updates in the treatment and management of relapsed ... mm.pdfcurrent recommendations and treatment...

1

Rachid Baz, MD

Associate Professor, Departments of Oncologic Sciences and Medicine

University of South Florida

Associate Member, Myeloma Section Head and Director of Clinical Research

Department of Malignant Hematology

H. Lee Moffitt Cancer Center and Research Institute

Updates in the Treatment and Management of Relapsed/Refractory

Multiple Myeloma

Disclosures

Research Funding:

– Celgene

– Millennium

– Sanofi

– Bristol Myers Squibb

– Karyopharm Therapeutic

2

Overview

Selecting Therapy Based on Specific Patient and Disease Features

Current Recommendations and Treatment Options for Relapsed/Refractory Myeloma

Future Directions in the Salvage Setting

Management of Adverse Events

Selecting Therapy for Myeloma Based on Specific Patient and

Disease Features

3

When to Consider Retreatment

Need to consider biochemical vs symptomatic relapse

– Patients with asymptomatic rise in M-protein can be observed to determine the rate of rise and nature of relapse

– Caveat: Patients with known aggressive or high-risk disease should be considered for salvage, even in the setting of biochemical relapse

Factors in Selecting Treatment For Relapsed/Refractory Myeloma Disease-related factors

– Duration of response to initial therapy

Treatment-related factors

– Previous therapy exposure (relapsed or refractory)

– Toxicity of regimen (combination vs single agent)

– Mode of administration (eg, oral or intravenous)

4

How do We Synthesize These Variables?

Does the patient NEED therapy?

– Defined by presence of symptoms similar to initial treatment

– Not all patients with biochemical relapse need therapy

– Aggressiveness of previous relapse, risk of organ damage, and magnitude of M-protein increase all play into this decision

Relapsed/Refractory Myeloma: Preferred Regimens NCCN Category 1

– Bortezomib

– SC vs IV administration

– Bortezomib/PLD

– Carfilzomib/lenalidomide/ dexamethasone

– Panobinostat/bortezomib/ dexamethasone

– Lenalidomide/dexamethasone

NCCN Category 2A

– Repeat primary induction therapy if relapse at > 6 mos

– Bortezomib combinations

– With dex; len/dex; thalidomide

– Carfilzomib

– Cyclophosphamide

– High-dose or with bort/dex or len/dex

– Pomalidomide/dexamethasone

– Thalidomide/dexamethasone

– DCEP, DT-PACE, or VTD-PACE

NCCN clinical practice guidelines in oncology: multiple myeloma: v.2.2015. www.nccn.org

5

Treating Indolent, Slow-Growing Myeloma in First Relapse

• Initial treatment with bortezomib

• May consider single agent without dexamethasone

• Underlying PN

IMiD-Based Salvage PI-Based Salvage Transplant-Based Salvage

• Initial treatment with IMiD

• Previous bortezomib therapy but good or long response

• Renal dysfunction

• Transplant not part of initial therapy

• Long remission post transplant

Treating Relapsed/Refractory Myeloma

Carfilzomib-Based Salvage

Pomalidomide-Based Salvage

Other Salvage

• Intolerance to bortezomib

• Dexamethasone-sparing treatment as part of a combination

• Intolerance to IMiDs

• Lenalidomiderefractory

• Refractory to standard-dose PI

• Pts with del(17p)?

