The multiple myeloma treatment landscape: international guideline recommendations and clinical practice in Europe

ABSTRACT Introduction: Guidelines provide recommendations on the management of multiple myeloma (MM), but there are no standard algorithms for the choice and sequencing of treatments. As a result, there is widespread variation in the interpretation and implementation of these guidelines. Areas covered: This review will cover: the real-world data on MM treatment patterns; the approved agents available for the treatment of MM; a comparative summary of the national and international clinical guidelines; a discussion on the impact reimbursement decisions have on treatment availability. Expert commentary: In the future, treatment choices may become even more complex as clonal heterogeneity is better understood in the context of response to treatment, and next-generation agents become available. Although information on real-world practice patterns can provide further guidance, to date, few studies have generated data on patients treated with the newer agents in real-world settings. Furthermore, the translation of guideline recommendations into clinical practice across Europe is inconsistent. Additional real-world data are therefore vital to understanding current clinical practice patterns, so that new agents can be effectively incorporated into existing treatment strategies. Such information may aid the development of better guidance, which will ultimately help to ensure that patients receive the best possible care.

[1]  M. Dimopoulos,et al.  Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. , 2018, Blood.

[2]  H. Goldschmidt,et al.  Improvement in Overall Survival With Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  H. Goldschmidt,et al.  Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. , 2017, The Lancet. Oncology.

[4]  B. Lei,et al.  Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. , 2017 .

[5]  S. Jagannath,et al.  First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: Updated results. , 2017 .

[6]  B. Levine,et al.  B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) for Multiple Myeloma (MM): Initial Safety and Efficacy from a Phase I Study , 2016 .

[7]  P. Sonneveld,et al.  Upfront Single Versus Double Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: An Intergroup, Multicenter, Phase III Study of the European Myeloma Network (EMN02/HO95 MM Trial) , 2016 .

[8]  H. Goldschmidt,et al.  Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. , 2016, The New England journal of medicine.

[9]  M. Delforge,et al.  Multiple myeloma: practice patterns across Europe , 2016, British journal of haematology.

[10]  A. Palumbo,et al.  Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. , 2016, The New England journal of medicine.

[11]  D. Jayne,et al.  SUMMARY OF PRODUCT CHARACTERISTICS , 2014 .

[12]  M. Delforge,et al.  Multiple myeloma: patient outcomes in real‐world practice , 2016, British journal of haematology.

[13]  H. Goldschmidt,et al.  Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. , 2016, Blood.

[14]  B. Pégourié,et al.  VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. , 2016, Blood.

[15]  U. Mellqvist,et al.  Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). , 2016 .

[16]  K. Suryanarayan,et al.  Two phase 3 studies of the oral proteasome inhibitor (PI) ixazomib for multiple myeloma (MM) in the maintenance setting: TOURMALINE-MM3, and -MM4. , 2016 .

[17]  A. Palumbo,et al.  Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. , 2016, The New England journal of medicine.

[18]  J. Snowden,et al.  A Salvage Autologous Stem Cell Transplant (ASCT2) Induces Superior Overall Survival Following Bortezomib-Containing Re-Induction Therapy for Relapsed Multiple Myeloma (MM): Results from the Myeloma X (Intensive) Trial , 2015 .

[19]  N. Munshi,et al.  Autologous Transplantation for Multiple Myeloma in the Era of New Drugs: A Phase III Study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial) , 2015 .

[20]  M. Boccadoro,et al.  Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. , 2015, The Lancet. Oncology.

[21]  A. Palumbo,et al.  Bortezomib-thalidomide-dexamethasone (VTD) is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy prior to autologous stem cell transplantation in multiple myeloma , 2015, Leukemia.

[22]  M. Beksac,et al.  European Myeloma Network Guidelines for the Management of Multiple Myeloma-related Complications , 2015, Haematologica.

[23]  M. Boccadoro,et al.  Outcome of treatment for first versus later relapse in multiple myeloma (MM) in real-world clinical practice: Results from the third interim analysis of the multinational, non-interventional, observational EMMOS study , 2015 .

[24]  K. Ramasamy,et al.  Bendamustine in combination with thalidomide and dexamethasone is a viable salvage option in myeloma relapsed and/or refractory to bortezomib and lenalidomide , 2015, Annals of Hematology.

[25]  K. Anderson,et al.  Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. , 2015, Blood.

