In Canada, lenalidomide combined with dexamethasone (Len/Dex) is approved for use in relapsed or refractory multiple myeloma (RRMM). Our expert panel sought to provide an up-to-date practical guide on the use of lenalidomide in the managing RRMM within the Canadian clinical setting, including management of common adverse events (AEs). The panel concluded that safe, effective administration of Len/Dex treatment involves the following steps: (1) lenalidomide dose adjustment based on creatinine clearance and the extent of neutropenia or thrombocytopenia, (2) dexamethasone administered at 20–40？mg/week, and (3) continuation of treatment until disease progression or until toxicity persists despite dose reduction. Based on available evidence, the following precautions should reduce the risk of common Len/Dex AEs: (1) all patients treated with Len/Dex should receive thromboprophylaxis, (2) erythropoiesis-stimulating agents (ESAs) should be used cautiously, and (3) females of child-bearing potential and males in contact with such females must use multiple contraception methods. Finally, while Len/Dex can be administered irrespective of prior therapy and in all prognostic subsets, patients with chromosomal deletion 17(p13) have less favorable outcomes with all treatments, including Len/Dex. New directions for the use of lenalidomide in RRMM are also considered. 1. Introduction Multiple myeloma (MM), the second most common hematological malignancy in adults, is associated with various clinical manifestations including anemia, lytic bone lesions, and renal and immune impairments. According to Canadian Cancer statistics, an estimated 2300 Canadians will be diagnosed with MM and 1350 will die from this disease in 2011 [1]. While no cure for MM is available, five-year survival rates have risen substantially in Canada and elsewhere over the last decade, partly due to novel therapies such as thalidomide, bortezomib, and lenalidomide [2, 3]. Nonetheless, regardless of initial treatment, most patients will eventually relapse and require salvage therapy, often consisting of novel agents, alone or in combination. Lenalidomide is an immunomodulatory drug with direct effects on myeloma cells as well as their microenvironment. Early clinical trials with lenalidomide as a single agent in relapsed or refractory MM (RRMM) patients demonstrated its antimyeloma activity [4]. In preclinical studies, the agent has been shown to kill myeloma cells by upregulating certain cyclin-dependent kinase inhibitors and other early response factors [5]. Lenalidomide can also induce apoptosis by
References
[1]
Canadian Cancer Society's Steering Committee on Cancer Statistics, Canadian Cancer Statistics, Canadian Cancer Society, Toronto, ON, 2011.
[2]
S. K. Kumar, S. V. Rajkumar, A. Dispenzieri et al., “Improved survival in multiple myeloma and the impact of novel therapies,” Blood, vol. 111, no. 5, pp. 2516–2520, 2008.
[3]
C. P. Venner, J. M. Connors, H. J. Sutherland et al., “Novel agents improve survival of transplant patients with multiple myeloma including those with high-risk disease defined by early relapse (<12 months),” Leukemia and Lymphoma, vol. 52, no. 1, pp. 34–41, 2011.
[4]
P. Richardson, S. Jagannath, M. Hussein et al., “Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma,” Blood, vol. 114, no. 4, pp. 772–778, 2009.
[5]
A. K. Gandhi, J. Kang, L. Capone et al., “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, vol. 10, no. 2, pp. 155–167, 2010.
[6]
N. Mitsiades, C. S. Mitsiades, V. Poulaki et al., “Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications,” Blood, vol. 99, no. 12, pp. 4525–4530, 2002.
[7]
T. Hideshima, D. Chauhan, Y. Shima et al., “Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy,” Blood, vol. 96, no. 9, pp. 2943–2950, 2000.
[8]
D. Verhelle, L. G. Corral, K. Wong et al., “Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells,” Cancer Research, vol. 67, no. 2, pp. 746–755, 2007.
[9]
A. De Luisi, A. Ferrucci, A. M. L. Coluccia et al., “Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma,” Clinical Cancer Research, vol. 17, no. 7, pp. 1935–1946, 2011.
