Extramedullary Disease in Multiple Myeloma

Saad Z. Usmani, MD FACPChief, Plasma Cell Disorders program

Director, Clinical ResearchDepartment of Hematologic Oncology & Blood Disorders

Clinical Professor of Medicine, UNC-CH School of Medicine

Conflict of Interest

• Research funding: Amgen, BMS, Celgene, Janssen, Pharmacyclics, Prothena, Sanofi, Seattle Genetics, Takeda

• Consultancy: Abbvie, Amgen, BMS, Celgene, GSK, Janssen, Sanofi, Seattle Genetics, Takeda

• Speaking fees: Amgen, Celgene, Takeda, Janssen

What is Extra-medullary Disease(EMD)?

• Aggressive MM clinical phenotype involving organs other than the skeleton:– Skin, Soft Tissues, Lymph Nodes,

Liver, Pleura, CNS, etc. – One can also consider plasma cell

leukemia as an EMD phenotype.

• Occur in ~ 3-4% of newly diagnosed MM2-4 and increases to 10% in relapsed disease.

• Must be distinguished from ‘para-skeletal disease’ where soft tissue arises from adjacent bone lesion.

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.

EMD Pathophysiology

• Hematogenous spread -- Emancipation of malignant plasma cells from the bone marrow microenvironment:– Elevated serum LDH levels– Circulating plasma cells/plasma cell leukemia– Plasmablastic morphology– Higher incidence in del17p, t(4;14) and t(14;16)

• Decreased expression of adhesion molecules.

• Low expression of cytokine receptors or increased angiogenesis

• GEP studies on BM CD138+ plasma cells PC found that association with high-risk features, particularly MAFB overexpression and markers of highly proliferative disease.

Usmani SZ et al. Haematologica 2012;97:1761-1767, Billecke L, et al Anticancer Research 2012; 32: 2031-2034, Billecke L et al. Br J Haematol 2013; 161: 87-94. Rasche Let al. Ann Hematol 2012; 91: 1031-1037.

Recognition of Extramedullary Disease At Diagnosis by PET-CT

Usmani SZ et al. Haematologica 2012;97:1761-1767

Event-Free SurvivalOverall

0%

20%

40%

60%

80%

100%

0 3 6 9 12Years From Transplant

No EMD Prior to TransplantEMD Prior to Transplant

Events / N792 / 1899

47 / 66

Medianin Years

5.01.1

Logrank P-value < .0001

Event-Free SurvivalTT Protocol

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10Years From Transplant

No EMD Prior to TransplantEMD Prior to Transplant

Events / N271 / 91414 / 22

Medianin Years

8.01.2

Logrank P-value < .0001

Event-Free SurvivalNon-TT Protocol

0%

20%

40%

60%

80%

100%

0 3 6 9 12Years From Transplant

No EMD Prior to TransplantEMD Prior to Transplant

Events / N133 / 230

8 / 10

Medianin Years

3.31.1

Logrank P-value = .07

Event-Free SurvivalNo Protocol

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10Years From Transplant

No EMD Prior to TransplantEMD Prior to Transplant

Events / N388 / 75525 / 34

Medianin Years

2.70.8

Logrank P-value = .0004

Recognition of Extramedullary Disease At Diagnosis by PET-CT

Usmani SZ et al. Haematologica 2012;97:1761-1767

EMD Incidence Higher in High Risk MM

Usmani SZ et al. Haematologica 2012;97:1761-1767

Para-skeletal Disease = EMD

Gagelmann N et al. Haematologica 2018

CNS Disease: We Have No Answer(CNS involvement by MRI along with clonal malignant plasma cells in CSF)

N=31Median time to CNS disease in pts receiving systemic chemo 8.3 mos(n=11)Median time to CNS disease in pts receiving systemic chemo + ASCT 32.1 mos(n=21)

IT therapy = cytarabine, methotrexate, hydrocortisone, and thiotepa

IT Alone 3IT + Systemic chemo 8IT + ASCT 13IT + ASCT + cranial XRT 4IT + cranial XRT 1IT + AlloSCT + cranial XRT 1IT + Allo SCT 1

Median OS 4 months (range 1-13 mos)

No difference in endpoints based on

type of treatment

Abdallah A, et al. Clin Lymphoma Myeloma Leuk. 2014;14(3):211-4

NEXT GENERATION MOAs NEED TO CONSIDER CNS PENETRATION, NEED CLINICAL TRIALS FOR THIS POPULATION.

pPCL and MM Patient Outcomes SEER Database (1973-2009)

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

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.