• Refractory to pomalidomide and carfilzomib

• Monoclonal antibody candidate

• Clinical trials

6

Treating Aggressive Myeloma With Rapid, Multiple Relapses

• DCEP vs DT-PACE

• Oral vs IV chemo

• Performance status of patient plays important role

Chemotherapy-Based Salvage

Likely Combination TherapyDo Not Wait for Symptomatic Relapse

Chemotherapy + Novel Agent

Transplant-Based Salvage

• Combinations of lenalidomide/ bortezomib and other chemotherapy agents

• Likely to be short lived

• Rapid disease control

• Reconstitute marrow

Current Recommendations and Treatment Options for

Relapsed/Refractory Myeloma

7

Summary of Combination Therapy in RR MM

60 65

31

6555

87

70

95

67 64

85

71

0

20

40

60

80

100

IMiD-Based PI-Based

11

4

9

4

26

10 10 119

30

1316

20

NR

NR

30 29

0

5

10

15

20

25

30

35

IMiD-Based PI-Based

1. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. 2. Morgan JG, et al. Br J Haematol. 2007;137:268-269. 3. San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066. 4. Baz R, et al. ASH 2014. Abstract 303. 5. Lendvai N, et al. Blood. 2014;124:899-906. 6. Stewart AK, et al. ASH 2014. Abstract 79. 7. Shah JJ, et al. ASH 2013. Abstract 690. 8. Bringhen S, et al. Blood. 2014;124:63-69. 9. Mikhael JR, et al. Br J Haematol. 2009;144:169-175. 10. Richardson PG, et al. Blood. 2014;123:1461-1469. 11. Lacy MQ, et al. ASH 2014. Abstract 304. 12. Monge J, et al. ASCO 2014. Abstract 8586.

Rd[

1] *

CyR

d[2

]

Pom

D[3

] *C

yPom

D[4

]

CD

[5]

CR

d[6

] *C

Pom

D[7

]

CyC

D[8

]

VD

[9] *

VR

d[1

0] *

VP

omD

[11

]

CyB

orD

[12

]

Rd[

1] *

Pom

D[3

] *

CyP

omD

[4]

CD

[5]

CR

d[6

] *

CP

omD

[7]

VR

d[1

0] *

VP

omD

[11

]

CyB

orD

[12

]

OR

R,

%

Sur

viva

l, m

onth

s*Data from phase III trials, all others from phase I or II trials

ORR PFS OS

Summary of IMiD Combination Therapy Regimen Phase N Outcomes

Len/dex vs dex[1] III 351 OS: NR vs 20.6 moTTP: 11.3 mo vs 4.7 mo

ORR: 60.2% vs 24%

Len/cyclo/dex [2] II 21 ORR: 65%

Pom/dex II[3]

III[4]

221

302

OS: 16.5 mo vs 13. 6 moPFS: 4.2 mo vs 2.7 mo

ORR: 33% vs 18%PFS: 4.0 mo vs 1.9 mo

Pom/cyclo/dex vs pom/dex[5] II 70 OS: 16.4 mo vs 10.5 moPFS: 9.2 mo vs 4.4 mo

ORR: 65% vs 39%

1. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. 2. Morgan JG, et al. Br J Haematol. 2007;137:268-269. 3. Richardson PG, et al. Blood. 2014;123:1826-1832. 4. San Miguel J, et al. Lancet Oncol. 2013;14:1055-1066. 5. Baz R, et al. ASH 2014. Abstract 303.

8

Summary of Proteasome Inhibitor Combination Therapy Regimen Phase N Outcomes

Carfilzomib ± dex[1] II 44 OS: 20.3 moPFS: 4.1 moORR: 55%

Carfilzomib/len/dexvs len/dex[2]

III 792 PFS: 26.3 mo vs 17.6ORR: 87.1% vs 66.7%

(Interim 24-mo OS: 73.3% vs 65.0%)

Carfilzomib/pom/dex[3] I/II 79 PFS: 9.7 moORR: 70%

Carfilzomib/cyclo/dex[4] II 58 2-yr OS: 87%2-yr PFS: 76%

ORR: 95%

1. Lendvai N, et al. Blood. 2014;124:899-906. 2. Stewart AK, et al. ASH 2014. Abstract 79. 3. Shah JJ, et al. ASH 2013. Abstract 690. 4. Bringhen S, et al. Blood. 2014;124:63-69.

Summary of Proteasome Inhibitor Combination Therapy Regimen Phase N Outcomes

Bortezomib ± dex[1] IIIb 638 ORR: 67%

Bortezomib/len/dex[2] II 64 OS: 30 moPFS: 9.5 moORR: 64%

Bortezomib/pom/dex[3] I/II 47 PFS: 10.7 moORR: 85%

Bortezomib/cyclo/dex[4] II 55 OS: 29 moPFS: 9.2 moORR: 71%

1. Mikhael JR, et al. Br J Haematol. 2009;144:169-175. 2. Richardson PG, et al. Blood. 2014;123:1461-1469. 3. Lacy MQ, et al. ASH 2014. Abstract 304. 4. Monge J, et al. ASCO 2014. Abstract 8586.

9

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

KRdCarfilzomib* 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(n = 396)

RdLenalidomide 25 mg Days 1–21

Dexamethasone 40 mg Days 1, 8, 15, 22(n = 396)

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 RR MM after 1-3 prior treatments with ≥ PR to ≥ 1 prior regimen

(N = 792)

Len/Dexamethasone ± Carfilzomib in RR MM (ASPIRE): PFS (ITT)

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

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

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n S

urv

ivin

gW

ith

ou

t P

rog

ress

ion

KRdRd

0 6 12 18 24 30 36 42 48Months 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, mo n Median PFS, mo

High 48 23.1 52 13.9 0.70 .083

Standard 147 29.6 170 19.5 0.66 .004

10

ASPIRE: Interim OS Analysis

OS results did not meet prespecified statistical boundary (P = .005) at interim

AEs consistent with previous studies; no unexpected toxicities observed– Grade ≥ 3 cardiac failure and ischemic heart disease: 3.8% and 3.3% in KRd arm

vs 1.8% and 2.1% in Rd arm, respectively

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

Median follow-up: 32 months

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n S

urv

ivin

g

KRdRd

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


ASPIRE: Select Adverse Events

AE, %KRd (n = 392) Rd (n = 389)

All Grade Grade ≥3 All Grade Grade ≥3Non-hematologic AEs occurring in ≥25% of patients

Diarrhea 42.3 3.8 33.7 4.1Fatigue 32.9 7.7 30.6 6.4Cough 28.8 0.3 17.2 0Pyrexia 28.6 1.8 20.8 0.5Upper respiratory tract infection 28.6 1.8 19.3 1.0Hypokalemia 27.6 9.4 13.4 4.9Muscle spasms 26.5 1.0 21.1 0.8

Hematologic AEs occurring in ≥25% of patients Anemia 42.6 17.9 39.8 17.2Neutropenia 37.8 29.6 33.7 26.5Thrombocytopenia 29.1 16.6 22.6 12.3

Other AEs of InterestPeripheral neuropathy* 17.1 2.6 17.0 3.1Hypertension 14.3 4.3 6.9 1.8Acute renal failure* 8.4 3.3 7.2 3.1Cardiac failure* 6.4 3.8 4.1 1.8Ischemic heart disease* 5.9 3.3 4.6 2.1


11

Phase III PANORAMA 1: Bort/Dex ±Panobinostat in RR Myeloma Randomized, double-blind trial

Panobinostat 20 mg (3x/wk)Bortezomib 1.3 mg/m2 IV (d1,4,8,11)

Dexamethasone 20 mg(d1,2,4,5,8,9,11,12)

(n = 387)

Placebo (3x/wk)Bortezomib 1.3 mg/m2 IV (d1,4,8,11)

Dexamethasone 20 mg(d1,2,4,5,8,9,11,12)

(n = 381)

Stratified by prior lines of therapy, and prior bortezomib

Richardson P, et al. ASCO 2014. Abstract 8510^.

Pts with symptomatic RR MM after 1-3 prior

treatments (bortezomib-refractory excluded)

(N = 768)

Panobinostat 20 mg (3x/wk)Bortezomib* 1.3 mg/m2 IVDexamethasone* 20 mg

*reduced frequency

Placebo (3x/wk)Bortezomib* 1.3 mg/m2 IVDexamethasone* 20 mg

*reduced frequency

Treatment Phase I:Eight 21-d cycles (24 wks)

Treatment Phase II:Four 42-d cycles (24 wks)

Patients with ≥ SD in tx phase I can proceed to tx phase II

Bort/Dex ± Panobinostat in RR Myeloma (PANORAMA 1): PFS Primary endpoint reached: median PFS ↑ by 3.9 months


GK6

k17

GK6 Design: For the PFS and OS slides, change to Pan/bort/dex and placebo/bort/dex both here and in legend. Also, hyphenate CI ranges. Change PFS column header to "Median PFS, mo (95% CI)"Gordon Kelley, 3/19/2015

k17 Creative, please redrawkrosenthal, 3/31/2015

12

Bort/Dex ± Panobinostat in RR Myeloma (PANORAMA 1): OS Interim OS analysis; final analysis forthcoming


k18

PANORAMA 1: Safety

Richardson P, et al. ASCO 2014. Abstract 8510^. San-Miguel JF, et al. Lancet Oncol. 2014;15:1195-1206.

Select AEs (≥ 10% incidence and ≥ 5% greater Incidence with Pano), %

Pano + Bort/Dex (n = 381) Pbo + Bort/Dex (n = 377)

All grades Grade 3/4 All grades Grade 3/4

Arrhythmia 12 3 5 2

Diarrhea 68 25 42 8

Nausea 36 6 21 1

Vomiting 26 7 13 1

Fatigue 60 25 42 12

Peripheral edema 29 2 19 <1

Pyrexia 26 1 15 2

Weight loss 12 2 5 1

Decreased appetite 28 3 12 1

Thrombocytopenia 97 67 83 31

Anemia 62 18 52 19

Neutropenia 75 34 36 11

Leukopenia 81 23 48 8

Lymphopenia 82 53 74 40

Cardiac

GI

Other

Heme

13

ENDEAVOR: Comparing Carfilzomib/Dex vs Bortezomib/Dex in Relapsed MM Randomized, Open-label, Phase III Study

Carfilzomib*Dexamethasone*

Bortezomib†

Dexamethasone †

Patients with MM Relapsed after 1-3 prior

regimens (primary refractory disease

excluded)

(N = 768)

*Carfilzomib: cycle 1 only, administered at 20 mg/m2 IV on Days 1, 2 followed by escalation to 56 mg/m2 on Days 8, 9, 15, and 16; then Days 1, 2, 8, 9, 15, and 16 on 28 day cycle.

*Dexamethasone: administered on Days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28 day cycle. On days when carfilzomib is administered, dexamethasone is to be given 30 minutes to 4 hours prior to carfilzomib.

†Bortezomib: 1.3 mg/m2 administered IV or SC on Days 1, 4, 8, and 11 of a 21-day cycle

†Dexamethasone: 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle

Clinicaltrials.gov NCT01568866

Salvage Auto-Transplant in the Relapsed Setting: Reasonable Option? Recent data from Mayo Clinic Transplant Center suggests that auto-

SCT2 appears safe and effective treatment for relapsed MM (N = 98)

– ORR: 86%; median PFS: 10.3 months; median OS: 33 months

– Rate of TRM: 4%. suggesting a favorable benefit-to-risk ratio

Shorter duration of TTP after auto-SCT1 predicts shorter OS post auto-SCT2

TTP after auto-SCT1 Median from auto-SCT2, months (range)

PFS OS

<12 months 5.6 (3-8) 12.6 (4-23)

<18 months 7.1 (6-8) 19.4 (10-42)

<24 months 7.3 (6-10) 22.7 (13-62)

<36 months 7.6 (7-12) 30.5 (19-62)

Gonsalves WI, et al. Bone Marrow Transplant. 2013;48:568-573.

14

Future Directions in the Salvage Setting

Ixazomib (MLN9708): Phase I Studies in Relapsed/Refractory Myeloma N = 50 evaluable

Dose: 0.24-2.97 mg/m2 on days 1,8,15 q28d

ORR: 9 pts (1 VGPR, 8 PR)

– MR: 1 pt

– SD: 15 pts

– Disease control up to 9 mos

Safety: generally well tolerated

– Heme, GI AEs manageable

– Low rate of discontinuation

– Infrequent PN; 1 grade 3 PN

PK profile supports wkly dosing

Kumar S, et al. Blood. 2014;124:1047-1055.

15

Primary Endpoint: PFS Secondary Endpoints: OS, OS and PFS in high-risk patients, response (ORR,

PR, VGPR, CR, DOR), safety, pain response, global health outcomes, PK analysis, association between response or resistance to ixazomib and cytogenetics

Patients with relapsed/refractory

MM; 1-3 prior therapies;

ECOG PS 0-2(Planned N = 703)

Treatment continued until

disease progression or unacceptable

toxicity

*Lenalidomide 25 mg PO Days 1-21; dexamethasone 40 mg PO Days 1,8,15,22

Ixazomib 4 mg PO D1,8,15 + RD*28-day cycles

Placebo PO D1,8,15 + RD*28-day cycles

Phase III TOURMALINE-MM1: IRD vs RD in Relapsed and/or Refractory MM

ClinicalTrials.gov. NCT01564537.

Single-Agent Oprozomib in RR MM: Summary of Efficacy

Response data not shown for step-up cohorts due to limited treatment exposure

2/7

Sch

edu

le5/

14 S

ched

ule

*ORR in 11 carfilzomib-refractory patients (phase II): 18.2%

Vij R, et al. ASH 2014. Abstract 34. Reproduced with permission.

0 50 100

Phase Ib150-330 mg/d

(n = 16)

Phase Ib + II150-270 mg/d

(n = 43)

PD SD MR PR VGPR CR

44 19 19 13

9 42 9 9 12 2

ORR: 31.3%

ORR: 23.3%*

CBR: 50.0%

CBR: 32.6%

16

Single-Agent Oprozomib in RR MM: Safety

Phase Ib study identified MTD of oprozomib for 2/7 dosing schedule (300 mg/day) and 5/14 dosing schedule (240 mg/day)

– 4 dose-limiting AEs observed: grade 3 diarrhea and grade 4 thrombocytopenia (2/7 schedule), grade 3 tumor lysis syndrome and grade 3 vomiting (5/14 schedule)

Overall safety improved in phase II, step-up dosing with introduction of extended-release oprozomib

– Incidence of grade ≥ 3 hematologic AEs declined

– Incidence of gastrointestinal AEs declined, except for grade 1/2 nausea and diarrhea in the 5/14 schedule

– Serious AEs occurred in approximately 30% to 33% of patients in phase II study (3 patients with each schedule)

– Overall fewer pts required dose reductions, discontinuations in phase II, but more discontinued treatment in phase II vs phase Ib with 2/7 schedule

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

Antibody-dependentcellular cytotoxicity (ADCC)

ADCC

Effector cells:

MM

FcR

Complement-dependentcytotoxicity (CDC)

CDC

MM

C1q

C1q

Apoptosis/growth arrest via targeting

signaling pathways

MM

Elotuzumab (SLAMF7)Daratumumab (CD38)

SAR650984 (CD38)

Daratumumab (CD38)

SAR650984 (CD38)

Tai YT, et al. Bone Marrow Res. 2011;2011:924058.

MAb-Based Targeting of Myeloma

Daratumumab (CD38)SAR650984 (CD38)

17

Phase Ib/II 1703 Trial: Elotuzumab in Combination with Len/Dex in RR MM Patients treated with elotuzumab 10 or 20 mg/kg +

lenalidomide/dexamethasone

– Approximately 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.

