primary plasma cell leukemia comy congress...

Primary Plasma Cell Leukemia

Saad Z. Usmani, MD FACP Chief, Plasma Cell Disorders program

Director, Clinical Research

Department of Hematologic Oncology & Blood Disorders

Clinical Professor of Medicine, UNC-CH School of Medicine COMy C

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Conflict of Interest

• Research funding: Amgen/Onyx, Array BioPharma, BMS, Celgene, Janssen,

Pharmacyclics, Prothena, Sanofi, Takeda

• Consultancy: Amgen/Onyx, Array BioPharma, BMS, Celgene, GSK, Janssen,

Sanofi, Seattle Genetics, Takeda

• Speaking fees: Amgen, Celgene, Takeda, Janssen

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What is Plasma Cell Leukemia (PCL)?

• Aggressive MM clinical

phenotype.

• Classically defined by 20%

circulating plasma cells and >

2x109 cells/L1.

• Makes up 2-4% of newly

diagnosed MM2-4 and called

primary PCL.

– When PCL occurs in

relapsed disease, it is

referred as secondary PCL.

1. Kyle RA et al. Arch Intern Med 1974; 133: 813–818; 2. Dimopoulos MA et al. Br J Haematol 1994; 88: 754–759; 3.

Garcı´a-Sanz R et al. Blood 1999; 93: 1032–1037; 4.Ramsingh G et al. Cancer 2009; 115: 5734–5739.

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pPCL and MM Patient Outcomes

SEER Database (1973-2009)

Gonsalves et al. Blood. 2014;124(6):907-912

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Frequency of Karyotypic

Abnormalities in pPCL

Royer B, Minvielle S, Diouf M, et al. J Clin Oncol. 2016;34:2125–2132 ; Musto P, Simeon V, Martorelli MC, et al. Leukemia.

2014;28:222–225.

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Gene Mutations in pPCL

Lionetti M, Barbieri M, Todoerti K, et al. Oncotarget. 2015;6:26129–26141.

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pPCL and Disease Biology

Keats JJ, et al. Blood. 2012;120:1067-1076. Usmani SZ et al. Leukemia 2012

• Unsupervised hierarchical clustering of baseline bone marrow samples from pPCL patients (n=20)

and non-PPCL patients (n= 1096) for the 203 probe sets distinguishing pPCL and non-pPCL at the

0.01 level of false discovery rate.

• pPCL were overrepresented in the MF and CD1 molecular subgroups.

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pPCL and Disease Biology

Keats JJ, et al. Blood. 2012;120:1067-1076.

Statistically significant recurrently affected genes with potential driver role in pPCL

Cifola I et al. Oncotarget 2015

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sPCL : Terminal Pathway in RRMM

Keats JJ, et al. Blood. 2012;120:1067-1076.

Clone 1.1 Clone 1.2 Clone 2.1 Clone 2.2 Misc

Diagnosis ~ 2N

Remission ~ 2N

Relapse 1 ~ 2N

Relapse 2 ~ 2N

Relapse 3 ~ 2N

Secondary Plasma Cell Leukemia ~ 3N Relapse 4

~ 3N

clg-high 37%

clg-high 66%

clg-low 34% clg-low

63%

72%

11%

10%

31%

64%

64%

21%

9%

19%

58%

71%

17%

78% 95%

96% 96%

Len/Dex, lenalidomide/dexamethasone; MPV, melphalan/prednisone/bortezomib.

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NCI MYSC-High Risk MM Criteria

• Poor Risk Score by Gene Expression Profiling:

– Arkansas 70-gene model (MyPRS)

– EMC 92-gene model (SKY92)

• FISH

– Translocation (14;20)(q32;q12).

– Translocation (14;16)(q32.3;q23).

– Deletion 17p.

– Chromosome 1q21 amplification.

• Primary plasma cell leukemia.

• Elevated serum LDH.

(Usmani et al. Blood Can J 2015)

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Treatment Strategies

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pPCL in Total Therapy Experience

Usmani SZ et al. Leukemia 2012

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Rd in pPCL (Phase II, n=23, median follow-up 34 months)

Musto P, Simeon V, Martorelli MC, et al. Leukemia. 2014;28:222–225.

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Bortezomib-based Induction in pPCL (Phase II, n=40, median follow-up 28.7 months)

Royer B, Minvielle S, Diouf M, et al. J Clin Oncol. 2016;34:2125–2132

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RVD Consolidation and Maintenance in HRMM

Nooka A et al. Leukemia (2014) 28, 690–693

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Approach to pPCL Therapy & Management

Induction*

Age < 65 years : V(R)D-PACE (x 2

cycles)

Age >65 : RVd (CyBorD for IP before

RVd transition as OP) for 4-6 cycles

Transplant Eligible

Mel-200 Auto-SCT followed by RVd

maintenance until relapse/progression

RIC-AlloSCT consideration for age < 65

years.

