ 1 prior lines of therapy

Vij R, et al. ASH 2014. Abstract 34.

Trial Parameter 2/7 Schedule(n = 21)

5/14 Schedule(n = 47)

2/7 Step-up Schedule(n = 10)

5/14 Step-up Schedule

(n = 9)

Phase Ib Ib/II II II

Schedule, every 2 wks Days 1, 2, 8, 9 Days 1-5 Days 1, 2, 8, 9 Days 1-5

Dose, mg/day 150-330 150-270 240/300 150/180

Median tx duration, wks (range) 23.4 (0.3-76.4) 6.7 (0.7-93.1) 5.6 (0.1-11.3) 6.7 (3.0-16.7)


Single-Agent Oprozomib in Relapsed/ Refractory MM: Conclusions Single-agent oprozomib appears safe, with promising activity in

pts with relapsed/ refractory MM

– Continues to show promising antitumor activity; ORR between 23% and 31% overall

– Preliminary data suggest that step-up dosing is associated with improved tolerability, with few grade ≥ 3 GI adverse events observed

Enrollment on phase II 2/7 and 5/14 schedules ongoing

– Target enrollment for the phase II portion: 94 pts with MM

All current and newly enrolled pts will receive new, extended-release tablet formulation



Ibrutinib ± Dexamethasone: Overall Response and PFS Response rate PFS

Pts

(%

)

Cohort 1(n = 13)

Cohort 2(n = 18)

Cohort 3(n = 18)

Cohort 4(n = 20)

Vij R, et al. ASH 2014. Abstract 31. Reproduced with permission.

0 6 12

Mos

0

20

40

60

80

100

Pts

(%

)

Cohorts 1, 2, and 3Cohort 4

93

Cohort: 1 2 3 4

Median PFS, mos

1.0 4.3 2.8 5.6

50

40

30

20

10

0

PR MR SD ≥ 4 cycles

8%

8%

22%

6%

33%

25%

20%

5%


Ibrutinib ± Dexamethasone: Safety

22% of pts required a dose modification due to an AE, while 10% led to treatment discontinuation

Hematologic AEs Nonhematologic AEs

Vij R, et al. ASH 2014. Abstract 31. Reproduced with permission.

Grades 3-5All grades

Anemia

Thrombocytopenia

Neutropenia

Pts (%)

0 20 40 60 80 100

Cohort 4

All

Cohort 4

All

Cohort 4

All

Diarrhea

Fatigue

Nausea

Pts (%)

0 20 40 60 80 100

Cohort 4

All

Cohort 4

All

Cohort 4

All

Dizziness

Muscle Spasms

Arthralgia

Pts (%)

0 20 40 60

Cohort 4

All

Cohort 4

All

Cohort 4

All


Ibrutinib ± Dexamethasone: Conclusions

Ibrutinib ± weekly dex appears safe, with promising activity in heavily pretreated pts with relapsed/refractory MM

– Highest activity was seen in cohort 4 with:

– 25% CBR

– Sustained SD in an additional 25%

– Median PFS of 5.6 months

– Safety profile tolerable, with AE rates consistent with those seen in other histologies

Enrollment of 23 additional pts in cohort 4 is complete; evaluation is ongoing

Further study of ibrutinib in combination with other backbone agents is warranted



Phase I Trial: Daratumumab in Combination With Len/Dex in Rel/Ref MM Phase I/II dose-escalation trial of daratumumab in combination with

len/dex in rel/ref MM (safety cohort: n =45; efficacy cohort: n = 43)

– Daratumumab is a human mAb targeting CD38-expressing cells

– Dose escalation: daratumumab 2-16 mg/kg/wk for 8 wks, twice monthly for 16 wks, then once monthly for 24 mos in total or until PD, unmanageable AE

– Lenalidomide 25 mg on Days 1-21 of each 28-day cycle

– Dexamethasone 40 mg/wk for of each 28-day cycle

Median prior lines of therapy: 2 (range: 1-4); most with prior exposure to IMiDs and/or a proteasome inhibitor; 3 pts refractory to len

MTD: daratumumab 16 mg/kg + len 25 mg and dex 40 mg/wk

Plesner T, et al. ASH 2014. Abstract 84.


Daratumumab in Combination With Len/Dex: Safety Daratumumab related serious AEs

– Pneumonia, neutropenia, diarrhea (1 pt each receiving 16 mg/kg, early infusion program)

– Laryngeal edema (1 pt receiving 16 mg/kg, accelerated infusion program)

19/45 pts reported infusion-related reactions; mostly grade 1/2

– 18/19 pts with infusion-related reactions recovered and were able to continue the subsequent infusion

≤ 8 mg/kgPart 1

(n = 10)

16 mg/kgPart 1(n = 3)

16 mg/kgPart 2

Current InfusionProgram (n = 21)

16 mg/kgPart 2

Accelerated InfusionProgram (n = 11)

Plesner T, et al. ASH 2014. Abstract 84. Reproduced with permission.

60

40

20

0

Pts

(%

)

20.0 20.0

33.338.1

4.8

63.6Infusion-Related Reactions

First Infusion

Subsequent Infusion


Phase I Trial: SAR650984 in Combination With Len/Dex in Relapsed/Refractory MM Phase Ib trial of SAR650984 + len/dex in relapsed/refractory MM

– SAR650984 is a humanized IgG1 mAb to the CD38 receptor widely expressed in many heme malignancies

– Dose escalation: SAR650984 3-10 mg/kg on Days 1 and 15 of each 28-day cycle + lenalidomide 25 mg on Days 1-21 of each 28-day cycle and dexamethasone 40 mg/wk during each 28-day cycle

Martin TG, et al. ASH 2014. Abstract 83.

Previous MM Treatment

SAR650984 Dose, mg/kg q2w

Overall(N = 31)3 (n = 4) 5 (n = 3) 10 (n = 24)

Median prior regimens, n (range) 10 (3-14) 7 (6-7) 6 (2-12) 7 (2-14)

Median prior lines, n (range) 6 (2-11) 6 (4-6) 4 (1-9) 4 (1-11)

Median time on last Len, mos (range)

7 (3-17) 3 (3-10) 10 (1-54) 9 (1-54)

Relapsed/refractory to IMiD 3 (75) 2 (67) 21 (88) 26 (84)


SAR650984 + Len/Dex: PFS by Previous Lines of Therapy

Pro

bab

ility

0

10

20

30

40

50

60

70

80

90

100

Mos

50 1 2 3 4 6 7 8 9 10 11 12 13 14 15 16 17

≥ 3 prior lines (n = 24)

Overall (N = 31)

Median PFS: NR (95% CI: 6.2-NR)

Median PFS: 6.2 mos (95% CI: 4.80-13.33)

Median PFS: 5.8 mos (95% CI: 2.10-10.30)

1-2 prior lines (n = 7)

Martin TG, et al. ASH 2014. Abstract 83. Reproduced with permission.


SAR650984 + Len/Dex: Efficacy Analysis

DoR: 9.13 mo (range: 1.2-15.2)


Response, % Total (N = 31)

ORR 58

sCR 6

VGPR 23

PR 29

CBR 65

MR 6

SD 19

PD 13

Not evaluable 3

Pts

(%

)

SAR650984 Dose Level, mg/kg q2w

ORR 25%CBR 50%

ORR 67%CBR 67%

ORR 63%CBR 67%

ORR 58%CBR 65%

100

80

60

40

20

03

(n = 4)5

(n = 3)10

(n = 24)Overall(n = 31)

25

25

67

8

29

6

29

6

25 23

4

PR sCRVGPRMR


SAR650984 plus Len/Dex: Tx-Emergent AEs in ≥ 30% (Any) or 5% (Grade 3/4) of Pts

There were 15 incidences of infusion reaction, all occurring in the first 2 cycles – 2 pts discontinued treatment: 1 serious grade 3 anaphylactic reaction in cycle 1 and

1 nonserious grade 3 maculopapular rash in cycle 2 (AEs resolved in both pts)

– Remaining incidents were grade 1/2 and did not lead to treatment discontinuation

Pts

(n

= 3

1) (

%)

Thro

mbo

cyto

peni

a

Febrile

neut

rope

nia Mus

cle

spas

ms


100

80

60

40

20

0

Grade 1 Grade 2 Grade 3 Grade 4Ane

mia

Neutro

peni

a

Diarrh

ea

Fatig

ueIn

som

nia

Nause

aPne

umon

ia

Pyrex

ia

URTI


SAR650984 + Len/Dex: Conclusions

Combination SAR650984 with len/dex appears safe and effective in heavily pretreated pts with relapsed/refractory MM

– ORR was 58%; 63% at the SAR650984 10 mg/kg dose level

– Manageable safety profile, consistent with those of individual agents

– At 9-mo follow-up, overall median PFS was 6.2 mos

Martin TG, et al. ASH 2014. Abstract 83.


Phase I Trial: Elotuzumab in Combination With Len/Dex in Relapsed/Refractory MM Phase Ib/II 1703 trial of elotuzumab + len/dex in relapsed/refractory

MM

– Elotuzumab is a humanized IgG1 mAb targeting SLAMF7, a glycoprotein highly expressed on myeloma and NK cells

– Elotuzumab 10 or 20 mg/kg on Days 1, 8, 15, 22 for cycles 1-2; Days 1, 15 for subsequent cycles

– Lenalidomide 25 mg on Days 1-21 of each 28-day cycle

– Dexamethasone 28 mg + 8 mg IV on elotuzumab dosing days, or 40 mg/wk for of each 28-day cycle

Current analysis on phase II data to assess efficacy and safety of combination

– ~ 60% of pts received previous treatment with bortezomib and/or thalidomide and 20% to 30% were refractory to previous treatment

Richardson PG, et al. ASH 2014. Abstract 302.


Elotuzumab in Combination With Len/Dex: Conclusions Combination elotuzumab with len/dex appears safe and

effective in heavily pretreated pts with relapsed/refractory MM

– ORR: 92% with 10 mg/kg elotuzumab; 84% overall

– Median PFS: 32.5 mos with 10 mg/kg; 29 mos overall

Favorable safety profile; most common treatment-related AEs included diarrhea, fatigue, muscle spasms, constipation

Accelerated infusion well tolerated and pretreatment regimen decreased rate of infusion reactions

Phase III trials with elotuzumab + len/dex in newly diagnosed MM and relapsed/refractory MM currently ongoing

Richardson PG, et al. ASH 2014. Abstract 302.


Combination Therapy With Carfilzomib and Panobinostat: Preliminary SafetyAny Grade AEs in ≥ 20% of Pts, %

Overall(n = 26)

All 100

Nausea 65

Diarrhea 50

Thrombocytopenia 50

Fatigue 38

Vomiting 35

Hypokalemia 31

Pyrexia 31

Decreased appetite 27

Hypocalcemia 27

Insomnia 23

Grade 3/4 AEs in ≥ 5% of Pts, %

Overall (n = 26)

≥ 1 grade 3/4 AE 77

Anemia 38

Thrombocytopenia 38

Neutropenia 19

Fatigue 12

Decreased appetite 8

Diarrhea 8

Elevated creatinine 8

Hyperglycemia 8

Hypertension 8

Hyponatremia 8



Combination Therapy With Carfilzomib and Panobinostat: Conclusions Combination carfilzomib/panobinostat appears safe and

effective in pts with relapsed/refractory MM

– MTD of the combination: carfilzomib 36 mg/m2 + panobinostat 20 mg TIW for 3 of 4 wks

Promising response rate, DoR, PFS, and OS

Manageable adverse events in pts with no unexpected toxicities



Weekly Carfilzomib + Cyclophosphamide/ Dex: Preliminary EfficacyOutcome Phase I (n = 12) MTD (n = 19) Total (N = 28)

Median cycles received, n (range) 9 (1-9) 4 (1-9) 8 (1-9)

ORR (≥ PR), n (%) 11 (92) 15 (79) 24 (86)

≥ VGPR 9 (75) 11 (58) 18 (64)

sCR + CR + nCR 4 (33) 4 (21) 7(25)

1. Palumbo A, et al. ASH 2014. Abstract 175. 2. Bringhen S, et al. Blood. 2014;124:63-69.Reproduced with permission.

Once weekly[1] Twice weekly[2]

At Least nCR At Least VGPR50

40

30

20

10

0

Pts

(%

)

Cycle 4 Cycle 9

3024

4147 100

80

60

40

20

0

Pts

(%

)

Cycle 4 Cycle 9

89

57

9177


Melphalan/Dexamethasone ± Bortezomib in AL Amyloidosis: Efficacy Summary

Kastritis E, et al. ASH 2014. Abstract 35. Reproduced with permission.

Response After Cycle 3, n (%)

Response MDex (29 pts) BMDex (30 pts) P

Overall Hem 15 (52) 22 (73) .086

CR 1 (3) 4 (13) .173

VGPR 9 (31) 11 (37) .648

PR 4 (14) 7 (23) .347

Cardiac 5/23 (22) 4/17 (23) .893

Renal 6/15 (40) 3/16 (19) .193

Best Response (Median 5 Cycles), n (%)

Response MDex (29 pts) BMDex (30 pts) P

Overall Hem 15 (52) 23 (77) .045

CR 6 (21) 7 (23) .807

VGPR 6 (21) 11 (37) .176

PR 3 (10) 5 (17) .478

Cardiac 5/23 (22) 4/17 (23) .893

Renal 7/15 (47) 5/16 (31) .378

100

80

60

40

20

0

Su

rviv

al P

rob

abil

ity

(%)

PFS

P = .109

BMDexMDex

Mos0 12 24 36 40

100

80

60

40

20

0

Su

rviv

al P

rob

abil

ity

(%)

OS

P = .504

BMDexMDex

Mos0 12 24 36 40


Melphalan/Dexamethasone ± Bortezomib in AL Amyloidosis: Conclusions Higher hematologic response rates BMDex vs MDex in

treatment-naive pts with systemic AL amyloidosis

– Best overall hematologic response: 77% vs 52%, respectively (P = .045)

– Overall hematologic response after 3 cycles: 73% vs 52%, respectively (P = .086)

BMDex was well tolerated, with cytopenias the only grade ≥ 3 AE occurring in > 2% of pts

Additional follow-up needed to assess differences in organ improvement, survival

Kastritis E, et al. ASH 2014. Abstract 35.


Actual treatment <65

Thal/Dex triple induction

harvest stem cells

Velcade/Dex Auto

Revlimid

AUTOTRANSPLANT IN MYELOMA

COMPARED TO OLDER CHEMOTHERAPY ALONE, PROVEN BENEFIT FOR BETTER SURVIVAL WITH HD MELPHALAN

STUDIES COMPARING AUTOTRANSPLANT GIVEN AFTER NOVEL INDUCTION THERAPY (VS NOVEL THERAPY ALONE) ARE PENDING

PFS CAN BE IMPROVED WITH HD MELPHALAN, AND AUTO TRANSPLANT IS STILL COMMONLY USED FOR CONSOLIDATION IN THE US

MAINTENANCEALL THE TIME? MOST OF THE TIME?


Maintenance in Myeloma: Still a Work in Progress? Provides PFS advantage

– Longer follow-up needed

OS improvements noted

Toxicities of treatment

– Myelosuppression

– Second primary malignancies

– Quality of life

Unknown response to higher doses of lenalidomide at relapse; potential development of resistant clones

Observation is still an option

Unclear whether all patients benefit from maintenance

– Tailor treatment choice to individual patient

Van de Donk N, et al. Cancer Management Res. 2012;4:253-268.


Lenalidomide Maintenance Therapy: Meta-analysis of Randomized Trials In a study of 4 RCTs (N = 1935), lenalidomide maintenance

vs no maintenance or placebo associated with:

– Improved PFS (overall HR: 0.49; P < .001)

– Trend toward improved OS (overall HR: 0.77; P = .071)

– Significantly higher risk of grade 3/4 neutropenia, VTE, thrombocytopenia, fatigue

– Significantly higher risk of secondary malignancies (overall OR: 1.62; P = .006)

Patient subset most benefitting from lenalidomide maintenance therapy remains undefined

Singh PP, et al. ASH 2013. Abstract 407.

Ixazomib Maintenance: Efficacy and Safety

Safety in maintenance period similar to induction period No grade 4 AEs, grade 3

drug-related AEs reported in 62% of pts

52% during induction

14% during maintenance

Limited new onset AEs during maintenance New onset AEs ≤ 10%

except:

Diarrhea (~ 45%)

Nausea (~ 20%)

Pain in extremities (~ 15%)

Kumar S, et al. ASH 2014. Abstract 82. Reproduced with permission.

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ility

of

PF

S

0 3 6 9 12 15 18 21 24 27 30 33

Phase II pts who received maintenance

All phase II pts (pts who proceeded to ASCT [n = 14] were censored at last response assessment before ASCT)

Median PFS among censored phase II pts who received maintenance (n = 21): not reached, 10 pts progressed

‒ Estimated 2-yr PFS: 57%

Median PFS among all phase II pts (n = 50): 28.7 mos


Mos


Ixazomib Maintenance: Efficacy and Safety

Safety in maintenance period similar to induction period

– No grade 4 AEs, grade 3 drug-related AEs reported in 62% of pts

– 52% during induction

– 14% during maintenance

Limited new onset AEs during maintenance

– New onset AEs ≤ 10% except:

– Diarrhea (~ 45%)

– Nausea (~ 20%)

– Pain in extremities (~ 15%)Kumar S, et al. ASH 2014. Abstract 82. Reproduced with permission.