ORR92%

ORR76%

ORR84%

Per

cent

of

patie

nts,

%

34

Phase 2 efficacy: progression-free survival

363773

322759

292453

232144

191534

181331

161329

333265

302656

262147

211940

181533

181331

151227

151227

139

22

117

18

000

246

86

14

149

23

128

20

107

17

46

10

022

10 mg/kg20 mg/kg

Total

Numberat risk:

Median time to progression/death:

10 mg/kg (n=36): 32.49 mos

20 mg/kg (n=37): 25.00 mos

Total (n=73): 28.62 mos

0

10

20

30

40

50

60

70

80

90

100

0 4 8 12 16 20 24 28 32 36 48Time (months)

Prog

ress

ion-

free

pat

ient

s (%

)

44402 6 10 14 18 22 26 30 34 38 42 46

18

Elotuzumab in Combination with Len/Dex in RR MM (Phase Ib/II): Safety

Infusion reactions: if pts tolerated 2 mL/min, flow rate increased to 5 mL/min

– 33% of infusions were at 5 mL/min

– 11% experienced infusion reactions

– 7 at < 2 mL/min rate

– 1 at ≥ 2 mL/min rate

– Most common events included pyrexia (3), nausea (1), rash (3)

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

Grade 3/4 AEs, n (%) Elo 10 mg/kg (n = 36)

Elo 20 mg/kg (n = 37)

Lymphopenia 10 (28) 5 (14)Diarrhea 5 (14) 2 (5)Neutropenia 7 (19) 7 (19)Thrombocytopenia 7 (19) 6 (16)Anemia 6 (17) 5 (14)Hyperglycemia 2 (6) 5 (14)Fatigue 3 (8) 2 (5)Back pain 3 (8) 1 (3)Dyspnea 3 (8) 1 (3)Muscle spasms 2 (6) 0Insomnia 0 2 (5)Asthenia 1 (3) 1 (3)URI 1 (3) 1 (3)Pyrexia 1 (3) 1 (3)Peripheral edema 0 1 (3)Nausea 0 1 (3)

Primary endpoints: PFS and ORR Secondary endpoints: OS, pain response Exploratory endpoints: Safety, time to response, DOR, time to subsequent

therapy, health-related QoL, PK and immunogenicity of elotuzumab

Patients with relapsed/refractory MM and 1-3 prior

therapies(Planned N = 640)

Treatment continued until

disease progression,

death, or withdrawal of

consent

Randomized 1:1

Elotuzumab + RD28-day cycles

RD28-day cycles

Phase III ELOQUENT-2: Len/Dex ±Elotuzumab in RR MM

Lonial S, et al. ASCO 2012. Abstract TPS8112; ClinicalTrials.gov. NCT01239797.

Elotuzumab 10 mg/kg IV weekly D1,8,15,22 (Cycles 1-2) and D1,15 (Cycles 3+); Lenalidomide 25 mg PO D1-21; Dexamethasone 40 mg D1,8,15,22 (8 mg IV + 28 mg PO during elotuzumab dosing)

19

GEN 501: Daratumumab Monotherapy

Pts with R/R MM; ≥2 prior lines of therapy;

ineligible for ASCT

Daratumumab3+3 dose escalation

0.005 to 24 mg/kg(N = 32)

Daratumumab(N = 50)

Part 1 (dose‐escalation)Part 2 (expansion cohorts)

n=3

n=4

n=1

n=2

ORR=10%

ORR=35% Manageable safety profile

Quality of responses better in the 16 mg/kg vs. 8 mg/kg group

8 mg/kg 16 mg/kg

ORR, % 10 35

Median PFS, wks 14.9 23

Lokhorst et al. ASCO 2014. Abstract 8513

Phase I/II Trial: Daratumumab + Len/Dex in RR MM Phase I/II dose-escalation trial of daratumumab in combination with len/dex in

RR MM (safety cohort: n = 45; efficacy cohort: n = 43)

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

MTD: Daratumumab 16 mg/kg + len 25 mg and dex 40 mg weeklyPlesner T, et al. ASH 2014. Abstract 84.

k16

20

Daratumumab + Len/Dex in RR MM: Overall Best Response

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 patients reported infusion-related reactions; mostly grade 1 and 2