Transplant Ineligible

RVd maintenance until

relapse/progression

*IN ABSENCE OF BETTER THAN PR TO INDUCTION, APPROACH AS PRIMARY REFRACTORY AND

SWITCH TO 2ND LINE REGIMEN.

Consider CSF Analysis at Diagnosis and IT Chemo Therapy Given

High Proportion of CNS Involvement at Diagnosis/Relapse

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Emerging Data

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ASPIRE TRIAL: PFS by Risk Group

KRd

(n=396)

Rd

(n=396)

Risk

Group by

FISH

N Median,

months N

Median,

months HR

P-value

(one-sided)

High 48 23.1 52 13.9 0.70 0.083

Standard 147 29.6 170 19.5 0.66 0.004

Dimopoulos M, et al. J Clin Oncol 2015; 33(suppl; abstr 8525).

pPCL EXCLUDED FROM STUDY

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Survival end points for the cohort as a whole and in either subgroup, deletion 17p or t(4;14).

Xavier Leleu et al. Blood 2015;125:1411-1417 ©2015 by American Society of Hematology

pPCL EXCLUDED FROM STUDY

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Approach to pPCL Therapy & Management

Induction*

Age < 65 years : V(R)D-PACE (x 2

cycles)

Age >65 : RVd (CyBorD for IP before

RVd transition as OP) for 4-6 cycles

Transplant Eligible

Mel-200 Auto-SCT followed by RVd

maintenance until relapse/progression

RIC-AlloSCT consideration for age < 65

years.

Special considerations for maintenance:

KPd for patients with t(4:14) and/or Del17p

Transplant Ineligible

RVd maintenance until

relapse/progression

Special considerations for maintenance:

KPd for patients with t(4:14) and/or

Del17p

*IN ABSENCE OF BETTER THAN PR TO INDUCTION, APPROACH AS PRIMARY REFRACTORY AND SWITCH TO 2ND LINE

REGIMEN.

Consider CSF Analysis at Diagnosis and IT Chemo Therapy Given

High Proportion of CNS Involvement at Diagnosis/Relapse

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POLLUX: PFS by Cytogenetic Riska

Usmani SZ et al, ASH 2016

% s

urv

ivin

g w

ith

ou

t p

rog

ressio

n

0

20

40

60

80

100

0 3 6 9 12 15 18 24

113

133

37

28

104

128

32

22

92

120

21

21

77

116

18

19

71

111

15

19

57

98

13

18

20

41

6

9

1

4

0

2

Rd std risk

DRd std risk

Rd high risk

DRd high risk

No. at risk Months

Rd standard risk

DRd standard risk

21

0

0

0

0

Rd high risk

DRd high risk

NR, not reached; NS, not significant. aITT/Biomarker risk–evaluable analysis set. High-risk patients had any of t(4;14), t(14;16), or del17p. Standard-risk patients had an absence of high-risk abnormalities.

Comparable results in 1 to 3 prior lines population

DRd improves outcomes regardless of cytogenetic risk

DRd

n = 133

Rd

n = 113

Standard

risk

0.30 (0.18-0.49)

<0.0001

NR 17.1

95 82

0.0020

n = 132 n = 111

Median PFS,

mo

HR (95% CI)

P value

ORR, %

P value

DRd

n = 28

Rd

n = 37

Median PFS,

mo NR 10.2

HR (95% CI)

P value

High

risk

0.44 (0.19-1.03)

0.0475

ORR, % 85 67

P value NS

n = 27 n = 36

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SWOG 1211: Optimal Induction for

High Risk Newly Diagnosed MM

PHASE I PORTION RANDOMIZED PHASE II PORTION

Induction Maintenance

RVd + Elotuzumab

8 cycles of Induction

Therapy followed by

Maintenance until

progression or relapse

n=6

RVd x

8 Cycles1,2

n=70

RVd-Elo x

8 Cycles1,2

n=70

RVd

Dose reduced

KRd

Dose reduced

1. ONE CYCLE OF PRIOR THERAPY ALLOWED PRIOR TO ENROLLMENT

2. STEM CELL COLLECTION ALLOWED AFTER CYCLE 2 ON PROTOCOL. ASCT ALLOWED OFF-PROTOCOL AT

PROGRESSION/RELAPSE

Off-Protocol at

Progression/Rel

apse

Phase I completed Arms A/B ~ Accrued; Arms C/D Being Added:

