Risk and Response-Adapted Treatment in Multiple Myeloma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Lessons from the Past: Consider the Risk at Diagnosis
2.1. Age and Vulnerability
2.2. Aggressive Clinical Presentations
2.3. The Huge Prognostic Value of Cytogenetics
2.4. What Impact on the Choice of Treatment?
3. The Near Future (Tomorrow): Adapt the Strategy to the Response and the MRD
3.1. Induction/Intensification
3.2. Consolidation/Maintenance
3.3. Relapse Treatment
4. In the Long Run (after Tomorrow): A Combined Approach Including Molecular Characteristics?
5. On the Finish Line, the Clinical Pragmatic Approach
Author Contributions
Funding
Conflicts of Interest
References
- Palumbo, A.; Bringhen, S.; Ludwig, H.; Dimopoulos, M.A.; Bladé, J.; Mateos, M.V.; Rosiñol, L.; Boccadoro, M.; Cavo, M.; Lokhorst, H.; et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: A report of the European Myeloma Network (EMN). Blood 2011, 118, 4519–4529. [Google Scholar] [CrossRef]
- Fried, L.P.; Tangen, C.M.; Walston, J.; Newman, A.B.; Hirsch, C.; Gottdiener, J.; Seeman, T.; Tracy, R.; Kop, W.J.; Burke, G.; et al. Frailty in Older AdultsEvidence for a Phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 2001, 56, M146–M157. [Google Scholar] [CrossRef]
- Rockwood, K.; Song, X.; MacKnight, C.; Bergman, H.; Hogan, D.B.; McDowell, I.; Mitnitski, A. A global clinical measure of fitness and frailty in elderly people. CMAJ 2005, 173, 489–495. [Google Scholar] [CrossRef] [Green Version]
- Palumbo, A.; Bringhen, S.; Mateos, M.-V.; Larocca, A.; Facon, T.; Kumar, S.K.; Offidani, M.; McCarthy, P.; Evangelista, A.; Lonial, S.; et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report. Blood 2015, 125, 2068–2074. [Google Scholar] [CrossRef]
- Engelhardt, M.; Domm, A.-S.; Dold, S.M.; Ihorst, G.; Reinhardt, H.; Zober, A.; Hieke, S.; Baayen, C.; Müller, S.J.; Einsele, H.; et al. A concise revised Myeloma Comorbidity Index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients. Haematologica 2017, 102, 910–921. [Google Scholar] [CrossRef] [PubMed]
- Isaacs, A.; Fiala, M.; Tuchman, S.; Wildes, T.M. A comparison of three different approaches to defining frailty in older patients with multiple myeloma. J. Geriatr. Oncol. 2020, 11, 311–315. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bringhen, S.; Mateos, M.V.; Zweegman, S.; Larocca, A.; Falcone, A.P.; Oriol, A.; Rossi, D.; Cavalli, M.; Wijermans, P.; Ria, R.; et al. Age and organ damage correlate with poor survival in myeloma patients: Meta-analysis of 1435 individual patient data from 4 randomized trials. Haematologica 2013, 98, 980–987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fernández de Larrea, C.; Kyle, R.A.; Durie, B.G.M.; Ludwig, H.; Usmani, S.; Vesole, D.H.; Hajek, R.; San Miguel, J.F.; Sezer, O.; Sonneveld, P.; et al. Plasma cell leukemia: Consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia 2013, 27, 780–791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bhutani, M.; Foureau, D.M.; Atrash, S.; Voorhees, P.M.; Usmani, S.Z. Extramedullary multiple myeloma. Leukemia 2020, 34, 1–20. [Google Scholar] [CrossRef]
- Musto, P.; Statuto, T.; Valvano, L.; Grieco, V.; Nozza, F.; Vona, G.; Bochicchio, G.B.; Rocca, F.L.; D’Auria, F. An update on biology, diagnosis and treatment of primary plasma cell leukemia. Expert Rev. Hematol. 2019, 12, 245–253. [Google Scholar] [CrossRef]
- Granell, M.; Calvo, X.; Garcia-Guiñón, A.; Escoda, L.; Abella, E.; Martínez, C.M.; Teixidó, M.; Gimenez, M.T.; Senín, A.; Sanz, P.; et al. Prognostic impact of circulating plasma cells in patients with multiple myeloma: Implications for plasma cell leukemia definition. Haematologica 2017, 102, 1099–1104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ravi, P.; Kumar, S.K.; Roeker, L.; Gonsalves, W.; Buadi, F.; Lacy, M.Q.; Go, R.S.; Dispenzieri, A.; Kapoor, P.; Lust, J.A.; et al. Revised diagnostic criteria for plasma cell leukemia: Results of a Mayo Clinic study with comparison of outcomes to multiple myeloma. Blood Cancer J. 2018, 8, 116. [Google Scholar] [CrossRef] [PubMed]
- Royer, B.; Minvielle, S.; Diouf, M.; Roussel, M.; Karlin, L.; Hulin, C.; Arnulf, B.; Macro, M.; Cailleres, S.; Brion, A.; et al. Bortezomib, Doxorubicin, Cyclophosphamide, Dexamethasone Induction Followed by Stem Cell Transplantation for Primary Plasma Cell Leukemia: A Prospective Phase II Study of the Intergroupe Francophone du Myélome. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2016, 34, 2125–2132. [Google Scholar] [CrossRef] [PubMed]
- Musto, P.; Simeon, V.; Martorelli, M.C.; Petrucci, M.T.; Cascavilla, N.; Di Raimondo, F.; Caravita, T.; Morabito, F.; Offidani, M.; Olivieri, A.; et al. Lenalidomide and low-dose dexamethasone for newly diagnosed primary plasma cell leukemia. Leukemia 2014, 28, 222–225. [Google Scholar] [CrossRef] [PubMed]
- Parrondo, R.D.; Roy, V.; Sher, T.; Alegria, V.; Chanan-Khan, A.A.; Ailawadhi, S. Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review. Case Rep. Hematol. 2020, 2020, 4360926. [Google Scholar] [CrossRef] [PubMed]
- Gavriatopoulou, M.; Musto, P.; Caers, J.; Merlini, G.; Kastritis, E.; van de Donk, N.; Gay, F.; Hegenbart, U.; Hajek, R.; Zweegman, S.; et al. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias. Leukemia 2018, 32, 1883–1898. [Google Scholar] [CrossRef]
- Larsen, J.T.; Chee, C.E.; Lust, J.A.; Greipp, P.R.; Rajkumar, S.V. Reduction in plasma cell proliferation after initial therapy in newly diagnosed multiple myeloma measures treatment response and predicts improved survival. Blood 2011, 118, 2702–2707. [Google Scholar] [CrossRef]
- Garand, R.; Avet-Loiseau, H.; Accard, F.; Moreau, P.; Harousseau, J.L.; Bataille, R. t(11;14) and t(4;14) translocations correlated with mature lymphoplasmacytoid and immature morphology, respectively, in multiple myeloma. Leukemia 2003, 17, 2032–2035. [Google Scholar] [CrossRef]
- Fonseca, R.; Bergsagel, P.L.; Drach, J.; Shaughnessy, J.; Gutierrez, N.; Stewart, A.K.; Morgan, G.; Van Ness, B.; Chesi, M.; Minvielle, S.; et al. International Myeloma Working Group molecular classification of multiple myeloma: Spotlight review. Leukemia 2009, 23, 2210–2221. [Google Scholar] [CrossRef] [Green Version]
- Avet-Loiseau, H.; Durie, B.G.M.; Cavo, M.; Attal, M.; Gutierrez, N.; Haessler, J.; Goldschmidt, H.; Hajek, R.; Lee, J.H.; Sezer, O.; et al. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma: An International Myeloma Working Group collaborative project. Leukemia 2013, 27, 711–717. [Google Scholar] [CrossRef] [Green Version]
- Drach, J.; Ackermann, J.; Fritz, E.; Krömer, E.; Schuster, R.; Gisslinger, H.; DeSantis, M.; Zojer, N.; Fiegl, M.; Roka, S.; et al. Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy. Blood 1998, 92, 802–809. [Google Scholar] [CrossRef]
- Lonial, S.; Dimopoulos, M.; Palumbo, A.; White, D.; Grosicki, S.; Spicka, I.; Walter-Croneck, A.; Moreau, P.; Mateos, M.-V.; Magen, H.; et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2015, 373, 621–631. [Google Scholar] [CrossRef] [Green Version]
- Avet-Loiseau, H.; Attal, M.; Moreau, P.; Charbonnel, C.; Garban, F.; Hulin, C.; Leyvraz, S.; Michallet, M.; Yakoub-Agha, I.; Garderet, L.; et al. Genetic abnormalities and survival in multiple myeloma: The experience of the Intergroupe Francophone du Myélome. Blood 2007, 109, 3489–3495. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thakurta, A.; Ortiz, M.; Blecua, P.; Towfic, F.; Corre, J.; Serbina, N.V.; Flynt, E.; Yu, Z.; Yang, Z.; Palumbo, A.; et al. High subclonal fraction of 17p deletion is associated with poor prognosis in multiple myeloma. Blood 2019, 133, 1217–1221. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Walker, B.A.; Mavrommatis, K.; Wardell, C.P.; Ashby, T.C.; Bauer, M.; Davies, F.; Rosenthal, A.; Wang, H.; Qu, P.; Hoering, A.; et al. A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. Leukemia 2019, 33, 159–170. [Google Scholar] [CrossRef]
- Corre, J.; Perrot, A.; Caillot, D.; Belhadj Merzoug, K.; Hulin, C.; Leleu, X.; Mohty, M.; Facon, T.; Buisson, L.; Do Souto, L.; et al. Del17p without TP53 mutation confers poor prognosis in intensively treated newly diagnosed multiple myeloma patients. Blood 2020. [Google Scholar] [CrossRef] [PubMed]
- Chretien, M.-L.; Corre, J.; Lauwers-Cances, V.; Magrangeas, F.; Cleynen, A.; Yon, E.; Hulin, C.; Leleu, X.; Orsini-Piocelle, F.; Blade, J.-S.; et al. Understanding the role of hyperdiploidy in myeloma prognosis: Which trisomies really matter? Blood 2015, 126, 2713–2719. [Google Scholar] [CrossRef] [Green Version]
- Du, C.; Mao, X.; Xu, Y.; Yan, Y.; Yuan, C.; Du, X.; Liu, J.; Fan, H.; Wang, Q.; Sui, W.; et al. 1q21 gain but not t(4;14) indicates inferior outcomes in multiple myeloma treated with bortezomib. Leuk. Lymphoma 2020, 61, 1201–1210. [Google Scholar] [CrossRef] [PubMed]
- Perrot, A.; Corre, J.; Avet-Loiseau, H. Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside. Am. Soc. Clin. Oncol. Educ. Book 2018, 38, 675–680. [Google Scholar] [CrossRef] [PubMed]
- Hebraud, B.; Leleu, X.; Lauwers-Cances, V.; Roussel, M.; Caillot, D.; Marit, G.; Karlin, L.; Hulin, C.; Gentil, C.; Guilhot, F.; et al. Deletion of the 1p32 region is a major independent prognostic factor in young patients with myeloma: The IFM experience on 1195 patients. Leukemia 2014, 28, 675–679. [Google Scholar] [CrossRef] [PubMed]
- Walker, B.A.; Boyle, E.M.; Wardell, C.P.; Murison, A.; Begum, D.B.; Dahir, N.M.; Proszek, P.Z.; Johnson, D.C.; Kaiser, M.F.; Melchor, L.; et al. Mutational Spectrum, Copy Number Changes, and Outcome: Results of a Sequencing Study of Patients With Newly Diagnosed Myeloma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2015, 33, 3911–3920. [Google Scholar] [CrossRef] [PubMed]
- Palumbo, A.; Avet-Loiseau, H.; Oliva, S.; Lokhorst, H.M.; Goldschmidt, H.; Rosinol, L.; Richardson, P.; Caltagirone, S.; Lahuerta, J.J.; Facon, T.; et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J. Clin. Oncol. 2015, 33, 2863–2869. [Google Scholar] [CrossRef] [PubMed]
- Mikhael, J.R.; Dingli, D.; Roy, V.; Reeder, C.B.; Buadi, F.K.; Hayman, S.R.; Dispenzieri, A.; Fonseca, R.; Sher, T.; Kyle, R.A.; et al. Management of newly diagnosed symptomatic multiple myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin. Proc. 2013, 88, 360–376. [Google Scholar] [CrossRef] [PubMed]
- Sonneveld, P.; Salwender, H.-J.; Van Der Holt, B.; el Jarari, L.; Bertsch, U.; Blau, I.W.; Zweegman, S.; Weisel, K.C.; Vellenga, E.; Pfreundschuh, M.; et al. Bortezomib Induction and Maintenance in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of the HOVON-65/GMMG-HD4 Trial. Blood 2015, 126, 27. [Google Scholar] [CrossRef]
- Neben, K.; Lokhorst, H.M.; Jauch, A.; Bertsch, U.; Hielscher, T.; van der Holt, B.; Salwender, H.; Blau, I.W.; Weisel, K.; Pfreundschuh, M.; et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood 2012, 119, 940–948. [Google Scholar] [CrossRef] [Green Version]
- Stewart, A.K.; Rajkumar, S.V.; Dimopoulos, M.A.; Masszi, T.; Špička, I.; Oriol, A.; Hájek, R.; Rosiñol, L.; Siegel, D.S.; Mihaylov, G.G.; et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 2015, 372, 142–152. [Google Scholar] [CrossRef]
- Moreau, P.; Masszi, T.; Grzasko, N.; Bahlis, N.J.; Hansson, M.; Pour, L.; Sandhu, I.; Ganly, P.; Baker, B.W.; Jackson, S.R.; et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016, 374, 1621–1634. [Google Scholar] [CrossRef]
- Richardson, P.G.; Weller, E.; Lonial, S.; Jakubowiak, A.J.; Jagannath, S.; Raje, N.S.; Avigan, D.E.; Xie, W.; