Follow-Up Study of a Multiple Myeloma Patient Successfully Treated with Clarithromycin (CAM), Low-Dose Lenalidomide and Low-Dose Dexamethasone: Significance and Possible Mechanism of Action of CAM as an Add-On Therapy

Nobuo Takemori¹, Toshio Fukuda², Masaru Kojima³

¹Division of Hematology, Internal Medicine, Imai Hospital, Ashikaga, Japan.
²Graduate School of Health Sciences, Gunma University, Maebashi, Japan.
³Department of Anatomic and Diagnostic Pathology, Dokkyo Medical University School of Medicine, Shimotsuga-gun, Japan.

DOI: 10.4236/crcm.2014.312142                

Abstract

Background: Recently, high efficacy of the chemotherapeutic regimen combining clarithromycin (CAM) with lenalidomide (Len) and dexamethasone (Dex) (BiRD) in treating multiple myeloma (MM) patients has been reported. However, the exact mechanism of added CAM has not been fully elucidated. This case report will provide helpful information for understanding the significance and the mechanism of action of CAM as an add-on therapy. Patient: A 78-year-old female patient with IgA-λ type MM was treated with low-dose Len coupled with low-dose Dex (low Rd), and excellent response was achieved for long term, but she later became refractory to this treatment. Then, CAM was added to low Rd (low Rd-CAM, i.e., modified BiRD therapy). This add-on-therapy was found to be effective, but later suspended because of pneumonitis. Then, low-dose Len coupled with CAM (low R-CAM) treatment was applied; but effect of this Dex-free treatment was insufficient. Thus, low Rd-CAM was reapplied and satisfactory reduction of IgA was achieved. This fact suggests that low Rd-CAM is the favorable combination, Dex is requisite and CAM might have enhanced the effect of Dex. In this case, various serum cytokines were examined during the course of illness. Only interleukin-6 showed apparent increase, and tumor necrosis factor-α, transforming growth factor-β, soluble IL-2 receptors and C-reactive protein showed the slight increase during low Rd-CAM treatment. The results seem somewhat conflicting, but it seems that intricate cytokine response due to immune activation might have occurred during low Rd-CAM treatment.

Keywords

Follow-Up Study, Multiple Myeloma, Clarithromycin (CAM), Lenalidomide, Dexamethasone, Significance, Mechanism of Action of CAM, Add-On Therapy