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ility

of

PF

S

0 3 6 9 12 15 18 21 24 27 30 33

Phase II pts who received maintenance

All phase II pts (pts who proceeded to ASCT [n = 14] were censored at last response assessment before ASCT)

Median PFS among censored phase II pts who received maintenance (n = 21): not reached, 10 pts progressed


Median PFS among all phase II pts (n = 50): 28.7 mos


Mos


Ixazomib Maintenance: Conclusions

All-oral regimen of ixazomib/lenalidomide/dexamethasone associated with high response rate in pts with NDMM

– 90% of pts had PR or better

– 48% of pts had deepening of response with ixazomib maintenance

Regimen was tolerable with no grade 4 AEs

– Most common AEs: skin and subcutaneous tissue disorders, diarrhea, fatigue, nausea, peripheral neuropathy

Ongoing phase III trial comparing ixazomib vs placebo in combination with lenalidomide/dexamethasone in pts with NDMM

Kumar S, et al. ASH 2014. Abstract 82.


Weekly Carfilzomib + Cyclophosphamide/ Dex: Preliminary EfficacyOutcome Phase I (n = 12) MTD (n = 19) Total (N = 28)

Median cycles received, n (range) 9 (1-9) 4 (1-9) 8 (1-9)

ORR (≥ PR), n (%) 11 (92) 15 (79) 24 (86)

≥ VGPR 9 (75) 11 (58) 18 (64)

sCR + CR + nCR 4 (33) 4 (21) 7(25)

1. Palumbo A, et al. ASH 2014. Abstract 175. 2. Bringhen S, et al. Blood. 2014;124:63-69.Reproduced with permission.

Once weekly[1] Twice weekly[2]

At Least nCR At Least VGPR50

40

30

20

10

0

Pts

(%

)

Cycle 4 Cycle 9

3024

4147 100

80

60

40

20

0

Pts

(%

)

Cycle 4 Cycle 9

89

57

9177


Weekly Carfilzomib in Combination With Cyclophosphamide/Dex in NDMM Phase I/II trial to assess feasibility of reduction of carfilzomib dosing

from twice weekly to once weekly when used in combination with cyclophosphamide/dexamethasone in elderly pts with NDMM

– Carfilzomib given weekly using standard 3+3 phase I dose-escalation (starting at 45 mg/m2, increasing to 56 or 70 mg/m2)

Phase I data (n = 12) identified MTD as 70 mg/m2

– 3 of 12 pts in phase I portion received MTD

Phase II cohort currently enrolling

– 18 pts included in current analysis

Similar baseline characteristics across all pts in phase I and II cohorts, with 30% of pts aged ≥ 75 yrs and 33% with unfavorable cytogenetics

Palumbo A, et al. ASH 2014. Abstract 175.


Phase III Maintenance Studies: Transplantation-Ineligible PatientsTrial N Regimen Outcomes

MM-015[5] 459 MPR followed by R maintenance vs MPR vs MP, transplantation-ineligible pts

Median PFS: 31 vs 14 vs 13 mos

Median OS: 56 vs 52 vs 54 mos

GIMEMA-MM-03-05[2]

511 VMPT followed by bortezomib/thalidomide maintenance vs VMP

Median PFS:35 mo vs 25 mos

5-yr OS: 61% vs 51%

GEM2005MAS65[3]

260 VMP followed by bortezomib/thalidomide maintenance vs VTP followed by

bortezomib/prednisone maintenance

Median PFS:39 vs 32 mos

5-yr OS: 69% vs 50%

1. Dimopoulos MA, et al. ASH 2013. Abstract 405. 2. Palumbo A, et al. J Clin Oncol. 2014;32:634-640. 3. Mateos MV, et al. Blood. 2012;120:2581-2588.

clinicaloptions.com/oncologyOptimal Approaches for the Care of Veterans With Multiple Myeloma

What We Know and Don’t Know

New drugs improve induction CRs, higher CRs after ASCT

– Which drug combinations are optimal for patients proceeding to transplantation?

Do higher response rates observed after novel drug combinations plus ASCT improve survival?

Some new drugs affect stem cell yields

If a patient achieves CR after novel induction therapies, is a transplantation optional?

Gertz MA, Dingli D. Blood. 2014;124:882-890.Giralt S, et al. Bio Blood Marrow Transplant. 2014;20:295-308.

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MYELOMA 2015: WHERE HAVE WE BEEN..WHERE ARE WE GOING?

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