[10]
V. Kotla, S. Goel, S. Nischal et al., “Mechanism of action of lenalidomide in hematological malignancies,” Journal of Hematology and Oncology, vol. 2, p. 36, 2009.
[11]
F. Davies and R. Baz, “Lenalidomide mode of action: Linking bench and clinical findings,” Blood Reviews, vol. 24, supplement 1, pp. S13–S19, 2010.
[12]
D. M. Weber, C. Chen, R. Niesvizky et al., “Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America,” The New England Journal of Medicine, vol. 357, no. 21, pp. 2133–2142, 2007.
[13]
M. Dimopoulos, A. Spencer, M. Attal et al., “Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma,” The New England Journal of Medicine, vol. 357, no. 21, pp. 2123–2132, 2007.
[14]
Revlimid Product Monograph. Celgene Inc. July 30, 2011.
[15]
D. Reece, K. W. Song, T. Fu et al., “Influence of cytogenetics in patients with relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone: adverse effect of deletion 17p13,” Blood, vol. 114, no. 3, pp. 522–525, 2009.
[16]
U. Klein, A. Jauch, T. Hielscher et al., “Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone,” Cancer, vol. 117, no. 10, pp. 2136–2144, 2011.
[17]
H. Avet-Loiseau, J. Soulier, J. P. Fermand et al., “Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexaméthasone,” Leukemia, vol. 24, no. 3, pp. 623–628, 2010.
[18]
M. A. Dimopoulos, E. Kastritis, D. Christoulas et al., “Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies,” Leukemia, vol. 24, no. 10, pp. 1769–1778, 2010.
[19]
M. Wang, M. A. Dimopoulos, C. Chen et al., “Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure,” Blood, vol. 112, no. 12, pp. 4445–4451, 2008.
[20]
A. Palumbo, P. Falco, P. Corradini et al., “Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA—Italian Multiple Myeloma Network,” Journal of Clinical Oncology, vol. 25, no. 28, pp. 4459–4465, 2007.
[21]
A. Palumbo, M. Delforge, J. Catalano, et al., “A phase 3 study evaluating the efficacy and safety of lenalidomide combined with melphalan and prednisone in patients >= 65 years with newly diagnosed multiple myeloma (ndmm): continuous use of lenalidomide vs fixed-duration regimens,” Blood, vol. 116, abstract no. 622, 2010.
[22]
A. Palumbo, A. Larocca, P. Falco et al., “Lenalidomide, melphalan, prednisone and thalidomide (RMPT) for relapsed/refractory multiple myeloma,” Leukemia, vol. 24, no. 5, pp. 1037–1042, 2010.
[23]
P. G. Richardson, E. Weller, S. Jagannath et al., “Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma,” Journal of Clinical Oncology, vol. 27, no. 34, pp. 5713–5719, 2009.
[24]
P. G. Richardson, E. Weller, S. Lonial et al., “Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma,” Blood, vol. 116, no. 5, pp. 679–686, 2010.
[25]
D. E. Reece, E. Masih-Khan, A. Khan, et al., “Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide (Revlimid) for the treatment of patients with relapsed and refractory multiple myeloma,” Blood, vol. 116, abstract no. 3055, 2010.
[26]
S. A. Schey, G. J. Morgan, K. Ramasamy et al., “The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study,” British Journal of Haematology, vol. 150, no. 3, pp. 326–333, 2010.
[27]
S. K. Kumar, I. Flinn, S. J. Noga et al., “Bortezomib, dexamethasone, cyclophosphamide and lenalidomide combination for newly diagnosed multiple myeloma: phase 1 results from the multicenter EVOLUTION study,” Leukemia, vol. 24, no. 7, pp. 1350–1356, 2010.
[28]
S. K. Kumar, M. Q. Lacy, S. R. Hayman et al., “Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial,” American Journal of Hematology, vol. 86, no. 8, pp. 640–645, 2011.