[26]  P. Mazza,et al.  "Real world" outcome of lenalidomide plus dexamethasone in the setting of recurrent and refractory multiple myeloma: extended follow-up of a retrospective multicenter study by the "rete ematologica pugliese". , 2015, Leukemia research.

[27]  D. Betticher,et al.  Current status and updated recommendations for diagnosis and treatment of plasma cell myeloma in Switzerland. , 2015, Swiss medical weekly.

[28]  F. Morabito,et al.  Autologous stem cell transplantation in multiple myeloma is not dead but alive and well , 2015, Expert opinion on biological therapy.

[29]  J C Irish,et al.  Adherence to and uptake of clinical practice guidelines: lessons learned from a clinical practice guideline on chemotherapy concomitant with radiotherapy in head-and-neck cancer. , 2015, Current oncology.

[30]  Michael L. Wang,et al.  Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. , 2015, The New England journal of medicine.

[31]  Hans Erik Johnsen,et al.  International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. , 2014, The Lancet. Oncology.

[32]  G. Morgan,et al.  GUIDELINES FOR THE DIAGNOSIS AND MANAGEMENT OF MULTIPLE MYELOMA 2014 , 2014 .

[33]  M. Beksac,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. , 2014, The Lancet. Oncology.

[34]  M. Boccadoro,et al.  Autologous transplantation and maintenance therapy in multiple myeloma. , 2014, The New England journal of medicine.

[35]  Christian Jacques,et al.  Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. , 2014, The New England journal of medicine.

[36]  M. Drayson,et al.  High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. , 2014, The Lancet. Oncology.

[37]  M. Dimopoulos,et al.  International Myeloma Working Group recommendations for global myeloma care , 2014, Leukemia.

[38]  B. Faiman,et al.  Innovative Agents in Multiple Myeloma , 2014, Journal of the advanced practitioner in oncology.

[39]  T. Chevassut,et al.  The Genetic Architecture of Multiple Myeloma , 2014, Advances in hematology.

[40]  Michele Cavo,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. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  R. Greil,et al.  Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma. , 2014, Blood.

[42]  M. Beksac,et al.  European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma , 2014, Haematologica.

[43]  H. Goldschmidt,et al.  IMWG consensus on risk stratification in multiple myeloma , 2014, Leukemia.

[44]  G. Parmigiani,et al.  Heterogeneity of genomic evolution and mutational profiles in multiple myeloma , 2014, Nature Communications.

[45]  D. Hose,et al.  GMMG MM5 Trial In Newly Diagnosed Multiple Myeloma To Evaluate PAd Vs VCD Induction Prior To High Dose Treatment Followed By Lenalidomide Consolidation and Maintenance – Final Analysis On Induction Therapy , 2013 .

[46]  H. Goldschmidt,et al.  Double Vs Single Autologous Stem Cell Transplantation After Bortezomib-Based Induction Regimens For Multiple Myeloma: An Integrated Analysis Of Patient-Level Data From Phase European III Studies , 2013 .

[47]  S. Chen‐Kiang,et al.  Immunomodulation as a therapeutic strategy in the treatment of multiple myeloma. , 2013, Critical reviews in oncology/hematology.

[48]  H. Goldschmidt,et al.  Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. , 2013, The Lancet. Oncology.

[49]  X. Mao,et al.  Dissecting bortezomib: development, application, adverse effects and future direction. , 2013, Current pharmaceutical design.

[50]  P. Sonneveld,et al.  Real‐world health care costs of relapsed/refractory multiple myeloma during the era of novel cancer agents , 2013, Journal of clinical pharmacy and therapeutics.

[51]  A. Oriol,et al.  Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. , 2012, Blood.

[52]  M. Kersten,et al.  Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[53]  A. Badros,et al.  Role of carfilzomib in the treatment of multiple myeloma , 2012, Expert review of hematology.

[54]  H. Heinzl,et al.  Influence of the American ODAC statement on Austrian bevacizumab prescribing practice for metastatic breast cancer. , 2012, The oncologist.

[55]  H. Goldschmidt,et al.  European perspective on multiple myeloma treatment strategies: update following recent congresses. , 2012, The oncologist.

[56]  M. Boccadoro,et al.  SIE, SIES, GITMO evidence-based guidelines on novel agents (thalidomide, bortezomib, and lenalidomide) in the treatment of multiple myeloma , 2012, Annals of Hematology.

