Conventional chemotherapy

for

extra-medullary disease

COMY April 2017

Laurent Garderet

Hôpital Saint Antoine

Service d’hématologie et thérapie cellulaire

Paris 75012, France

COMy C

ongr

ess 2

017

Case report (1)

• 72 year old man with IgGK MM (32% PCs

in bone marrow aspirate) in Feb 2012

• ISS=2, normal karyotype, t(4-14) by FISH

• At diagnosis: L3 fracture with soft tissue

plasmacytoma + T4 and T12 bone lesions

COMy C

ongr

ess 2

017

Case report (2)

• L3 kyphoplasty plus 30 Gy from L1 to L5

• VMP 12 cycles + Zometa: CR

• Surgical stabilization L2 to L4 in June 2012 and D11 to L5

in Dec 2013

COM

y Con

gres

s 201

7

Case report (3)

• Relapse 10 months later with voluminous lumbar plasmacytoma : 14 cm X 8 cm

(PET-CT SUV max: 24)

• VRD X 9: PR, PAD X 5: complete haematological response but plasmacytoma progress

• 4th line: DT-PACE

COMy C

ongr

ess 2

017

DT-PACE

• Dexamethasone: 40 mg/d 4 days

Thalidomide: 200 mg/d every day

• Cisplatine: 10 mg/m2 D1 to D4

• Adriamycine: 10 mg/m2 D1 to D4

• Cyclophosphamide: 400 mg/m2 D1 to D4

• Etoposide: 40 mg/m2 D1 to D4

Lee CK, Barlogie B, Munshi N, et al. DTPACE : an effective, novel combination chemotherapy

with thalidomide for previously treated patients with myeloma. J Clin Oncol 2003;21:2732-2739.

COMy C

ongr

ess 2

017

COMy C

ongr

ess 2

017

COMy C

ongr

ess 2

017

COMy C

ongr

ess 2

017

Follow-up

• Successful first DT-PACE, plasmacytoma

relapsed

• Pomalidomide Dex was unsuccessful

• Resume DT-PACE half dose: 2 more cycles

• Daratumumab in 7th line: failure

• Melphalan: 100 mg/m2 with ASCT

COMy C

ongr

ess 2

017

Extramedullary myeloma

• Up to 30% of MM during disease course

• Hematogenous spread or bone-related

• 4 entities

Bone-related plasmacytoma

Extramedullary disease

Plasma Cell Leukemia

Solitary Plasmacytoma

• not increased by lenalidomide/bortezomib but by allo SCT

Bladé J, JCO 2011;29:3805, Weinstock M, Leuk Lymph 2013;54:1135,

Touzeau C, Blood 2016;127:971.

COMy C

ongr

ess 2

017

Extramedullary spread:

potential mechanisms

• Decreased adhesion molecules (CD56)

• Down regulation of chemokine receptors (CXCR-4/SDF-1)

• Increased angiogenesis

• Bone marrow hypoxia

COMy C

ongr

ess 2

017

Treatment of EMD

• Thalidomide: fail1

• Bortezomib: efficacious2

• Lenalidomide : some response3

• Pomalidomide: 31% response4

• Daratumumab, Elotuzumab? (Cassiopeia and GMMG-HD6 on going)

• Vemurafenib (if BRAF mutation)5

• CAR T cells?6

1/Rosinol L, et al. Haematologica 2004;89:832. 2/ Laura R, et al. Eur J Haematol 2006;76:405. 3/ Nakazato T, et al. Ann Hematol 2012;91:473. 4/Short KD, et al. Leukemia 2001;25:906. 5/ Andrulis M, et al. Cancer Discov 2013;3:862. 6/ Rapoport AP, et al. Nat Med 2015;21:914.

COMy C

ongr

ess 2

017

Chemotherapy (lymphoma-like)

• VAD

• CHOP

• PAD

• DT-PACE (efficacious but temporary)1

• High dose melphalan (ASCT)2 (conflicting

results)

1/ Ronchetti AM, et al. Leuk Lymphoma 2013;54:1117. 2/ Varettoni M, et al. Ann Oncol 2010;21: 325. Wu P, et al. Leuk Lymphoma 2009;50:230. Lonial S, et al. Blood 2015;126:1536.