[29]
A. J. Jakubowiak, K. A. Griffith, D. E. Reece et al., “Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 multiple myeloma research consortium trial,” Blood, vol. 118, no. 3, pp. 535–543, 2011.
[30]
S. V. Rajkumar, S. Jacobus, N. S. Callander et al., “Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial,” The Lancet Oncology, vol. 11, no. 1, pp. 29–37, 2010.
[31]
A. Palumbo, R. Hajek, M. Delforge, et al., “Continuous lenalidomide treatment for newly diagnosed multiple myeloma,” Blood, vol. 366, pp. 1759–1769, 2012.
[32]
A. Palumbo, F. Cavallo, i. Hardan, et al., “Melphalan/Prednisone/Lenalidomide (MPR) Versus High-Dose Melphalan and Autologous Transplantation (MEL200) in Newly Diagnosed Multiple Myeloma (MM) Patients <65 Years: results of a randomized phase III study,” Blood, vol. 118, abstract no. 3069, 2011.
[33]
M. Attal, V. Cances-Lauwers, G. Marit, et al., “Lenalidomide maintenance treatment after stem-cell transplantation for multiple myeloma,” The New England Journal of Medicine, vol. 366, pp. 1782–1791, 2010.
[34]
P. McCarthy, K. Owzar, and K. Anderson, “Phase III Intergroup study of lenalidomide versus placebo maintenance therapy following single autologous hematopoietic stem cell transplantation (AHSC T) for multiple myeloma: CALGB, 100104,” Blood, vol. 116, abstract no. 37, 2010.
[35]
E. A. Stadtmauer, D. M. Weber, R. Niesvizky et al., “Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma,” European Journal of Haematology, vol. 82, no. 6, pp. 426–432, 2009.
[36]
M. Kleber, G. Ihorst, B. Deschler et al., “Detection of renal impairment as one specific comorbidity factor in multiple myeloma: multicenter study in 198 consecutive patients,” European Journal of Haematology, vol. 83, no. 6, pp. 519–527, 2009.
[37]
J. F. San Miguel, M. Dimopoulos, D. Weber, et al., “Dexamethasone dose adjustments seem to result in better efficacy and improved tolerability in patients with relapsed/refractory multiple myeloma who are treated with lenalidomide/dexamethasone (MM-009/010 sub-analysis),” Blood, vol. 110, abstract no. 2712, 2007.
[38]
A. K. Hsu, H. Quach, T. Tai et al., “The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy,” Blood, vol. 117, no. 5, pp. 1605–1613, 2011.
[39]
J. F. San-Miguel, M. A. Dimopoulos, E. A. Stadtmauer et al., “Effects of lenalidomide and dexamethasone treatment duration on survival in patients with relapsed or refractory multiple myeloma treated with lenalidomide and dexamethasone,” Clinical Lymphoma, Myeloma and Leukemia, vol. 11, no. 1, pp. 38–43, 2011.
[40]
M. Dimopoulos and N. R. Orlowski, “Lenalidomide and dexamethasone (LEN plus DEX) treatment in relapsed/refractory multiple myeloma (RRMM) patients (pts) and risk of second primary malignancies (SPM): analysis of MM-009/010.,” Journal of Clinical Oncology, vol. 29, abstract no. 8009, 2011.
[41]
B. Nair, F. Van Rhee, J. D. Shaughnessy et al., “Superior results of total therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance,” Blood, vol. 115, no. 21, pp. 4168–4173, 2010.
[42]
T. Guglielmelli, S. Bringhen, S. Rrodhe et al., “Previous thalidomide therapy may not affect lenalidomide response and outcome in relapse or refractory multiple myeloma patients,” European Journal of Cancer, vol. 47, no. 6, pp. 814–818, 2011.
[43]
S. Madan, M. Q. Lacy, A. Dispenzieri, et al., “Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma,” Blood, vol. 118, pp. 1763–1765, 2011.
[44]
K. C. Altekruse SF, M. Krapcho, N. Neyman et al., Eds., SEER Cancer Statistics Review, 1975–2007, National Cancer Institute, Bethesda, MD, USA, 2010.