[57]  D. Dingli,et al.  Early versus delayed autologous transplantation after immunomodulatory agents‐based induction therapy in patients with newly diagnosed multiple myeloma , 2012, Cancer.

[58]  P. Sonneveld,et al.  Critical review of economic evaluations in multiple myeloma: an overview of the economic evidence and quality of the methodology. , 2011, European journal of cancer.

[59]  G. Morgan,et al.  Guidelines for the diagnosis and management of multiple myeloma 2011 , 2011, British journal of haematology.

[60]  M. Dimopoulos,et al.  International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. , 2011, Blood.

[61]  Hartmut Goldschmidt,et al.  Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. , 2011, Blood.

[62]  D. Koleva,et al.  Healthcare costs of multiple myeloma: an Italian study. , 2011, European journal of cancer care.

[63]  F. Fagnani,et al.  Management of relapsed or refractory multiple myeloma in French hospitals and estimation of associated direct costs: a multi‐centre retrospective cohort study , 2011, Journal of clinical pharmacy and therapeutics.

[64]  M. Baccarani,et al.  Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study , 2010, The Lancet.

[65]  J. Byrd,et al.  Early versus delayed autologous stem cell transplant in patients receiving novel therapies for multiple myeloma , 2010, Leukemia & lymphoma.

[66]  M. Mohty,et al.  Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[67]  P. J. Kennedy,et al.  Clinical practice variation , 2010, The Medical journal of Australia.

[68]  D. Esseltine,et al.  Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. , 2010, Blood.

[69]  H. Goldschmidt,et al.  Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[70]  S. Williamson Patient access schemes for high-cost cancer medicines. , 2010, The Lancet. Oncology.

[71]  Robert A Kyle,et al.  Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. , 2009, Mayo Clinic proceedings.

[72]  M. Dimopoulos,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 , 2009, European journal of haematology.

[73]  N. Conradi,et al.  Direct hospital resource utilization and costs of treating patients with multiple myeloma in Southwest Sweden: a 5-year retrospective analysis. , 2008, Clinical therapeutics.

[74]  Michael Wang,et al.  Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. , 2007, The New England journal of medicine.

[75]  Alessandro Corso,et al.  Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. , 2007, The New England journal of medicine.

[76]  Zab Mosenifar,et al.  Population issues in clinical trials. , 2007, Proceedings of the American Thoracic Society.

[77]  Hartmut Goldschmidt,et al.  Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. , 2005, The New England journal of medicine.

[78]  Y. M. van der Linden,et al.  [Modern treatment methods for multiple myeloma: guidelines from the Dutch Haemato-Oncology Association (HOVON)]. , 2005, Nederlands tijdschrift voor geneeskunde.

[79]  D. Esseltine,et al.  A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma , 2004, British journal of haematology.

[80]  C. Carey United States food and drug administration , 2020 .

[81]  H. Goldschmidt,et al.  Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. , 2016, The Lancet. Oncology.

[82]  S. Esteves,et al.  Efficacy and safety of lenalidomide in relapse/refractory multiple myeloma—Real life experience of a tertiary cancer center , 2014, Annals of Hematology.

[83]  P. L. Bergsagel,et al.  Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. , 2013, Mayo Clinic proceedings.

[84]  E. Hatzimichael,et al.  “Real-world” data on the efficacy and safety of lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group , 2013, Annals of Hematology.

[85]  E. Zamagni,et al.  Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes , 2013, Annals of Hematology.

[86]  M. Naunton Lenalidomide and dexamethasone for multiple myeloma , 2013 .

[87]  A. Stewart Erratum: Management of newly diagnosed symptomatic multiple myeloma: Updated Mayo stratification of myeloma and risk-adapted therapy (mSMART) consensus guidelines 2013 (Mayo Clinic Proceedings (2013) 88:4 (360-376)) , 2013 .

[88]  B. Djulbegovic,et al.  Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. , 2009, Journal of the National Cancer Institute.

[89]  P. Sonneveld,et al.  [Modern treatment methods for multiple myeloma: guidelines from the Dutch Haemato-Oncology Association (HOVON)]. , 2005, Nederlands tijdschrift voor geneeskunde.

[90]  Myeloomwerkgroep Van De Stichting De moderne behandeling van het multipel myeloom : een richtlijn van de Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON) , 2005 .