Phase I/II trial of the CXCR4 inhibitor plerixafor in combination with bortezomib as a chemosensitization strategy in relapsed/refractory multiple myeloma

被引：51

作者：

Ghobrial, Irene M. ^{[1
]}

Liu, Chia-Jen ^{[1
]}

Zavidij, Oksana ^{[1
]}

Azab, Abdel K. ^{[1
,2
]}

Baz, Rachid ^{[3
]}

Laubach, Jacob P. ^{[1
]}

Mishima, Yuji ^{[1
]}

Armand, Philippe ^{[1
]}

Munshi, Nikhil C. ^{[1
]}

Basile, Frank ^{[4
]}

Constantine, Michael ^{[5
]}

Vredenburgh, James ^{[6
]}

Boruchov, Adam ^{[6
]}

Crilley, Pamela ^{[7
]}

Henrick, Patrick M. ^{[1
]}

Hornburg, Kalvis T. V. ^{[1
]}

Leblebjian, Houry ^{[1
]}

Chuma, Stacey ^{[1
]}

Reyes, Kaitlen ^{[1
]}

Noonan, Kimberly ^{[1
]}

Warren, Diane ^{[1
]}

Schlossman, Robert ^{[1
]}

Paba-Prada, Claudia ^{[1
]}

Anderson, Kenneth C. ^{[1
]}

Weller, Edie ^{[8
]}

Trippa, Lorenzo ^{[8
]}

Shain, Kenneth ^{[3
]}

Richardson, Paul G. ^{[1
]}

机构：

[1] Harvard Med Sch, Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA

[2] Washington Univ, Sch Med, Div Canc Biol, Dept Radiat Oncol, St Louis, MO USA

[3] H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Haematol, Tampa, FL USA

[4] Cape Cod Hosp, Dept Med Oncol, Davenport Mugar Canc Ctr, Hyannis, MA USA

[5] Dana Farber Brigham & Womens Canc Ctr, Milford Reg Med Ctr, Dept Med Oncol, Milford, MA USA

[6] St Francis Hosp & Med Ctr, Dept Med Oncol, Hartford, CT USA

[7] Eastern Reg Med Ctr, Dept Med Oncol, Canc Treatment Ctr Amer, Philadelphia, PA USA

[8] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA

来源：

AMERICAN JOURNAL OF HEMATOLOGY | 2019年 / 94卷 / 11期

关键词：

BONE-MARROW; DEXAMETHASONE; THERAPY; AMD3100; CELLS; MICROENVIRONMENT; LENALIDOMIDE; MOBILIZATION; MULTICENTER; DARATUMUMAB;

D O I：

10.1002/ajh.25627

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

We tested the hypothesis that using CXCR4 inhibition to target the interaction between the tumor cells and the microenvironment leads to sensitization of the tumor cells to apoptosis. Eligibility criteria included multiple myeloma (MM) patients with 1-5 prior lines of therapy. The purposes of the phase I study were to evaluate the safety and maximal-tolerated dose (MTD) of the combination. The treatment-related adverse events and response rate of the combination were assessed in the phase II study. A total of 58 patients were enrolled in the study. The median age of the patients was 63 years (range, 43-85), and 78% of them received prior bortezomib. In the phase I study, the MTD was plerixafor 0.32 mg/kg, and bortezomib 1.3 mg/m(2). The overall response rate for the phase II study was 48.5%, and the clinical benefit rate 60.6%. The median disease-free survival was 12.6 months. The CyTOF analysis demonstrated significant mobilization of plasma cells, CD34+ stem cells, and immune T cells in response to plerixafor. This is an unprecedented study that examines therapeutic targeting of the bone marrow microenvironment and its interaction with the tumor clone to overcome resistance to therapy. Our results indicate that this novel combination is safe and that the objective response rate is high even in patients with relapsed/refractory MM. , NCT00903968.

引用

页码：1244 / 1253

页数：10

共 30 条

[1] Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma [J].

Alsayed, Yazan ;

Ngo, Hai ;

Runnels, Judith ;

Leleu, Xavier ;

Singha, Ujjal K. ;

Pitsillides, Costas M. ;

Spencer, Joel A. ;

Kimlinger, Teresa ;

Ghobrial, Joanna M. ;

Jia, Xiaoying ;

Lu, Ganwei ;

Timm, Michael ;

Kumar, Ashok ;

Cote, Daniel ;

Veilleux, Israel ;

Hedin, Karen E. ;

Roodman, G. David ;

WitZig, Thomas E. ;

Kung, Andrew L. ;

Hideshima, Teru ;

Anderson, Kenneth C. ;

Lin, Charles P. ;

Ghobrial, Irene M. .

BLOOD, 2007, 109 (07) :2708-2717

[2] CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy [J].

Azab, Abdel Kareem ;

Runnels, Judith M. ;

Pitsillides, Costas ;

Moreau, Anne-Sophie ;

Azab, Feda ;

Leleu, Xavier ;

Jia, Xiaoying ;

Wright, Renee ;

Ospina, Beatriz ;

Carlson, Alicia L. ;

Alt, Clemens ;

Burwick, Nicholas ;

Roccaro, Aldo M. ;

Ngo, Hai T. ;

Farag, Mena ;

Melhem, Molly R. ;

Sacco, Antonio ;

Munshi, Nikhil C. ;

Hideshima, Teru ;

Rollins, Barrett J. ;

Anderson, Kenneth C. ;

Kung, Andrew L. ;

Lin, Charles P. ;

Ghobrial, Irene M. .

BLOOD, 2009, 113 (18) :4341-4351

[3]

Bonora M, 2015, ONCOGENE, V34, P1608, DOI [10.1038/onc.2014.96, 10.1038/onc.2014.462]

[4] AMD3100 plus G-CSF can successfully mobilize CD34+cells from non-Hodgkin's lymphoma, Hodgkin's disease and multiple myeloma patients previously failing mobilization with chemotherapy and/or cytokine treatment: compassionate use data [J].

Calandra, G. ;

McCarty, J. ;

McGuirk, J. ;

Tricot, G. ;

Crocker, S-A ;

Badel, K. ;

Grove, B. ;

Dye, A. ;

Bridger, G. .

BONE MARROW TRANSPLANTATION, 2008, 41 (04) :331-338

[5] Rapid mobilization of CD34+cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma [J].

Devine, SM ;

Flomenberg, N ;

Vesole, DH ;

Liesveld, J ;

Weisdorf, D ;

Badel, K ;

Calandra, G ;

DiPersio, JF .

JOURNAL OF CLINICAL ONCOLOGY, 2004, 22 (06) :1095-1102

[6] Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma [J].

Dimopoulos, M. A. ;

Oriol, A. ;

Nahi, H. ;

San-Miguel, J. ;

Bahlis, N. J. ;

Usmani, S. Z. ;

Rabin, N. ;

Orlowski, R. Z. ;

Komarnicki, M. ;

Suzuki, K. ;

Plesner, T. ;

Yoon, S. -S. ;

Ben Yehuda, D. ;

Richardson, P. G. ;

Goldschmidt, H. ;

Reece, D. ;

Lisby, S. ;

Khokhar, N. Z. ;

O'Rourke, L. ;

Chiu, C. ;

Qin, X. ;

Guckert, M. ;

Ahmadi, T. ;

Moreau, P. .

NEW ENGLAND JOURNAL OF MEDICINE, 2016, 375 (14) :1319-1331

[7] A review on CXCR4/CXCL12 axis in oncology: No place to hide [J].

Domanska, Urszula M. ;

Kruizinga, Roeliene C. ;

Nagengast, Wouter B. ;

Timmer-Bosscha, Hetty ;

Huls, Gerwin ;

de Vries, Elisabeth G. E. ;

Walenkamp, Annemiek M. E. .

EUROPEAN JOURNAL OF CANCER, 2013, 49 (01) :219-230

[8] Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group [J].

Fernandez de Larrea, C. ;

Kyle, R. A. ;

Durie, B. G. M. ;

Ludwig, H. ;

Usmani, S. ;

Vesole, D. H. ;

Hajek, R. ;

San Miguel, J. F. ;

Sezer, O. ;

Sonneveld, P. ;

Kumar, S. K. ;

Mahindra, A. ;

Comenzo, R. ;

Palumbo, A. ;

Mazumber, A. ;

Anderson, K. C. ;

Richardson, P. G. ;

Badros, A. Z. ;

Caers, J. ;

Cavo, M. ;

Leleu, X. ;

Dimopoulos, M. A. ;

Chim, C. S. ;

Schots, R. ;

Noeul, A. ;

Fantl, D. ;

Mellqvist, U-H ;

Landgren, O. ;

Chanan-Khan, A. ;

Moreau, P. ;

Fonseca, R. ;

Merlini, G. ;

Lahuerta, J. J. ;

Blade, J. ;

Orlowski, R. Z. ;

Shah, J. J. .

LEUKEMIA, 2013, 27 (04) :780-791

[9]

Harousseau JL, 2006, HAEMATOLOGICA, V91, P1498

[10] The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis [J].

Hunter, Zachary R. ;

Xu, Lian ;

Yang, Guang ;

Zhou, Yangsheng ;

Liu, Xia ;

Cao, Yang ;

Manning, Robert J. ;

Tripsas, Christina ;

Patterson, Christopher J. ;

Sheehy, Patricia ;

Treon, Steven P. .

BLOOD, 2014, 123 (11) :1637-1646

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