[45]
C. Chen, D. E. Reece, D. Siegel et al., “Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma,” British Journal of Haematology, vol. 146, no. 2, pp. 164–170, 2009.
[46]
J. D. Ishak, M. A. Weber, D. Knight, et al., “Declining rates of adverse events and dose modifications with lenalidomide in combination with dexamethasone,” Blood, vol. 112, abstract no. 3708, 2008.
[47]
S. B. Lonial, R. Swern, A. S. . Weber, et al., “Neutropenia is a predictable and early event in affected patients with relapsed/refractory multiple myeloma treated with lenalidomide in combination with dexamethasone,” Blood, vol. 114, abstract no. 2879, 2009.
[48]
R. Niesvizky, T. Naib, P. J. Christos et al., “Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-na？ve patients undergoing front-line lenalidomide and dexamethasone therapy,” British Journal of Haematology, vol. 138, no. 5, pp. 640–643, 2007.
[49]
S. Kumar, A. Dispenzieri, M. Q. Lacy et al., “Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma,” Leukemia, vol. 21, no. 9, pp. 2035–2042, 2007.
[50]
U. Popat, R. Saliba, R. Thandi et al., “Impairment of filgrastim-induced stem cell mobilization after prior lenalidomide in patients with multiple myeloma,” Biology of Blood and Marrow Transplantation, vol. 15, no. 6, pp. 718–723, 2009.
[51]
A. Nazha, R. Cook, D. T. Vogl et al., “Stem cell collection in patients with multiple myeloma: impact of induction therapy and mobilization regimen,” Bone Marrow Transplantation, vol. 46, no. 1, pp. 59–63, 2011.
[52]
T. Mark, J. Stern, J. R. Furst et al., “Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma,” Biology of Blood and Marrow Transplantation, vol. 14, no. 7, pp. 795–798, 2008.
[53]
I. N. M. Micallef, A. D. Ho, L. M. Klein, S. Marulkar, P. J. Gandhi, and P. A. McSweeney, “Plerixafor (Mozobil) for stem cell mobilization in patients with multiple myeloma previously treated with lenalidomide,” Bone Marrow Transplantation, vol. 46, no. 3, pp. 350–355, 2011.
[54]
R. L. Baz, S. Hussein, M. Swern, et al., “Lenalidomide (LEN) therapy in combination with dexamethasone (DEX) is associated with a low incidence of viral infections,” Blood, vol. 116, abstract no. 1950, 2010.
[55]
M. Carrier, G. Le Gal, J. Tay, C. Wu, and A. Y. Lee, “Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis,” Journal of Thrombosis and Haemostasis, vol. 9, no. 4, pp. 653–663, 2011.
[56]
A. Palumbo, M. Cavo, S. Bringhen et al., “Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial,” Journal of Clinical Oncology, vol. 29, no. 8, pp. 986–993, 2011.
[57]
A. Larocca, F. Cavallo, S. Bringhen, et al., “Aspirin or enoxaparin thromboprophylaxis for newly-diagnosed multiple 11 myeloma patients treated with lenalidomide,” Blood, vol. 119, no. 4, pp. 933–939, 2012.
[58]
H. P. Sviggum, M. D. P. Davis, S. V. Rajkumar, and A. Dispenzieri, “Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma,” Archives of Dermatology, vol. 142, no. 10, pp. 1298–1302, 2006.
[59]
J. Phillips, J. Kujawa, M. Davis-Lorton, and A. Hindenburg, “Successful desensitization in a patient with lenalidomide hypersensitivity,” American Journal of Hematology, vol. 82, no. 11, p. 1030, 2007.
[60]
E. Nucera, D. Schiavino, S. Hohaus et al., “Desensitization to thalidomide in a patient with multiple myeloma,” Clinical Lymphoma and Myeloma, vol. 8, no. 3, pp. 176–178, 2008.
