[en] During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.
Disciplines :
Hematology
Author, co-author :
Ludwig, Heinz
Delforge, Michel
Facon, Thierry
Einsele, Hermann
Gay, Francesca
Moreau, Philippe
Avet-Loiseau, Herve
Boccadoro, Mario
Hajek, Roman
Mohty, Mohamad
Cavo, Michele
Dimopoulos, Meletios A.
San-Miguel, Jesus F.
Terpos, Evangelos
Zweegman, Sonja
Garderet, Laurent
Mateos, Maria-Victoria
Cook, Gordon
Leleu, Xavier
Goldschmidt, Hartmut
Jackson, Graham
Kaiser, Martin
Weisel, Katja
van de Donk, Niels W. C. J.
Waage, Anders
Beksac, Meral
Mellqvist, Ulf H.
Engelhardt, Monika
Caers, Jo ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Multiple Myeloma. Version 1.2018. 2017. https://www.nccn.org/professionals/physician-gls/pdf/myeloma-blocks.pdf. Accessed 03 Oct 2017.
International conference on harmonization of technical requirements for registration of pharmaceuticals for human use. Clinical safety data management: Definitions and standards for expedited reporting. E2A. 1994. http://www.ich.org/fileadmin/Public-Web-Site/ICH-Products/Guidelines/Efficacy/E2A/Step4/E2A-Guideline.pdf. Accessed 5 Dec 2016.
Palumbo A, Rajkumar SV, San Miguel JF, Larocca A, Niesvizky R, Morgan G, et al. International Myeloma Working Group consensus statement for the management, treatment, and supportive care of patients with myeloma not eligible for standard autologous stem-cell transplantation. J Clin Oncol. 2014;32:587-600.
Ludwig H, Miguel JS, Dimopoulos MA, Palumbo A, Garcia Sanz R, Powles R, et al. International Myeloma Working Group recommendations for global myeloma care. Leukemia. 2014;28:981-92.
Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Blade J, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood. 2011;117:6063-73.
Terpos E, Kleber M, Engelhardt M, Zweegman S, Gay F, Kastritis E, et al. European Myeloma Network guidelines for the management of multiple myeloma-related complications. Haematologica. 2015;100:1254-66.
National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections. Version 1.2018. December 1. 2017. https://www.nccn.org/professionals/physician-gls/pdf/infections.pdf. Accessed 11. February 2018.
Snowden JA, Ahmedzai SH, Ashcroft J, D'Sa S, Littlewood T, Low E, et al. Guidelines for supportive care in multiple myeloma 2011. Br J Haematol. 2011;154:76-103.
Dispenzieri A, Lacy MQ, Greipp PR. Multiple myeloma. In: Gertz MA, Greipp PR, editors. Hematologic malignancies: Multiple myeloma and related plasma cell disorders. Berlin Heidelberg: Springer-Verlag; 2004. p. 55-109.
European Medicines Agency. Thalidomide celgene: EPAR-product information. 2015. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/000823/WC500037050.pdf. Accessed 10 Nov 2016.
European Medicines Agency. Revlimid: EPAR-product information. 2017. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/000717/WC500056018.pdf. Accessed 03 Oct 2017.
European Medicines Agency. Imnovid: EPAR-product information. 2017. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/000717/WC500056018.pdf. Accessed 03 Oct 2017.
United States Food and Drug Administration. Thalidomide celgene: Label information. 2015. http://www.accessdata.fda.gov/drugsatfda-docs/label/2015/020785s051lbl.pdf. Accessed 10 Nov 2016.
United States Food and Drug Administration. Revlimid: Label information. 2017. https://www.accessdata.fda.gov/drugsatfda-docs/label/2017/021880s051lbl.pdf. Accessed 03 Oct 2017.
United States Food and Drug Administration. Pomalyst: Label information. 2016. https://www.accessdata.fda.gov/drugsatfda-docs/label/2016/204026s012s014lbl.pdf. Accessed 03 Oct 2017.
Johnson DC, Corthals SL, Walker BA, Ross FM, Gregory WM, Dickens NJ, et al. Genetic factors underlying the risk of thalidomide-related neuropathy in patients with multiple myeloma. J Clin Oncol. 2011;29:797-804.
Glasmacher A, Hahn C, Hoffmann F, Naumann R, Goldschmidt H, von Lilienfeld-Toal M, et al. A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma. Br J Haematol. 2006;132:584-93.
Kapoor P, Rajkumar SV, Dispenzieri A, Gertz MA, Lacy MQ, Dingli D, et al. Melphalan and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: A meta-analysis. Leukemia. 2011;25:689-96.
Palumbo A, Waage A, Hulin C, Beksac M, Zweegman S, Gay F, et al. Safety of thalidomide in newly diagnosed elderly myeloma patients: A meta-analysis of data from individual patients in six randomized trials. Haematologica. 2013;98:87-94.
Mateos MV. Management of treatment-related adverse events in patients with multiple myeloma. Cancer Treat Rev. 2010;36:S24-32.
Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906-17.
Pawlyn C, Khan MS, Muls A, Sriskandarajah P, Kaiser MF, Davies FE, et al. Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment. Blood. 2014;124:2467-8.
Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-69.
Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-91.
McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-81.
Usmani SZ, Sexton R, Hoering A, Heuck CJ, Nair B, Waheed S, et al. Second malignancies in total therapy 2 and 3 for newly diagnosed multiple myeloma: Influence of thalidomide and lenalidomide during maintenance. Blood. 2012;120:1597-1600.
Palumbo A, Bringhen S, Kumar SK, Lupparelli G, Usmani S, Waage A, et al. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: A meta-analysis of individual patient data. Lancet Oncol. 2014;15:333-42.
Jones JR, Cairns DA, Gregory WM, Collett C, Pawlyn C, Sigsworth R, et al. Second malignancies in the context of lenalidomide treatment: An analysis of 2732 myeloma patients enrolled to the Myeloma XI trial. Blood Cancer J. 2016;6:e506.
Chen N, Zhou S, Palmisano M. Clinical pharmacokinetics and pharmacodynamics of lenalidomide. Clin Pharmacokinet. 2017;56:139-52.
European Medicines Agency. Velcade: EPAR-product information. 2016. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/000539/WC500048471.pdf. Accessed 3 Dec 2016.
United States Food and Drug Administration. Velcade: Label information. 2017. https://www.accessdata.fda.gov/drugsatfda-docs/label/2017/021602s043lbl.pdf. Accessed 03 Oct 2017.
European Medicines Agency. Kyprolis: EPAR-product information. 2017. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/003790/WC500197692.pdf. Accessed 03 Oct 2017.
United States Food and Drug Administration. Kyprolis: Label information. 2017. https://www.accessdata.fda.gov/drugsatfda-docs/label/2017/202714s016lbl.pdf. Accessed 03 Oct 2017.
United States Food and Drug Administration. Ninlaro: Label information. 2016. https://www.accessdata.fda.gov/drugsatfda-docs/label/2016/208462s001lbl.pdf. Accessed 03 Oct 2017.
European Medicines Agency. Ninlaro: EPAR-product information. 2017. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/003844/WC500217620.pdf. Accessed 03 Oct 2017.
San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: A multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15:1195-206.
European Medicines Agency. Farydak: EPAR-product information. 2017. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/003725/WC500193298.pdf. Accessed 03 Oct 2017.
United States Food and Drug Administration. Farydak: Label information. 2015. https://www.accessdata.fda.gov/drugsatfda-docs/label/2015/205353s000lbl.pdf. Accessed 03 Oct 2017.
European Medicines Agency. Empliciti: EPAR-product information. 2017. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/003967/WC500206673.pdf. Accessed 3 Oct 2017.
United States Food and Drug Administration. Empliciti: Label information. 2017. https://www.accessdata.fda.gov/drugsatfda-docs/label/2017/761035s005lbl.pdf. Accessed 03 Oct 2017.
European Medicines Agency. Darzalex: EPAR-product information. 2016. http://www.ema.europa.eu/docs/en-GB/document-library/EPAR-Product-Information/human/004077/WC500207296.pdf. Accessed 5 Dec 2016.
United States Food and Drug Administration. Darzalex: Label information. 2017. https://www.accessdata.fda.gov/drugsatfda-docs/label/2017/761036s005lbl.pdf. Accessed 03 Oct 2017.
van de Donk NW, Otten HG, El Haddad O, Axel A, Sasser AK, Croockewit S, et al. Interference of daratumumab in monitoring multiple myeloma patients using serum immunofixation electrophoresis can be abrogated using the daratumumab IFE reflex assay (DIRA). Clin Chem Lab Med. 2016;54:1105-9.
Flores-Montero J, Sanoja-Flores L, Paiva B, Puig N, Garcia-Sanchez O, Bottcher S, et al. Next generation flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. 2017;31:2094-103.
De Stefano V, Za T, Rossi E. Venous thromboembolism in multiple myeloma. Semin Thromb Hemost. 2014;40:338-47.
Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San Miguel J, Barlogie B, et al. Prevention of thalidomide- A nd lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-23.
Nagge J, Crowther M, Hirsh J. Is impaired renal function a contraindication to the use of low-molecular-weight heparin? Arch Intern Med. 2002;162:2605-9.
ten Cate-Hoek AJ, Weitz JI, Gailani D, Meijer K, Philippou H, Bouman AC, et al. Theme 3: Non-invasive management of (recurrent) venous thromboembolism (VTE) and post thrombotic syndrome (PTS). Thromb Res. 2015;136:S13-18.
