Comparative analysis of multiple myeloma treatment by CD138 antigen targeting with bismuth-213 and Melphalan chemotherapy.
BACKGROUND
Multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow. Despite intense research to develop new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) has been shown to be effective in vivo in a MM model. In order to define where alpha-RIT stands in MM treatment, the aim of this study was to compare Melphalan, MM standard treatment, with alpha-RIT using a [213Bi]-anti-mCD138 antibody in a syngeneic MM mouse model.


METHODS
C57BL/KaLwRij mice were grafted with 1 × 10(6) 5T33 murine MM cells. Luciferase transfected 5T33 cells were used for in vivo localization. The first step of the study was to assess the dose-response of Melphalan 21 days after engraftment. The second step consisted in therapeutic combination: Melphalan followed by RIT at day 22 or day 25 after engraftment. Toxicity (animal weight, blood cell counts) and treatment efficacy were studied in animals receiving no treatment, injected with Melphalan alone, RIT alone at day 22 or day 25 (3.7 MBq of [213Bi]-anti-CD138) and Melphalan combined with alpha-RIT.


RESULTS
Fifty percent of untreated mice died by day 63 after MM engraftment. In mice treated with Melphalan alone, only the 200 μg dose improved median survival. No animal was cured after Melphalan treatment whereas 60% of the mice survived with RIT alone at day 22 after tumor engraftment with only slight and reversible hematological radiotoxicity. No therapeutic effect was observed with alpha-RIT 25 days after engraftment. Melphalan and alpha-RIT combination does not improve overall survival compared to RIT alone, and results in increased leukocyte and red blood cell toxicity.


CONCLUSIONS
Alpha-RIT seems to be a good alternative to Melphalan. Association of these two treatments provides no benefit. The perspectives of this work would be to evaluate RIT impact on the regimens incorporating the novel agents bortezomide, thalidomide and lenalidomide.
INSERM UMR 892 - CRCNA, France; University of Nantes, France; CNRS UMR 6299, Nantes, France.
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Gouard
INSERM UMR 892 - CRCNA, France; University of Nantes, France; CNRS UMR 6299, Nantes, France; CHU Nantes, Nuclear medicine department, Nantes, France.
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Pallardy
INSERM UMR 892 - CRCNA, France; University of Nantes, France; CNRS UMR 6299, Nantes, France.
J
J
Gaschet
INSERM UMR 892 - CRCNA, France; University of Nantes, France; CNRS UMR 6299, Nantes, France; CHU Nantes, Nuclear medicine department, Nantes, France; Institut de Cancérologie de l'Ouest, Saint-Herblain, France.
A
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Faivre-Chauvet
Institute for Transuranium Elements, Karlsruhe, Germany.
F
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Bruchertseifer
Institute for Transuranium Elements, Karlsruhe, Germany.
A
A
Morgenstern
INSERM UMR 892 - CRCNA, France; University of Nantes, France; CNRS UMR 6299, Nantes, France.
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Maurel
INSERM UMR 892 - CRCNA, France; University of Nantes, France; CNRS UMR 6299, Nantes, France.
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Matous
INSERM UMR 892 - CRCNA, France; University of Nantes, France; CNRS UMR 6299, Nantes, France; CHU Nantes, Nuclear medicine department, Nantes, France; Institut de Cancérologie de l'Ouest, Saint-Herblain, France.
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Kraeber-Bodéré
INSERM UMR 892 - CRCNA, France; University of Nantes, France; CNRS UMR 6299, Nantes, France.
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Davodeau
INSERM UMR 892 - CRCNA, France; University of Nantes, France; CNRS UMR 6299, Nantes, France; Institut de Cancérologie de l'Ouest, Saint-Herblain, France. Electronic address: Michel.Cherel@univ-nantes.fr.
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Chérel
D000818:Animals; D001729:Bismuth / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods*; D005260:Female; D008558:Melphalan / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000473:pathology / Q000628:therapy*; D061848:Optical Imaging; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011868:Radioisotopes / Q000627:therapeutic use*; D053668:Syndecan-1 / Q000276:immunology*
D011868:Radioisotopes; D053668:Syndecan-1; D008558:Melphalan; D001729:Bismuth
Alpha particle; Bismuth-213; CD138; Melphalan; Oncology: multiple myeloma; Radioimmunotherapy