Open to all National Clinical Trials Network members

A

B

KRd x

8 Cycles1,2

n=70

KRd-Dara x

8 Cycles1,2

n=70

RVd-Elo

Dose reduced

KRD-Dara

Dose reduced

C

D COMy C

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Venetoclax Monotherapy (N=66)

Design: Phase I, open label, study of venetoclax monotherapy

Study Population: RRMM

• Median age: 63 yrs

• ISS stage II/III: 62%

• Median prior therapies: 5 (1-5)

• Prior BTZ: 94% (70% ref)

• Prior REV: 94% (77% ref)

Dosing & Schedule:

VEN: initial 2 week lead in period with weekly dose-escalation

• Final doses: daily at 300 mg, 600 mg, 900 mg, or 1200 mg

• Patients who progressed could receive VEN + dex and remain

on study

Kumar S, et al. ASH 2016. Abstract 488.

Safety, n (%) Venetoclax

Gr 3/4 (≥10%) Thrombocytopenia (26%), neutropenia (20%),

lymphopenia (15%), anemia (14%), and decreased white

blood cells (12%)

SAEs ≥2 pts Pneumonia (n=5), sepsis (3), pain, pyrexia, cough, and

hypotension (2 each)

Deaths 8 (all considered unrelated to VEN)

• Median time on VEN: 2.5 mo (0.2-23); 26% received VEN

+ dex for a median of 1.4 mo (0.1-11) COMy C

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Venetoclax + Vd (N=66)

Design: Phase Ib, open label, dose escalation study of

venetoclax + Vd


• Median age: 64 yrs

• ISS stage II/III: 59%

• Median prior therapies: 3 (1-13)

• Prior BTZ: 32% ref

• Prior REV: 56% ref

Dosing & Schedule:

VEN: daily, 50 mg – 1200 mg dose escalation

• RP2D: 800 mg qd

Vd: Dose and schedule not reported

Moreau P, et al. ASH 2016. Abstract 975.

Safety, n (%) Venetoclax

Gr 3/4 (≥10%) Thrombocytopenia (29%), anemia (15%) and

neutropenia (14%)

SAEs ≥2 pts Febrile neutropenia, thrombocytopenia, cardiac

failure, pyrexia, influenza, lower respiratory tract

infection, pneumonia, sepsis, acute kidney

injury, respiratory failure, embolism, and

hypotension

1 DLT: lower abdominal pain (1200 mg Ven)

Deaths 5 (4=PD, 1=RSV infection)

• Discontinuations: 43 (65%), PD (33), AE (5), withdrawn consent (2), not specified (3)

Efficacy All 1-3 Priors

DOR 8.8 mo V non-ref: 10.6 mo

V naïve: 15.8 mo

TTP 8.6 mo V non-ref: 11.3 mo

V naïve: 17.1 mo

Efficacy With t(11;14) Without t(11;14)

ORR 78% 66%

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STORM: Selinexor + Dex (N=79)

Design: Phase II study of Sd


• 48 pts refractory to REV, POM, V, K

(Quad)

• 33 pts refractory to above + anti-CD38

mAbs (Penta)

Dosing & Schedule:

S: 80 mg BIW for 6 or 8 doses of a 28 d

cycle

D: 20 mg BIW

Median age: 68 yrs

Efficacy All Quad Penta

ORR

CBR

21%

32%

21%

29%

20%

37%

Vogl DT, et al. ASH 2016. Abstract 491.

Safety, n (%)

Gr 3/4 (≥10%) All patients

Thrombocytopenia

Neutropenia

Anemia

Fatigue

Hyponatremia

58 21 25 14 20

• Most quad patients (83%) received 6 doses/cycle; penta patients (65%) received 8

doses/cycle

Efficacy All Responders

Non-

responders

mOS

PFS

DOR

9.3 mo

2.1 mo

NR (>11 mo)

5 mo

5.7 mo

Efficacy ORR, n (%)

Standard Risk

High Risk

(17p13)

t(14;16)

t(4;14)

4 (17)

6 (33)

3 (38)

1 (100)

2 (50)

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Summary

• pPCL carries very poor prognosis with current strategies:

• Novel agents have improved PFS/OS outcomes but do not overcome poor prognosis (majority of patients die within 3 years).

• Area of unmet need and excluded from clinical trials.

• Need to either include these patients in upfront trials OR develop enrichment design trials focused on pPCL.

• Novel mechanisms of actions offer some hope:

• Bcl2 inhibitors, XPO1 inhibitors, next generation IMiDs, etc.

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AnMed

Blue Ridge

Cleveland Regional

CMC

LCI-Lincoln

LCI-Mercy

LCI-Northeast

LCI-Pineville

LCI-Union

Roper St. Francis Stanly Regional LCI-University

LCI-Main

Thank you for your attention!

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primary plasma cell leukemia comy congress...

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