Delforge M, Blade J, Dimopoulos MA, Facon T, Kropff M, Ludwig H, et al. Treatment-related peripheral neuropathy in multiple myeloma: The challenge continues. Lancet Oncol. 2010;11:1086-95.
Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-25.
Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: A link to clinical adverse events. Clin Cancer Res. 2011;17:2734-43.
Kelly JJ. The evaluation of peripheral neuropathy. Part I: Clinical and laboratory evidence. Rev Neurol Dis. 2004;1:133-40.
Park SB, Goldstein D, Krishnan AV, Lin CS, Friedlander ML, Cassidy J, et al. Chemotherapy-induced peripheral neurotoxicity: A critical analysis. CA Cancer J Clin. 2013;63:419-37.
Richardson PG, Delforge M, Beksac M, Wen P, Jongen JL, Sezer O, et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia. 2012;26:595-608.
Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: A randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-40.
World Health Organization. WHO's cancer pain ladder for adults. 2016. http://www.who.int/cancer/palliative/painladder/en/. Accessed 20 Dec 2016.
Stacey BR. Management of peripheral neuropathic pain. Am J Phys Med Rehabil. 2005;84:S4-16.
Krone A, Reuther P, Fuhrmeister U. Autonomic dysfunction in polyneuropathies: A report on 106 cases. J Neurol. 1983;230:111-21.
Lee WS, Kim DH, Shin SH, Woo SI, Kwan J, Park KS, et al. Complete atrioventricular block secondary to bortezomib use in multiple myeloma. Yonsei Med J. 2011;52:196-8.
Figueroa JJ, Basford JR, Low PA. Preventing and treating orthostatic hypotension: As easy as A, B, C. Cleve Clin J Med. 2010;77:298-306.
Basler M, Lauer C, Beck U, Groettrup M. The proteasome inhibitor bortezomib enhances the susceptibility to viral infection. J Immunol. 2009;183:6145-50.
Advisory Committee for Immunization Practices. Vaccine-specific recommendations. 2016. https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/. Accessed 30 Dec 2016.
The University of Hong Kong. VZV vaccine for hematopoietic stem cell transplantation (VZIDST). 2015. https://clinicaltrials.gov/ct2/show/study/NCT02329457. Accessed 30 Dec 2016.
Stadtmauer EA, Sullivan KM, Marty FM, Dadwal SS, Papanicolaou GA, Shea TC, et al. A phase 1/2 study of an adjuvanted varicella-zoster virus subunit vaccine in autologous hematopoietic cell transplant recipients. Blood. 2014;124:2921-9.
Hata A, Asanuma H, Rinki M, Sharp M, Wong RM, Blume K, et al. Use of an inactivated varicella vaccine in recipients of hematopoietic-cell transplants. N Engl J Med. 2002;347:26-34.
Redman RL, Nader S, Zerboni L, Liu C, Wong RM, Brown BW, et al. Early reconstitution of immunity and decreased severity of herpes zoster in bone marrow transplant recipients immunized with inactivated varicella vaccine. J Infect Dis. 1997;176:578-85.
Hahn M, Schnitzler P, Schweiger B, Kunz C, Ho AD, Goldschmidt H, et al. Efficacy of single versus boost vaccination against influenza virus in patients with multiple myeloma. Haematologica. 2015;100:e285-288.
Teng CJ, Liu HT, Liu CY, Hsih CH, Pai JT, Gau JP, et al. Chronic hepatitis virus infection in patients with multiple myeloma: Clinical characteristics and outcomes. Clinics. 2011;66:2055-61.
Sampathkumar P, Drage LA, Martin DP. Herpes zoster (shingles) and postherpetic neuralgia. Mayo Clin Proc. 2009;84:274-80.
MacFarlane LL, Simmons MM, Hunter MH. The use of corticosteroids in the management of herpes zoster. J Am Board Fam Pract. 1998;11:224-8.
Sandherr M, Hentrich M, von Lilienfeld-Toal M, Massenkeil G, Neumann S, Penack O, et al. Antiviral prophylaxis in patients with solid tumours and haematological malignancies-update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). Ann Hematol. 2015;94:1441-50.
Blimark C, Holmberg E, Mellqvist UH, Landgren O, Bjorkholm M, Hultcrantz M, et al. Multiple myeloma and infections: A population-based study on 9253 multiple myeloma patients. Haematologica. 2015;100:107-13.
Teh BW, Harrison SJ, Worth LJ, Spelman T, Thursky KA, Slavin MA. Risks, severity and timing of infections in patients with multiple myeloma: A longitudinal cohort study in the era of immunomodulatory drug therapy. Br J Haematol. 2015;171:100-8.
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-52.