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Dimopoulos, M., Spencer, A., Attal, M., et al. (2007) Lenalidomide plus Dexamethasone for Relapsed or Refractory Multiple Myeloma. The New England Journal of Medicine, 357, 2123-2132. http://dx.doi.org/10.1056/NEJMoa070594
[2]	Dimopoulos, M.A., Chen, C., Spencer, A., et al. (2009) Long-Term Follow-Up on Overall Survival from the MM-009 and MM-010 Phase III Trials of Lenalidomide plus Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma. Leukemia, 23, 2147-2152. http://dx.doi.org/10.1038/leu.2009.147
[3]	Rajkumar, S.V., Hayman, S.R., Lacy, M.Q., et al. (2005) Combination Therapy with Lenalidomide plus Dexamethasone (Rev/Dex) for Newly Diagnosed Myeloma. Blood, 106, 4050-4053. http://dx.doi.org/10.1182/blood-2005-07-2817
[4]	Richardson, P., Mitsiades, C., Laubach, J., et al. (2009) Lenalidomide in Multiple Myeloma: An Evidence-Based Review of Its Role in Therap. Core Evidence, 4, 215-245. http://dx.doi.org/10.2147/CE.S6002
[5]	Zonder, J.A., Crowley, J., Hussein, M.A., et al. (2010) Lenalidomide and High-Dose Dexamethasone Compared with Dexamethasone as Initial Therapy for Multiple Myeloma: A Randomized Southwest Oncology Group Trial (S0232). Blood, 116, 5838-5841. http://dx.doi.org/10.1182/blood-2010-08-303487
[6]	Dimopoulos, M.A. and Terpos, E. (2010) Lenalidomide: An Update on Evidence from Clinical Trials. Blood Reviews, 24, 521-526. http://dx.doi.org/10.1016/S0268-960X(10)70005-9
[7]	Rajkumar, S.V., Jacobus, S., Callander, N., et al. (2010) Lenalidomide plus High-Dose Dexamethasone versus Lenalidomide plus Low-Dose Dexamethasone as Initial Therapy for Newly Diagnosed Multiple Myeloma: An Open-Label Randomized Controlled Trial. Lancet Oncology, 11, 29-37. http://dx.doi.org/10.1016/S1470-2045(09)70284-0
[8]	Niesvitzky, R., Jayabalan, D.S., Christos, P.J., et al. (2008) BiRD (Biaxin [Clarithromycin]/Revlimid [Lenalidomide]/ Dexamethasone) Combination Therapy Results in High Complete- and Overall-Response Rates in Treatment-Naive Symptomatic Multiple Myeloma. Blood, 111, 1101-1109. http://dx.doi.org/10.1182/blood-2007-05-090258
[9]	Gay, F., Rajikumar, S.V., Coleman, M., et al. (2010) Clarithromycin (Biaxin)-Lenalidomide-Low-Dose Dexamethasone (BiRd) versus Lenalidomide-Low-Dose Dexamethasone (Rd) for Newly Diagnosed Myeloma. American Journal of Hematology, 85, 664-669. http://dx.doi.org/10.1002/ajh.21777
[10]	Culic, O., Eracovic, V. and Parnham, M.J. (2001) Anti-Inflammatory Effects of Macrolide Antibiotics. European Journal of Pharmacology, 429, 209-229. http://dx.doi.org/10.1016/S0014-2999(01)01321-8
[11]	Kanoh, S. and Rubin, B.K. (2010) Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications. Clinical Microbiology Reviews, 23, 590-615. http://dx.doi.org/10.1128/CMR.00078-09
[12]	Quach, H., Richie, D., Stewart, A.K., Neeson, P., Harrison, S., Smyth, M.J. and Prince, H.M. (2010) Mechanism of Action of Immunomodulatory Drugs (IMiDS) in Multiple Myeloma. Leukemia, 24, 22-32. http://dx.doi.org/10.1038/leu.2009.236
[13]	Vallet, S., Palumbo, A., Raje, N., Boccadoro, M. and Anderson, K.C. (2008) Thalidomide and Lenalidomide: Mechanism-Based Potential Drug Combinations. Leukemia & Lymphoma, 49, 1238-1245. http://dx.doi.org/10.1080/10428190802005191
[14]	Xu, Y.B., Sun, J., Sheard, M.A., Tran, H.C., Wan, Z.S., Liu, W.Y., et al. (2013) Lenalidomide Overcomes Suppression of Human Natural Killer Cell Anti-Tumor Functions by Neuroblastoma Microenvironment-Associated IL-6 and TGFβ1. Cancer Immunology, Immunotherapy, 62, 1637-1648. http://dx.doi.org/10.1007/s00262-013-1466-y