CR 31% CR 6.7%

VGPR 46%

PR 23%

VGPR 43%

PR 37%

CR 6.7%

CR 8.0%CR

11.8%

VGPR 43.3%

VGPR 52%

VGPR 52.9%

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

Part 10

20

40

60

80

100

Per

cen

tag

e (%

)

Overall Best Response

Part 2

PR

VGPR

CR

10086.7

50.0

60 64.7

0

20

40

60

Per

cen

tag

e (%

)

VGPR or Better Response (Part 2)

≥ 2 Cycles (n = 30)

≥ 4 Cycles (n = 25)

≥ 6 Cycles (n = 7)

Phase Ib Trial: SAR650984 in Combination with Len/Dex in RR MM SAR650984: humanized IgG1 antibody to the CD38 receptor widely

expressed in many heme malignancies

Dose escalation: SAR650984 3-10 mg/kg IV D1,15 of 28-day cycle + lenalidomide 25 mg on D1-21 + dexamethasone 40 mg weekly

Expansion cohort: SAR650984 10 mg/kg IV

MTD not reached

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

Previous MM TreatmentSAR650984 dose, mg/kg q2W Overall

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

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

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

Median time on last lenalidomide, mo (range)

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

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

21

SAR650984 in Combination with Len/Dex in RR MM (Phase Ib): Efficacy DoR: 9.13 mo (range: 1.2-15.2)

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

Response, %Total

(N = 31)

ORR 58

sCR 6

VGPR 23

PR 29

CBR 65

MR 6

SD 19

PD 13P

atie

nts

, % ORR 25%

CBR 50%

ORR 67%CBR 67%

ORR 63%CBR 67%

ORR 58%CBR 65%

100

80

60

40

20

03 mg/kg(n = 4)

5 mg/kg(n = 3)

10 mg/kg(n = 24)

Overall(N = 31)

25

25

67

8

29

6

23

6

25 29

4

PR sCRVGPRMR

Most common treatment-related grade 3/4 AEs: neutropenia, anemia, thrombocytopenia, and febrile neutropenia

15 incidences of infusion reaction, all occurring in the first 2 cycles

JS10

Additional Agents Currently in DevelopmentAgent MOA Phase in Development

Ibrutinib Tyrosine kinase inhibitor (BTK, ERK1/2, others)

Phase I and II

Filanesib Kinesin spindle protein (KSP) inhibitor

Phase II

Indatuximab ravtansine CD138 antibody-drugconjugate

Phase I and II

Ricolinostat HDAC inhibitor Phase I and I/II

Selinexor (KPT-330) XPO1 nuclear transport inhibitor

Phase I and II

JS10 The relative size of the PR and VGPR bars in the "overall" column need to be adjusted.Jill Sakai, 3/18/2015

22

Management of Adverse Effects

Peripheral Neuropathy: Risk Factors and General ConsiderationsGeneral Considerations Endocrine disorders

– Hypothyroidism

– Diabetes

Nutritional disease Connective tissue disease Vascular disease Medications Herpes zoster Most common symptoms

– Sensory deficits

– Neuropathic pain

Disease- and Treatment-Related Factors Hyperviscosity syndrome Hypergammaglobulinemia Incidence of peripheral neuropathy

in untreated patients: 39% Incidence of grade 3/4 CIPN with

novel agents– Bortezomib: 26% to 44%

– ↓ with weekly vs twice weekly dosing

– ↓ with SC administration

– Thalidomide: 28% to 41%– ↑ with higher doses and prolonged

therapy

– Carfilzomib: overall 14% Gleason C, et al. J Natl Compr Cancer Netw. 2009;7:971-979. Palumbo A, et al. J Clin Oncol. 2014;32:587-600. Kurtin S, et al. J Adv Pract Oncol. 2013;4:307-321.

23

How Should Neuropathy Be Managed?

