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Elimination of Chemoresistant Multiple Myeloma Clonogenic Colony-forming Cells by Combined Treatment with a Plasma Cell-reactive Monoclonal Antibody and a P-Glycoprotein-reactive Monoclonal Antibody¹

Cancer Immunology Research Unit [A. W. T., J. L., R. M. W., M. J. S.] and Bone Marrow Transplantation Unit [J. W. F.], Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas 75246; the Department of Medicine, University of Arizona Cancer Center, Tucson, Arizona 85724 [W. S. D.]; and the Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan [T. T.]

Patients with multiple myeloma (MM) commonly become refractory to chemotherapy despite a favorable response to induction treatment. We examined the effectiveness of a previously characterized plasma cell-reactive monoclonal antibody, MM4, in eliminating MM clonogenic colony-forming cells (CCC) with a multidrug-resistant (MDR) phenotype. Experiments were performed using MM cell lines that exhibit 6 (RPMI 8226/DOX₆)- and 40 (RPMI 8226/DOX₄₀)-fold resistance to doxorubicin (DOX). Both lines were selected from the chemosensitive MM line RPMI 8226/S and were cross-resistant to mitoxantrone, acronycine, etoposide, and vincristine. Surface marker analysis conducted in this study showed that DOX₆ and DOX₄₀ overexpressed the MDR1 gene product p170. Both MDR lines remained reactive to the plasma cell-reactive monoclonal antibodies MM4 and PCA-1 and expressed the relevant cytoplasmic immunoglobulin light chain. Treatment with MM4 and rabbit complement (C') was equally cytotoxic to RPMI 8226/S [80 ± 5.6% (SD)], DOX₆ [74 ± 8.5], and DOX₄₀ cells [75 ± 11.3%], based on short-term chromium release studies. Furthermore, MM4 + C' deleted up to 3 logs of CCC colonies from chemosensitive and MDR lines (RPMI 8226/S, 99.87 ± 0.11%; DOX₆, 99.91 ± 0.08%; DOX₄₀, 99.55 ± 0.44%). By comparison, the P-glycoprotein-reactive monoclonal antibody MRK-16 and C' inhibited tumor colony formation of MDR cells (8226/DOX₆, 95.71 ± 2.51%; 8226/DOX₄₀, 99.61 ± 0.43%) but affected that of chemosensitive cells only slightly (8.9 ± 17.8%). In an attempt to optimize the depletion of myeloma CCC, MM4 was used together with MRK-16. This approach resulted in uniform depletion of myeloma clonogenic colony-forming cells from the chemosensitive (98.32 ± 1.53%, n = 4) and MDR lines (8226/DOX₆, 98.83 ± 0.08%, n = 4; 8226/DOX₄₀, 99.29 ± 0.62, n = 7) but did not result in enhanced CCC depletion. When DOX₄₀ cells were mixed with normal bone marrow (BM) in the ratio of 90:10 (BM:MM), either MM4 or MRK-16 and C' depleted MM colonies (98.8 ± 0.71% and 98.10 ± 1.0%, respectively) without affecting the majority of BM progenitor cells. These observations suggest that either MM4 or MRK-16 is useful for depleting MDR myeloma clonogenic colony-forming cells.

¹ Supported in part by grants from the Charles A. Sammons Cancer Center Research Fund, the Baylor Research Foundation Oncology/Immunology Research Fund, and the Tri Delta Cancer Research Fund.

² To whom requests for reprints should be addressed, at Cancer Immunology Research Unit, Charles A. Sammons Cancer Center, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246.

Received 12/ 5/88. Revised 3/31/89. Accepted 6/ 8/89.

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