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Smoldering Multiple Myeloma

• Laboratory analysis

– Complete blood count and complete metabolic panel

• β2M, LDH

– M proteins

• Radiologic imaging

– Skeletal survey, MRI/CT, PET

• Bone marrow biopsy

• Specific tests to rule out other:

– Causes of anemia, renal insufficiency, hypercalcemia, etc.

Specific Diagnostic Tests

NCCN v4.2015.

a. Overall designated as best responses after a median potential follow-up of 17.3 months (patients with NDMM) or 15.9 months (patients with SMM).

b. One of 45 patients was not evaluable after 2 cycles (data not collected).

c. Three patients were not evaluable after 8 cycles (2 had not completed 8 cycles, and 1 patient’s disease had progressed prior to completion of 8 cycles).

d. One patient discontinued study participation before completing 8 cycles.

e. Twenty-nine patients were not evaluable after 20 cycles (26 patients had not completed 20 cycles, 1 patient’s disease had progressed prior to completion of 20

cycles, 1 patient’s disease had progressed just after completion of 20 cycles, and 1 patient had discontinued study participation for personal reasons).

f. Nine patients were not evaluable after 20 cycles (8 patients had not completed 20 cycles, and 1 patient had discontinued study participation before completing

8 cycles).

CRd-R in Patients with Smoldering or Newly Diagnosed Multiple Myeloma

Korde et al, JAMA Oncol 2015, doi:10.1001/jamaoncol.2015.2010

ISS or R-

ISS Stage

ISS Criteria R-ISS Criteria 5-year

OS

5-year

PFS

I Serum β2-microglobulin <

3.5 mg/L, serum albumin ≥

3.5 g/dL

ISS stage I and

standard-risk CA by

iFISH and normal LDH

82% 55%

II Not ISS stage I or III Not R-ISS stage I or III 62% 36%

III Serum β2-microglobulin ≥

5.5 mg/L

ISS stage III and either

high-risk CA by iFISH

or high LDH

40% 24%

Abbreviations: CA, chromosomal abnormalities; iFISH, interphase fluorescent in situ hybridization; ISS, International

Staging System; LDH, lactate dehydrogenase; MM, multiple myeloma; R-ISS, revised International Staging System

Revised-International Staging System for MM

Palumbo et al, J Clin Oncol 2015, doi: 10.1200/JCO.2015.61.2267

Multiple Myeloma Treatment Linesa

Induction Consolidation

Front-line treatment

Maintenance

Maintenance

Rescue

Relapsed

IMiD: Thal-Len

Proteasome Inh: Bor-Car

Steroids: Dex-Pred

Alkylator: Cyclo-Mel

Anthracycline: LipoDnr-Adr

SCT Observation

IMiD: Thal-Len

Proteasome Inh: Bor

Steroids: Dex-Pred

IMiD: Thal-Len-Pom

Proteasome Inh: Bor-Car-Ixa

Steroids: Dex-Pred

Alkylators: Mel-Cy-Benda

Investigational

HDAC Inh: Pan

MoAb: Dar-Elo

Transplant-eligible patients:

Bor/Dex; Bor/Cyclo/Dex; Bor/Dex/Dox;

Bor/Len/Dex; Bor/Thal/Dex; Len/Dex;

Thal/Dex; Dex/Vinc/LiposomalDox;

Car/Len/Dex; Dex.

NCCN v4.2015.

Is There an Optimal Bortezomib-containing

Induction Regimen?Alkylator Bor Dex vs IMID Bor Dex

(CyBORD vs VTD or RVD)

Optimal Induction Therapy in High-risk Patients

Cavo et al. Presented at: American Society of Hematology (ASH) 2015.

Optimal Induction Therapy in Low-risk Patients

Cavo et al. Presented at: American Society of Hematology (ASH) 2015.

What about CarfilzomibInduction?

Treatment Schema – 28-day Cycle

Attal et al. Presented at: American Society of Hematology (ASH) 2015.

Patient Disposition


SCC and ASCT

• Stem cells were collected from patients following G-CSF plerixafor treatment

– Median 9.0 x 106 CD34+ Cells/kg (range 2.9-16.8 x 106) after a median of 2 days of collection (range 1-8)

– 6 patients collected less than 4 x 106 CD34+ cells/kg, of which 3 were re-collected for a total of 2.9, 4.2, and 9.8 x 106 total CD34+ cells/kg

• There were no unusual events during ASCT


Time to Response



MRD Evaluation


Treatment Outcomes

• The 3-year post-randomization PFS rate was 61% in the transplant arm vs 48% in the RVD arm.

• The PFS benefit observed in the transplant arm was uniform across all the following subgroups: age (≤ or >60 years), ISS stage (I or II or III), cytogenetics (standard or high risk), and response after the 3 first cycles of RVD (complete response or not).

• The 3-year post randomization rate of overall survival was extremely high (88%) and similar between the 2 study groups (stratified P value for log rank test = 0.25).

• The complete response rate was significantly higher in the transplant arm compared to the RVD arm: 58% vs 46%, respectively (P<0.01). Forty-one second primary malignancies among 39 patients were recorded (Transplant arm=23, RVD arm=18).

Report from ASH 2015 IFM/DFCI


Relapsed/Refractory Multiple Myeloma

Single Agent and Doublet Efficacy

Trial Phase nIMiD

exposedPI

exposedORR

PFS (months)

OS (months)

Thalidomide 2 169 0% 0% 30% 2y : 20% 2y : 48%

BTZ vs DEX 3 669 49% 0% 38% 6.22 30

BTZ + Dox vs

BTZ3 646 41% 0% 43% 9 33

Len Dex MM009 3 177 41% 10% 61% 11.1 29.6

Len Dex MM010 3 349 30% 4.5% 60% 11.3 38

CFZ (+dex 8) 2 266 100% 99% 23.7% 3.7 15.6

Pom D vs Dex 3 302 100% 95% 31% 4.2 13.1

Barlogie B. Blood. 2001;98:492-494.

Richardson P. N Engl J Med. 2005;352:2487-2498.

Orlowski RZ. J Clin Oncol. 2007;25:3892-3901.

Weber D. N Engl J Med. 2007;357:2133-2142.

Dimopoulos M. N Engl J Med. 2007;357:2123-2132.

Siegel DS. Blood. 2012;120:2817-2825.

San Miguel J. Lancet Oncol. 2013;14:1055-1066.

Dimopoulos et al., EHA20, 2015; Abstract P273.

For phase 3 studies, data only provided for experimental arm

54.660.7

66.7

87.1

66

79

63

7771.5

78.3

611 9.3

31.8

7 4 613

6.611.7

4.3

14.1

0

10

20

30

40

50

60

70

80

90

100

Vd PanVd Rd KRd Rd EloRd Vd Kd Rd IRd

ORR

≥CR

sCR

Summary of Relapsed Refractory MM (1-3 Prior Therapies)Response Rates

Panorama-1 (1) Aspire (2) Eloquent-2 (3) Endeavor (4)

Per

cen

t

Tourmaline MM1 (5)

1. San-Miguel JF et al. Lancet Oncol. 2014;15:1195-1206.

2. Stewart AK et al. N Engl J Med. 2015;372:142-152.

3. Lonial S et al. Presented at: ASCO 2015. Abstract #8508.

4. Dimopoulos MA et al. Presented at: ASCO 2015. Abstract #8509.

5. Moreau P et al. Presented at: ASH 2015. Abstract #727.

8

12

18

26

15

19

9

18

14.7

20.6

0

5

10

15

20

25

30

Vd PanVd Rd KRd Rd Erd Vd Kd Rd IRd

PFS

Summary of Relapsed Refractory MM (1-3 Prior Therapies) PFS

Panorama-1 (1) Aspire (2) Eloquent-2 (3) Endeavor (4)

Mo

nth

s

Tourmaline MM1 (5)






Clinical Trial Len

Refr

Bort

Ref

High Risk PFS

(months)

Panorama 1 0% 15.2% Vd 8

Pan-Vd 12

Aspire 0% 0% 12.6% Rd 18

KRd 26

E-Ld (Phase II) 5.5% E-Ld 33

Eloquent 2 0% 22% 30.5% Ld 15

E-Ld 19

Endeavor 25% 0% 22.6% Vd 9

Kd 18

Tourmaline MM1 0% 0% 21% IRd 20.6

Rd 14.7

Patient Populations Trials

Summary of Relapsed Refractory MM (1-3 Prior Therapies) Hazard Ratios (with 95% CI)

Mo

nth

s

8

12

18

26

15

19

9

18

14.7

20.6

0

5

10

15

20

25

30

Vd PanVd Rd KRd Rd Erd Vd Kd Rd IRd

PFS

Panorama-1 (1) Aspire (2) Eloquent-2 (3) Endeavor (4) Tourmaline MM1 (5)

HR 0.69 (0.57-0.83)

P=0.001

HR 0.70 (0.57-0.85)

P=0.0004HR 0.53 0.44-0.65)

P<0.0001

HR 0.742 (0.587-0.939)

P=0.012

HR 0.63 (0.52-0.76)

P<0.0001






• Consider toxicity profile of each agent – GI, cardiac, HTN, neuropathy

• Convenience – oral vs IV therapy

• Presence/absence of high molecular risk features

• Prior therapies – if PI or IMID refractory, which study outcomes are generalizable

• Sequencing issues (e.g. if elotuzumab not used with RD, then no further role based on current approval)

Given comparable hazard ratios, there is no one right answer; instead requires risk/benefit assessment for each individual patient.