[15]	Lu, G., Middleton, R.E., Sun, H., Naniong, M., Ott, C.J., Mitsiades, C.S., et al. (2014) The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins. Science, 343, 305-309. http://dx.doi.org/10.1126/science.1244917
[16]	Krönke, J., Udeshi, N.D., Narla, A., Grauman, P., Hurst, S.N., McConkey, M., et al. (2014) Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells. Science, 343, 301-305. http://dx.doi.org/10.1126/science.1244851
[17]	Sakamoto, M., Mikasa, K., Hamada, K., et al. (1996) Long-Term Clarithromycin Treatment for Cancer Cachexia of Inoperable Non-Small Cell Lung Cancer Patients. Japanese Journal of Chemotherapy, 44, 879-882.
[18]	Majima, T., Mikasa, K., Hamada, K., Konishi, M., Maeda, K., Sakamoto, M., et al. (1999) Changes of Cytokine mRNA in Peripheral Blood Mononuclear Cells from Unresectable Non-Small Cell Lung Cancer Patients before and after Clarithromycin Therapy. Japanese Journal of Chemotherapy, 47, 345-348.
[19]	Hamada, K., Mikasa, K., Yunou, Y., Kurioka, T., Majima, T., Narita, N. and Kita, E. (2000) Adjuvant Effect of Clarithromycin on Chemotherapy for Murine Lung Cancer. Chemotherapy, 46, 49-61. http://dx.doi.org/10.1159/000007256
[20]	Majima, T., Mikasa, K., Sakamoto, M., Hamada, K., Konishi, M., Maeda, K., et al. (2000) Clarithromycin Regulates Cytokine mRNA in Non-Small Cell Lung Cancer. Japanese Journal of Chemotherapy, 48, 780-785.
[21]	Takemori, N., Nakamura, M., Kojima, M. and Eishi, Y. (2014) Successful Treatment in a Case of Propionibacterium acnes-Associated Sarcoidosis with Clarithromycin Administration: A Case Report. Journal of Medical Case Reports, 8, 15. http://dx.doi.org/10.1186/1752-1947-8-15
[22]	Takeshita, K., Yamagishi, I., Harada, M., Otomo, S., Nakagawa, T. and Mizushima, Y. (1989) Immunological and Anti-Inflammatory Effects of Clarithromycin: Inhibition of Interleukin 1 Production of Murine Peritoneal Macrophages. Drugs under Experimental and Clinical Research, 15, 527-533.
[23]	Morikawa, K., Zhang, J., Nonaka, M. and Morikawa, S. (2002) Modulatory Effect of Macrolide Antibiotics on the Th1- and Th2-Type Cytokine Production. International Journal of Antimicrobial Agents, 19, 53-59. http://dx.doi.org/10.1016/S0924-8579(01)00457-5
[24]	Sugiyama, K., Shirai, R., Mukae, H., Ishimoto, H., Nagata, T., Sakamoto, N., et al. (2007) Differing Effects of Clarithromycin and Azithromycin on Cytokine Production by Murine Dendritic Cells. Clinical & Experimental Immunology, 147, 540-546. http://dx.doi.org/10.1111/j.1365-2249.2007.03299.x
[25]	Kikuchi, T., Hagiwara, K., Honda, Y., Gomi, K., Kobayashi, T., Takahashi, H., et al. (2002) Clarithromycin Suppresses Lipopolysaccharide-Induced Interleukin-8 Production by Human Monocytes through AP-1 and NF-κB Transcription Factors. Journal of Antimicrobial Chemotherapy, 49, 745-755. http://dx.doi.org/10.1093/jac/dkf008
[26]	Sassa, K., Mizushima, Y. and Kobayashi, M. (1999) Differential Modulatory Effects of Clarithromycin on the Production of Cytokines by a Tumor. Antimicrobial Agents and Chemotherapy, 43, 2787-2789.
[27]	Greenstein, S., Ghias, K., Krett, N.L. and Rosen, S.T. (2002) Mechanisms of Glucocorticoid-Mediated Apoptosis in Hematological Malignancies. Clinical Cancer Research, 8, 1681-1694. http://clincancerres.aacrjournals.org/content/8/6/1681.long
[28]	Gandhi, A.K., Kang, J., Capone, L., Parton, A., Wu, L., Zhang, L.H., et al. (2010) Dexamethasone Synergizes with Lenalidomide to Inhibit Multiple Myeloma Tumor Growth, but Reduces Lenalidomide-Induced Immunomodulation of T and NK Cell Function. Current Cancer Drug Targets, 10, 155-167. http://dx.doi.org/10.2174/156800910791054239