Chapel HM, Lee M, Hargreaves R, Pamphilon DH, Prentice AG. Randomised trial of intravenous immunoglobulin as prophylaxis against infection in plateau-phase multiple myeloma. The UK Group for immunoglobulin replacement therapy in multiple myeloma. Lancet. 1994;343:1059-63.
Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: Systematic review and meta-analysis. Leuk Lymphoma. 2009;50:764-72.
van de Donk NW, Gorgun G, Groen RW, Jakubikova J, Mitsiades CS, Hideshima T, et al. Lenalidomide for the treatment of relapsed and refractory multiple myeloma. Cancer Manag Res. 2012;4:253-68.
Lee MJ, Wickner P, Fanning L, Schlossman R, Richardson P, Laubach J, et al. Lenalidomide desensitization for delayed hypersensitivity reactions in 5 patients with multiple myeloma. Br J Haematol. 2014;167:127-31.
Westergaard H. Bile Acid malabsorption. Curr Treat Options Gastroenterol. 2007;10:28-33.
Andreyev HJ, Davidson SE, Gillespie C, Allum WH, Swarbrick E, et al. Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer. Gut. 2012;61:179-92.
Benson AB 3rd, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA Jr., et al. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J Clin Oncol. 2004;22:2918-26.
Siegel DS, Weisel KC, Dimopoulos MA, Baz R, Richardson P, Delforge M, et al. Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: A pooled analysis of three clinical trials. Leuk Lymphoma. 2016;57:2833-8.
Rosenthal A, Luthi J, Belohlavek M, Kortum KM, Mookadam F, Mayo A, et al. Carfilzomib and the cardiorenal system in myeloma: An endothelial effect? Blood Cancer J. 2016;6:e384.
Dimopoulos MA, Roussou M, Gavriatopoulou M, Psimenou E, Ziogas D, Eleutherakis-Papaiakovou E, et al. Cardiac and renal complications of carfilzomib in patients with multiple myeloma. Blood Adv. 2017;1:449-54.
Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos MA, Hajek R, et al. Phase 3 study (CLARION) of carfilzomib, melphalan, prednisone (KMP) v bortezomib, melphalan, prednisone (VMP) in newly diagnosed multiple myeloma (NDMM). 16th International Myeloma Workshop: New Delhi; 2017. p. 044.
Russell SD, Lyon A, Lenihan DJ, Moreau P, Joshua D, Chng W-J, et al. Serial echocardiographic assessment of patients (Pts) with relapsed multiple myeloma (RMM) receiving carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd): A Substudy of the phase 3 Endeavor trial (NCT01568866). Blood. 2015;126: Abstract 4250.
Jakubowiak AJ, DeCara JM, Mezzi K. Cardiovascular events during carfilzomib therapy for relapsed myeloma: Practical management aspects from two case studies. Hematology. 2017;22:585-91.
Mikhael J. Management of carfilzomib-associated cardiac adverse events. Clin Lymphoma Myeloma Leuk. 2016;16:241-5.
Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015;373:621-31.
Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): An open-label, randomised, phase 2 trial. Lancet. 2016;387:1551-60.
Chari A, Mark TM, Krishnan A, Stockerl-Goldstein K, Usmani SZ, Londhe A, et al. Use of montelukast to reduce infusion reactions in an early access treatment protocol of daratumumab in United States Patients with relapsed or refractory multiple myeloma. ASH: San Diego; 2016. abstract 2142.
Usmani SZ, Nahi H, Mateos M-V, Lokhorst HM, Chari A, Kaufman JL, et al. Open-label, multicenter, dose escalation phase 1b study to assess the subcutaneous delivery of daratumumab in patients (pts) with relapsed or refractory multiple myeloma (PAVO). ASH: San Diego, CA; 2016. abstract 1149.
Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: A global perspective. Biol Blood Marrow Transplant. 2009;15:1143-238.
Cheuk DK, Chiang AK, Lee TL, Chan GC, Ha SY. Vaccines for prophylaxis of viral infections in patients with hematological malignancies. Cochrane Database Syst Rev. 2011; CD006505.
Boehmer LM, Waqar SN, Govindan R. Influenza vaccination in patients with cancer: An overview. Oncology. 2010;24:1167-70.
Chlibek R, Bayas JM, Collins H, de la Pinta ML, Ledent E, Mols JF, et al. Safety and immunogenicity of an AS01-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults>=50 years of age. J Infect Dis. 2013;208:1953-61.
Mallet V, van Bommel F, Doerig C, Pischke S, Hermine O, Locasciulli A, et al. Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: Recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5). Lancet Infect Dis. 2016;16: 606-17.
Wanchoo R, Abudayyeh A, Doshi M, Edeani A, Glezerman IG, Monga D, et al. Renal toxicities of novel agents used for treatment of multiple myeloma. Clin J Am Soc Nephrol. 2017;12:176-89.