Considerations in Choosing the Appropriate Evidence-based Therapy in Relapsed MM

PI + IMiD + Dex (Triplet) Efficacy

Trial Phase n IMiDexposed

IMiDrefractory

PIexposed

PIrefractory

ORR PFS(mos)

OS(mos)

Bort Thal

Dex1-2 85 74% most 0% 0% 65% 6 22

Bort Len

Dex2 64

73%T

6% L3% 53% 8% 64% 9.5 30

Bort Pom

Dex1 28 100% 100% 100% NA 71% NA NA

Car-Len-

Dex2 52 73% 44% 80% 25% 77% 15.4 NA

Car-Pom-

Dex1/2 79 100% 100% 89%

91% in

ph 170% 9.7 NR

Wang M et al. Blood. 2013;122:3122-3128.

Shah JJ et al. Presented at: ASH 2013. Abstract 690.

Pineda-Roman M. Leukemia. 2008;22:1419-1427.

Richardson PG et al. Blood. 2014;123:1461-1469.

Richardson PG et al. Presented at: ASCO 2014.

Baseline Refractory Status

Refractory to, n (%) n = 106

Last prior therapy 103 (97)

PI and IMiD 101 (95)

BORT 95 (90)

CARF 51 (48)

LEN 93 (88)

POM 67 (63)

Alkylating agent 82 (77)

BORT+LEN 87 (82)

BORT+LEN+CARF 42 (40)

BORT+LEN+POM 57 (54)

BORT+LEN+CARF+POM 33 (31)

BORT+LEN+CARF+POM+THAL 12 (11)

• Patients were heavily pretreated, and most patients were refractory to multiple lines of PI and IMiD treatment

– 97% were refractory to their last line of therapy

– 77% were refractory to alkylating agents

– 95% were double refractory

– 66% were refractory to 3 of 4 therapies (BORT, LEN, CARF, and POM)

– 63% were refractory to POM

– 48% were refractory to CARF

Lonial S et al. Presented at: ASCO 2015. Abstract LBA8512.

ORR by Subgroup

33 3330

21 20

30 29 28 2826

21

0

5

10

15

20

25

30

35

40

OR

R, %

Refractory to


Progression-free and Overall Survival

• 29 of 31 responders are still alive

• The 1-year survival rate was 65% (95% CI, 51.2–75.5)

96106 85 82 64 23 10 2 0Patients at risk

80

100

60

40

20

0

0 42 6 8 16141210

Months from start of treatmentP

atie

nts

aliv

e (%

)

Median OS = NE

(95% CI, 13.7–NE)

63106 38 32 17 5 4 1 0Patients at risk

80

100

60

40

20

0

0 42 6 8 16141210

Months from start of treatment

Pat

ient

s pr

ogre

ssio

n-fr

ee a

nd a

live

(%)


Treatment-emergent AEs >20%

Term Any Grade

n (%)

Grade 3

n (%)

Grade 4

n (%)

Fatigue 42 (40) 3 (3) -

Anemia 35 (33) 25 (24) -

Nausea 31 (29) - -

Thrombocytopenia 27 (26) 18 (17) 8 (8)

Neutropenia 24 (23) 12 (11) 3 (3)

Back pain 23 (22) 3 (3) -

Cough 22 (21) - -

• Serious treatment-emergent AEs (TEAEs)

in 32 (30%) patients and 24 (23%) had

Grade 3/4 serious TEAEs

• No discontinuations due to DARA-related

AEs

• No febrile neutropenia reported

• Few required additional supportive care

‒ Red blood cell transfusion (38%)

‒ Platelet transfusion (13%)

‒ Granulocyte colony stimulating factor

(8%)• Grade 3 or higher anemia and thrombocytopenia

occurred more frequently in nonresponders (32%

and 24%, respectively) than responders (3% and

7%, respectively)

• Grade 3 or higher neutropenia rates were similar in

nonresponders (12%) and responders (13%)


Infusion-Related Reactions (IRRs)

• Occurred in 43% of patients

• Predominantly Grade 1 or 2

– Grade 3: 5%; no Grade 4

• >90% of IRRs occurred during the first infusion

• 7% of patients had an IRR at >1 infusion

• Most common IRRs included nasal congestion (12%); throat irritation (7%); cough, dyspnea, chills, and vomiting (6% each)