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.

Treatment Strategies

Approach to Bulky EMD or 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 EligibleMel-200 Auto-SCT followed by RVd

maintenance until relapse/progression

RIC-AlloSCT consideration for age < 65 years.

Transplant IneligibleRVd 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

Emerging Data

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

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 

Approach to Bulky EMD or 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 EligibleMel-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 IneligibleRVd 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

POLLUX: PFS by Cytogenetic Riska

Usmani SZ et al, ASH 2016

% s

urvi

ving

with

out p

rogr

essi

on

0

20

40

60

80

100

0 3 6 9 12 15 18 24

1131333728

1041283222

921202121

771161819

711111519

57981318

204169

1402

Rd std riskDRd std riskRd high risk

DRd high risk

No. at risk Months

Rd standard risk

DRd standard risk

21

0000

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

DRdn = 133

Rdn = 113

Standard risk

0.30 (0.18-0.49)

<0.0001

NR 17.1

95 820.0020

n = 132 n = 111

Median PFS, mo

HR (95% CI)

P value

ORR, %

P value

DRdn = 28

Rdn = 37

Median PFS, mo NR 10.2HR (95% CI)

P value

High risk

0.44 (0.19-1.03)

0.0475

ORR, % 85 67P value NS

n = 27 n = 36

SWOG 1211: Optimal Induction for High Risk NDMM

PHASE I PORTION RANDOMIZED PHASE II PORTIONInduction Maintenance

RVd + Elotuzumab8 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

RVdDose 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 Opened to all National Clinical Trials Network members, accrued in 2016

A

B RVd-EloDose reduced

- Enrollment and randomization at diagnosis.

- Include both transplant eligible and ineligible pts

- High risk includes - Del17p,

t(14;16), amp 1q21 by FISH

- GEP high risk- Elevated serum

LDH- pPCL

SWOG Phase III in Development: Optimal Induction for High Risk NDMM

RANDOMIZED PHASE III Induction Maintenance

KRdDose 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

KRd x 8 Cycles1,2

n=85

KRd-Dara x 8 Cycles1,2

n=85

KRD-DaraDose reduced

- Enrollment and randomization at diagnosis.

- Include both transplant eligible and ineligible pts

- High risk includes - R-ISS III- Del17p,

t(14;16), amp 1q21 by FISH

- GEP high risk- Elevated serum

LDH- pPCL

Summary• EMD carries poor prognosis even in the era of novel therapies:

• Novel agents have improved PFS/OS outcomes but do not overcome poor prognosis (majority of patients die within 5 years).

• Get PET/CT and/or WB-MRI when suspecting EMD (e.g., elevated serum LDH, organ specific clinical symptoms).

• 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, CNS disease, EMD.

• Novel mechanisms of actions offer some hope:• Bcl2 inhibitors, XPO1 inhibitors, next generation IMiDs, mAbs, etc.

Acknowledgments• Our patients and their caregivers.

• Mentor: Bart Barlogie, MD PhD

• Clinical:– Saad Z. Usmani, MD– Manisha Bhutani, MD– Peter M. Voorhees, MD– Reed Friend, MD– Shebli Atrash, MD– Mauricio Pineda-Roman, MD– Chelsea Danahey, NP– Ami Ndiaye, NP– Jordan Robinson, PA

• Lab:– David Foureau, PhD– Lawrence Druhan, PhD– Nury Stuerwald, PhD– Katherine Rigby, BS

• Funding:• Bioinformatics/Biostats:

– James Symanowski– Qing Zhang– Myra Robinson

• Collaborators:– Bruno Paiva

(University of Salamanca, Spain)

– Ben Vincent (UNC Chapel Hill, NC),

– Wei Lin (Baylor University, Houston, TX)

Presented by: Saad Z. Usmani, MD FACP, @szusmani

Questions

Presented by: Saad Z. Usmani, MD FACP, @szusmani