Conventional chemotherapy for extra-medullary...
Transcript of Conventional chemotherapy for extra-medullary...
Conventional chemotherapy
for
extra-medullary disease
COMY April 2017
Laurent Garderet
Hôpital Saint Antoine
Service d’hématologie et thérapie cellulaire
Paris 75012, France
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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
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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
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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
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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.
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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
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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.
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Extramedullary spread:
potential mechanisms
• Decreased adhesion molecules (CD56)
• Down regulation of chemokine receptors (CXCR-4/SDF-1)
• Increased angiogenesis
• Bone marrow hypoxia
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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.
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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.
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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
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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
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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%)
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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
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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
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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)
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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)
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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
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• 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
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Conclusions
• Extra medullary disease has become a
recurrent problem with adverse prognosis
• Unmet medical need
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