• No patients discontinued treatment due to IRRs

0

5

10

15

20

25

30

35

40

45

Overall 1st infusion 2nd infusion 3rd or laterinfusion

Inci

den

ce o

f IR

R, %


MMY1001: DARA + POM-D Arm

Eligibility criteria

• Refractory to last line of therapy

• ≥2 prior lines of therapy, including 2 consecutive cycles of lenalidomide and bortezomib

• Pomalidomide naïve

• ECOG score ≤2

• Absolute neutrophil count ≥1.0×109/L, and platelet count ≥75×109/L for patients with <50% plasma cells (>50×109/L, otherwise)

• Calculated creatinine clearance ≥45 mL/min/1.73 m2

Treat 6 patients with DARA + POM-D

If ≤1 patient has DLTs

Enroll 6 additional patients

Expand up to 88 patients

DARA* IV 16 mg/kg +

Pomalidomide 4 mg (Days 1-21) +

Dexamethasone 40 mg QW

Open-label, multicenter, six-arm, Phase 1b

study (28-day cycles)

*QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W beyond.

Chari A et al. Presented at: ASH 2015. Abstract 508.

Overall Response Rate: DARA + POM-D

• ORR = 71%

• ORR in double-refractory patients = 67%

• Clinical benefit rate (ORR + minimal response) = 73%

DARA + POM-D

(N = 75)

n (%) 95% CI

Overall response rate

(sCR+CR+VGPR+PR)53 (71) 59.0-80.6

Best response

sCR

CR

VGPR

PR

MR

SD

PD

4 (5)

3 (4)

25 (33)

21 (28)

2 (3)

17 (23)

3 (4)

1.5-13.1

0.8-11.2

22.9-45.2

18.2-39.6

0.3-9.3

13.8-33.8

0.8-11.2

VGPR or better

(sCR+CR+VGPR)32 (43) 31.3-54.6

CR or better (sCR+CR) 7 (9) 3.8-18.3

ORR = 71%

43%

VGPR or

better

9%

CR or

better

28%

33%

4%

5%

0

10

20

30

40

50

60

70

80

16 mg/kg

OR

R, %

PR VGPR CR sCR

n = 75


Progression-free Survival at 6 Months: DARA + POM-D

0

Pat

ient

s pr

ogre

ssio

n-fr

ee a

nd a

live,

%

2 6Time from first dose, months

0

20

60

80

100

4

40

Patients at risk 98 67 39 19

6-month PFS rate = 66% (95% CI, 52.3-75.9)

Median follow-up of 4.2 months


• FDA Approved November 16, 2015 as a single agent for >3 lines of therapy including PI, IMiD , or double refractory

• High-risk Smoldering MM

– Phase II (long intense vs intermediate vs short intense)

• Newly Diagnosed

– Phase III (SCT eligible): DVTD vs VTD

– Phase III (non-SCT eligible): DRd vs Rd

– Phase III (non-SCT eligible): DVMP vs VMP

• Relapse (1+ lines of therapy)

– Phase III: DRd vs Rd

– Phase III: DVD vs VD

• Relapsed/Refractory

– Phase II: Dara

– Phase II: Dara + [VD, VMP, VTD, PomD, Kd, KRd]

Daratumumab Status

Treatment n Eligibility ORR PFS DOR

(mos)

OS (mos)

ixazomib + dex 33 88% Lexp; B sens 34%

[78.3%]

12.4

[20.6][20.5] 96% @ 6 mo

filanesib

in low AAG

32

21

75% IMiD Ref

53% PI ref

16%

24%

3.7

5.3

8.6

8.6

19

23.3

filanesib + dex

in low AAG

55

36

100% IMiD Ref

98% PI ref

15%

19%

3.4

5.1

5.1

5.1

10.5

10.8

afuresertib 34 97% I; 88% PI 8.8%

selinexor + dex 8 Ref to all classes 50% NR NR NR

LGH 447 59 NR 10.5% NR 5.8 NR

Filanesib granted orphan drug approval by FDA in May 2014.

Kumar S et al. Presented at: ASH 2013.

Lonial S. Presented at: ASH 2013.

Voorhees et al. Presented at: ASH 2013.

Summary of Novel Agents with

Single-agent Activity

Chen C et al. Presented at: EHA 2014.

Spencer A et al. Blood. 2014.

Raab et al. Presented at: ASH 2014. Abstract 301.

8019 OE MM NewSlides - Medscapeimg.medscape.com/images/837/670/837670_slides.pdfSCT Observation...

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