COMy C

ongr

ess 2

017

Impact of extramedullary disease in patients with newly diagnosed

multiple myeloma undergoing autologous stem cell

transplantation:

A study from the Chronic Malignancies Working Party of the European Society for

Blood and Marrow Transplantation

COMy C

ongr

ess 2

017

How? • 3744 newly diagnosed adult MM

patients

• After upfront single (n = 3391) or tandem ASCT (2nd ASCT within 6 months; n = 353)

• Between January 2005 and December 2014 with data on extramedullary involvement

• 3-year PFS and OS

• Landmark analysis at 6 months for comparison of single vs. tandem ASCT

COMy C

ongr

ess 2

017

Results

Without EMD (MM)

n = 3062 (81.8%)

Incidence – n = 3744

Paraskeletal (PS)

n = 543 (14.5%)

Number of sites – p < 0.001

• 0 (100%)

• 1 (n = 524; 96.5%)

• ≥2 (n = 19; 3.5%)

only paraskeletal

• 1 (n = 115; 82.7%)

• ≥2 (n = 24; 17.3%)

only extramedullary organ

Extramedullary organ (EM)

n = 139 (3.7%)

COMy C

ongr

ess 2

017

Results

EMD and PFS

• MM vs. PS:

47.9% (45.8 to

50.1) vs. 50.0%

(44.6 to 55.3;

p=0.78)

• MM vs. EM:

47.9% (45.8 to

50.1) vs. 39.9%

(30.3 to 49.5;

p=0.001)

• PS vs. EM:

p=0.01

COMy C

ongr

ess 2

017

Results

EMD and OS

• MM vs. PS:

80.1% (78.4 to

81.8) vs. 77.7%

(73.3 to 82.1;

p=0.09)

• MM vs. EM:

80.1% (78.4 to

81.8) vs. 58.0%

(48.1 to 67.9;

p<0.001)

• PS vs. EM:

p<0.001

COMy C

ongr

ess 2

017

Results

Sites and PFS

• 0 vs. 1:

47.9% (45.8 to

50.1) vs. 49.4%

(44.6 to 54.3;

p=0.36)

• 0 vs. ≥2:

47.9% (45.8 to

50.1) vs. 22.7%

(5.2 to 40.2;

p=0.001)

COMy C

ongr

ess 2

017

Results

Sites and OS

• 0 vs. 1:

80.1% (78.4 to

81.8) vs. 73.5%

(69.2 to 77.7;

p<0.001)

• 0 vs. ≥2:

80.1% (78.4 to

81.8) vs. 71.4%

(55.1 to 87.7;

p=0.05)

COMy C

ongr

ess 2

017

Results

Multivariate

3-year PFS 3-year OS

Factors* - reference

HR (95% CI) P HR (95% CI) P

Group – MM (no EMD) 0.001 <0.001

PS one site 1.02 (0.82 to 1.27) 0.86 1.33 (0.98 to 1.83) 0.07

PS multiple sites 2.46 (0.92 to 6.62) 0.07 0.74 (0.10 to 5.32) 0.77

EM one site 1.03 (0.66 to 1.62) 0.88 2.30 (1.43 to 3.70) 0.001

EM multiple sites 3.40 (1.74 to 6.61) <0.001 3.64 (1.48 to 8.94) 0.01

ASCT – single

Tandem 0.83 (0.66 to 1.06) 0.13 0.74 (0.51 to 1.09) 0.13

*other factors

included in the

model: sex, age, ISS

stage, Salmon and

Durie, year of ASCT,

status at ASCT (CR,

PR, <PR), type of

myeloma

COMy C

ongr

ess 2

017

• Incidence increased

• Similar outcome of patients without extramedullary disease and PS involvement after ASCT

• Number of EM sites influenced 3-year PFS

• EM involvement was associated with worse 3-year OS

• Not improved by use of tandem ASCT

Conclusions

COMy C

ongr

ess 2

017

COMy C

ongr

ess 2

017

COMy C

ongr

ess 2

017

Conclusions

• Extra medullary disease has become a

recurrent problem with adverse prognosis

• Unmet medical need

COMy C

ongr

ess 2

017

COMy C

ongr

ess 2

017