Multidrug-resistant myeloma

Laboratory and clinical effects of verapamil as a chemosensitizer

Sydney E. Salmon, William S. Dalton, Thomas M. Grogan, Patricia Plezia, Manfred Lehnert, Denise Roe, Thomas P Miller

Research output: Contribution to journalArticle

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Abstract

Verapamil was evaluated as a chemosensitizer for reversing multidrug resistance in multiple myeloma both in vitro and in clinical trials. Bone marrows from 59 myeloma patients in relapse were evaluated for several resistance parameters: expression of p-glycoprotein (MDR1), doxorubicin (Adriamycin) and vincristine sensitivity, and the ability of added verapamil to reduce resistance to the cytotoxic agents. We found that verapamil was capable of sensitizing myeloma cells that exhibited resistance to doxorubicin and vincristine in vitro, but did not enhance sensitivity of cells that were drug sensitive (P < .001). Myeloma cells expressing MDR1 immunohistochemically tended to be more doxorubicin resistant in vitro than MDR1-negative cells. In the clinical trials, 22 patients with myeloma refractory to vincristine-Adriamycin-dexamethasone (VAD) were treated with VAD plus high-dose intravenous verapamil (Ve). Among the 22 patients treated with VAD/Ve, five achieved a partial remission (23%). The median relapse-free survival for the VAD/Ve responders was 5.4 months and their overall survival from the start of VAD/Ve was better than that of the nonresponders. Among the subset of 10 patients whose myeloma cells were MDR1 positive, four responded clinically (40%), whereas none of five patients with MDR1-negative myeloma cells achieved remission with VAD/Ve. We also observed that myeloma cells from three of four VAD/Ve clinical responders exhibited in vitro chemosensitization with verapamil, whereas in vitro verapamil chemosensitization was seen in only one of six clinical nonresponders. Our observations demonstrate that clinical reversal of multidrug resistance can be achieved in some patients with VAD-refractory myeloma with the use of verapamil. In addition to their value in drug development, in vitro tests of MDRI expression and of chemosensitizers plus cytotoxic drugs on the patients' bone marrow myeloma cells may identify patients who will respond clinically to chemosensitizer-containing regimens. We anticipate that chemosensitizer regimens capable of inhibiting multidrug resistance will play an increasing role in the treatment of hematologic malignancies, including B-cell neoplasms such as multiple myeloma and the non-Hodgkin's lymphomas.

Original languageEnglish (US)
Pages (from-to)44-50
Number of pages7
JournalBlood
Volume78
Issue number1
StatePublished - Jul 1 1991
Externally publishedYes

Fingerprint

Verapamil
Doxorubicin
Vincristine
Dexamethasone
Multiple Drug Resistance
Multiple Myeloma
Refractory materials
Bone
Cells
Clinical Trials
Pharmaceutical Preparations
Recurrence
Survival
Cytotoxins
Hematologic Neoplasms
Bone Marrow Cells
Non-Hodgkin's Lymphoma
In Vitro Techniques
Glycoproteins
B-Lymphocytes

ASJC Scopus subject areas

  • Hematology

Cite this

Salmon, S. E., Dalton, W. S., Grogan, T. M., Plezia, P., Lehnert, M., Roe, D., & Miller, T. P. (1991). Multidrug-resistant myeloma: Laboratory and clinical effects of verapamil as a chemosensitizer. Blood, 78(1), 44-50.

Multidrug-resistant myeloma : Laboratory and clinical effects of verapamil as a chemosensitizer. / Salmon, Sydney E.; Dalton, William S.; Grogan, Thomas M.; Plezia, Patricia; Lehnert, Manfred; Roe, Denise; Miller, Thomas P.

In: Blood, Vol. 78, No. 1, 01.07.1991, p. 44-50.

Research output: Contribution to journalArticle

Salmon, SE, Dalton, WS, Grogan, TM, Plezia, P, Lehnert, M, Roe, D & Miller, TP 1991, 'Multidrug-resistant myeloma: Laboratory and clinical effects of verapamil as a chemosensitizer', Blood, vol. 78, no. 1, pp. 44-50.
Salmon SE, Dalton WS, Grogan TM, Plezia P, Lehnert M, Roe D et al. Multidrug-resistant myeloma: Laboratory and clinical effects of verapamil as a chemosensitizer. Blood. 1991 Jul 1;78(1):44-50.
Salmon, Sydney E. ; Dalton, William S. ; Grogan, Thomas M. ; Plezia, Patricia ; Lehnert, Manfred ; Roe, Denise ; Miller, Thomas P. / Multidrug-resistant myeloma : Laboratory and clinical effects of verapamil as a chemosensitizer. In: Blood. 1991 ; Vol. 78, No. 1. pp. 44-50.
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abstract = "Verapamil was evaluated as a chemosensitizer for reversing multidrug resistance in multiple myeloma both in vitro and in clinical trials. Bone marrows from 59 myeloma patients in relapse were evaluated for several resistance parameters: expression of p-glycoprotein (MDR1), doxorubicin (Adriamycin) and vincristine sensitivity, and the ability of added verapamil to reduce resistance to the cytotoxic agents. We found that verapamil was capable of sensitizing myeloma cells that exhibited resistance to doxorubicin and vincristine in vitro, but did not enhance sensitivity of cells that were drug sensitive (P < .001). Myeloma cells expressing MDR1 immunohistochemically tended to be more doxorubicin resistant in vitro than MDR1-negative cells. In the clinical trials, 22 patients with myeloma refractory to vincristine-Adriamycin-dexamethasone (VAD) were treated with VAD plus high-dose intravenous verapamil (Ve). Among the 22 patients treated with VAD/Ve, five achieved a partial remission (23{\%}). The median relapse-free survival for the VAD/Ve responders was 5.4 months and their overall survival from the start of VAD/Ve was better than that of the nonresponders. Among the subset of 10 patients whose myeloma cells were MDR1 positive, four responded clinically (40{\%}), whereas none of five patients with MDR1-negative myeloma cells achieved remission with VAD/Ve. We also observed that myeloma cells from three of four VAD/Ve clinical responders exhibited in vitro chemosensitization with verapamil, whereas in vitro verapamil chemosensitization was seen in only one of six clinical nonresponders. Our observations demonstrate that clinical reversal of multidrug resistance can be achieved in some patients with VAD-refractory myeloma with the use of verapamil. In addition to their value in drug development, in vitro tests of MDRI expression and of chemosensitizers plus cytotoxic drugs on the patients' bone marrow myeloma cells may identify patients who will respond clinically to chemosensitizer-containing regimens. We anticipate that chemosensitizer regimens capable of inhibiting multidrug resistance will play an increasing role in the treatment of hematologic malignancies, including B-cell neoplasms such as multiple myeloma and the non-Hodgkin's lymphomas.",
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