[61]
S. El-Tawil, T. Al Musa, H. Valli, M. P. Lunn, T. El-Tawil, and M. Weber, “Quinine for muscle cramps,” Cochrane database of systematic reviews, vol. 12, Article ID CD005044, 2010.
[62]
R. Zambello, T. Berno, L. Candiotto, et al., “Peripherial neuropathy clinical course during lenalidomide therapy for relapsed/refractory multiple myeloma: a single-centre prospective non interventional study,” Haematologica, vol. 96, abstract no. P-399, 2011.
[63]
C.-M. Wendtner, P. Hillmen, D. Mahadevan, et al., “Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia,” Leukemia and Lymphoma, vol. 53, no. 3, pp. 417–423, 2012.
[64]
C. S. Chim, “Rapid complete remission in multiple myeloma with bortezomib/thalidomide/ dexamethasone combination therapy following development of tumor lysis syndrome,” Cancer Chemotherapy and Pharmacology, vol. 62, no. 1, pp. 181–182, 2008.
[65]
D. J. Leddin, R. Enns, R. Hilsden et al., “Canadian Association of Gastroenterology position statement on screening individuals at average risk for developing colorectal cancer: 2010,” Canadian Journal of Gastroenterology, vol. 24, no. 12, pp. 705–714, 2010.
[66]
J. Izawa, K. L. D. Siemens, et al., “Prostate cancer screening: Canadian guidelines 2011,” Canadian Urological Association Journal, vol. 5, pp. 235–240, 2010.
[67]
S. Hussain, R. Browne, J. Chen, and S. Parekh, “Lenalidomide-induced severe hepatotoxicity,” Blood, vol. 110, no. 10, p. 3814, 2007.
[68]
M. K. Figaro, W. Clayton, C. Usoh et al., “Thyroid abnormalities in patients treated with lenalidomide for hematological malignancies: results of a retrospective case review,” American Journal of Hematology, vol. 86, no. 6, pp. 467–470, 2011.
[69]
F. Gay, S. S. Vincent Rajkumar, P. Falco et al., “Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma,” European Journal of Haematology, vol. 85, no. 3, pp. 200–208, 2010.
[70]
A. J. Jakubowiak, D. Dytfeld, S. Jagannath, et al., “Carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma: initial results of phase I/II MMRC trial,” Blood, vol. 116, abstract no. 862, 2010.
[71]
S. Lentzsch, A. O. 'Sullivan, R. Kennedy, et al., “Combination of bendamustine, lenalidomide, and dexamethasone in patients with refractory or relapsed multiple myeloma is safe and highly effective: results of a phase i clinical trial,” Blood, vol. 116, abstract no. 989, 2010.
[72]
S. Lonial, R. Vij, J. L. Harousseau, et al., “Elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma: interim results of a phase 1 study,” Blood, vol. 116, abstract no. 1936, 2010.
[73]
A. Palumbo, P. Falco, A. Falcone et al., “Melphalan, prednisone, and lenalidomide for newly diagnosed myeloma: kinetics of neutropenia and thrombocytopenia and time-to-event results,” Clinical Lymphoma and Myeloma, vol. 9, no. 2, pp. 145–150, 2009.
[74]
D. J. White, N. J. Bahlis, D. C. Marcellus, et al., “Phase II testing of lenalidomide plus melphalan for previously untreated older patients with multiple myeloma: the NCIC CTG MY. 11 trial,” Blood, vol. 112, abstract no. 2767, 2008.
[75]
W. Bensinger, M. Wang, R. Z. Orlowski, et al., “Dose-escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) plus low-dose dexamethasone (Dex) (CRd) in relapsed/refractory multiple myeloma (R/R MM),” Journal of Clinical Oncology, vol. 28, abstract no. 8029, 2010.
[76]
C. Chen, F. Baldassarre, S. Kanjeekal, et al., Lenalidomide in Multiple Myeloma, Program in Evidence-Based Care Evidence-Based Series no. 6-5, Cancer Care Ontario, Toronto, Canada, 2012.