Patient education

– Causes

– No clear established preventive guidelines, but exercise appears to be effective

Provider interventions

– Duloxetine, pregabalin, gabapentin

– Glutamine, alpha lipoic acid

– Investigate comorbid conditions

– SC bortezomib vs IV (if allowed by the study)

Bortezomib: SC vs IV Administration

Subcutaneous FDA approved SC in 2012

Equivalent efficacy as IV (numerous studies)

Reduced neuropathy, GI AEs– Consider for patients with preexisting or

high-risk PN

67.8% of patients prefer SC over IV– 54 mins less “chair time” on average

– 46 mins less clinic time on average

Intravenous FDA approved IV in 2003

Highly effective myeloma therapy

Neuropathy a notable AE

Reconstituting bortezomib (3.5 mg vial)

For SC administration, add 1.4 mL

0.9% sodium chloride

Hydration: a key nursing consideration, especially in patients with renal compromise

For IV administration, add 3.5 mL

0.9% sodium chloride

Barbee MS, et al. ASCO 2012. Abstract E18553. Mateos MV, et al. Ther Adv Hematol. 2012;3:117-124. Bortezomib [package insert]. 2014.

24

Risk Assessment for VTEs in Patients Receiving Thalidomide or Lenalidomide VTE prophylaxis for individual risk factors (eg, age or obesity) or

myeloma-related risk factors (eg, immobilization or hyperviscosity)

– If ≤ 1 risk factor present: aspirin 81-325 mg/day

– If ≥ 2 risk factors present: LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3)

VTE prophylaxis for myeloma therapy–related risk factors (eg, high-dose dexamethasone, IMiDs, doxorubicin, multiagentchemotherapy)

– LMWH (equivalent to enoxaparin 40 mg/day) or full-dose warfarin (target INR: 2-3)

Palumbo A, et al J Clin Oncol. 2014;32:587-600. Palumbo A, et al. Leukemia. 2008;22:414-423.

Myelosuppression and Infection

Myelosuppression is associated with both myeloma and the drugs used to treat it

– Risk of infection increased due to hypogammaglobulinemia

– Dose-modification guidelines are available in package inserts

Infection prophylaxis

– Patients should remain up-to-date on appropriate vaccinations

– VZV prophylaxis when receiving PIs

– Use of IVIG or prophylactic antibiotics is controversial, and should only be used when warranted

– Patient education emphasizing importance of alerting treating clinicians of potential infection can reduce unnecesary antibiotics

25

Current Management of Bone Disease

Treat the myeloma

Novel therapies have benefits– Direct effect on inflammatory

cytokines

– Inhibition of bone resorption

– Osteoclast stimulation

Bisphosphonates– Pamidronate

– Zoledronic acid

Supplement with calcium and vitamin D3 to maintain calcium homeostasis

Radiotherapy (low dose)– Impending fracture

– Cord compression

– Plasmacytomas

Orthopedic consultation

– Impending or actual long-bone fractures

– Bony compression of spinal cord

– Vertebral column instability

Niesvizky R, et al. J Natl Compr Canc Netw. 2010;8(suppl 1):S13-S20. Christoulas D, et al. Expert Rev Hematol. 2009;2:385-398. Drake MT. Oncology (Williston Park). 2009;23(14 suppl 5):28-32. Terpos E, et al. J Clin Oncol. 2013;31:2347-2357. Webb SL, et al. British J Pharmacol. 2014;[Epub ahead of print].

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 therapy

Incidence between 3%-4% with zoledronic acid or pamidronate

26

Overall Conclusions Doublet or triplet combination approaches should be considered

– Combination treatment with either bortezomib, carfilzomib, and/or pomalidomide with dexamethasone active and well tolerated

– Novel agents in combination can achieve prolonged responses even in relapsed disease

Optimal management approaches should emphasize improving QoL by identifying potential complications of therapy and minimizing long-term toxicity

New classes of agents and second-generation agents have activity and are of considerable interest

updates in the treatment and management of relapsed ... mm.pdfcurrent recommendations and treatment...

Documents