[29]	Fost, D.A., Leung, D.Y.M., Martin, R.J., Brown, E.E., Szefler, S.J. and Spahn, J.J. (1999) Inhibition of Methylprednisolone Elimination in the Presence of Clarithromycin Therapy. Journal of Allergy and Clinical Immunology, 103, 1031-1035. http://dx.doi.org/10.1016/S0091-6749(99)70175-2
[30]	Gentile, D.M., Tomlinson, E.S., Maggs, J.L., Park, B.K. and Back, D.J. (1996) Dexamethasone Metabolism by Human liver in Vitro. Metabolite Identification and Inhibition of 6-hydroxylation. The Journal of Pharmacology and Experimental Therapeutics, 277, 105-112.
[31]	Pint, A.G., Wang, Y.H., Chalasani, N., Skaar, T., Kolwankar, D., Gorski, J.C., et al. (2005) Inhibition of Human Intestinal Wall Metabolism by Macrolide Antibiotics: Effect of Clarithromycin on Cytochrome P450 3A4/5 Activity and Expression. Clinical Pharmacology & Therapeutics, 77, 178-188. http://dx.doi.org/10.1016/j.clpt.2004.10.002
[32]	Ishimatsu, Y., Kadota, J., Iwashita, T., Nagata, T., Ishii, H., Shikuwa, C., et al. (2004) Macrolide Antibiotics Induce Apoptosis of Human Peripheral Lymphocytes in Vitro. International Journal of Antimicrobial Agents, 24, 247-253. http://dx.doi.org/10.1016/j.ijantimicag.2004.03.022
[33]	Mizunoe, S., Kadota, J., Tokimatsu, I., Kishi, K., Nagai, H. and Nasu, M. (2004) Clarithromycin and Azithromycicn Induce Apoptosis of Activated Lymphocytes via Down-Regulation of Bcl-xL. International Immunopharmacology, 4, 1201-1207. http://dx.doi.org/10.1016/j.intimp.2004.05.011
[34]	Nakamura, M., Kikukawa, Y., Takeya, M., Mitsuya, H. and Hata, H. (2010) Clarithromycicn Attenuates Autophagy in Myeloma Cells. International Journal of Oncology, 37, 815-820.
[35]	Moreau, P., Huynh, A., Facon, T., Bouilly, I., Sotto, J.J., Legros, L., et al. (1999) Lack of Efficacy of Clarithromycin in Advanced Multiple Myeloma. Leukemia, 13, 490-491. http://dx.doi.org/10.1038/sj.leu.2401332
[36]	Musto, P., Falcone, A., Sanpaolo, G., Bodenizza, C., Carotenuto, M. and Carella, A.M. (2002) Inefficacy of Clarithromycic in Advanced Multiple Myeloma: A Definitive Report. Haematologica, 87, 658-659. http://www.haematologica.ws/2002_06/658.htm
[37]	Stewart, A.K., Trudel, S., Al-Berouti, B.M., Sutton, D.M. and Meharchand, J. (1999) Lack of Response to Short-Term Use of Clarithromycin (Biaxin) in Multiple Myeloma. Blood, 93, 4441-4449.
[38]	Burger, R. (2013) Impact of Interleukin-6 in Hematological Malignancies. Transfusion Medicine and Hemotherapy, 40, 336-343. http://dx.doi.org/10.1159/000354194
[39]	Marriott, J.B., Clarke, I.A., Dredge, K., Muller, G., Stirling, D. and Dalgleish, A.G. (2002) Thalidomide and Its Analogues Have Distinct and Opposing Effects on TNF-α and TNFR2 during Co-Stimulation of both CD4+ and CD8+ T Cells. Clinical & Experimental Immunology, 130, 75-84. http://dx.doi.org/10.1046/j.1365-2249.2002.01954.x
[40]	Nakamura, N., Kanemura, N., Shibata, Y., Matsumoto, T., Mabuchi, R., Nakamura, H., et al. (2014) Lenalidomide-Induced Cytokine Release Syndrome in a Patient with Multiple Myeloma. Leukemia & Lymphoma, 55, 1691-1693. http://dx.doi.org/10.3109/10428194.2013.853300
[41]	Harada, T., Ozaki, S., Oda, A., Fujii, S., Nakamura, S., Miki, H., et al. (2013) Association of Th1 and Th2 Cytokines with Transient Inflammatory Reaction during Lenalidomide Plus Dexamethasone Therapy in Multiple Myeloma. International Journal of Hematology, 97, 743-748. http://dx.doi.org/10.1007/s12185-013-1321-0
[42]	Morita, Y., Shimada, T., Yamaguchi, T., Rai, S., Hirase, C., Emoto, M., et al. (2011) Cytokine Profiles in Relapsed Multiple Myeloma Patients Undergoing Febrile Reactions to Lenalidomide. International Journal of Hematology, 94, 583-584. http://dx.doi.org/10.1007/s12185-011-0973-x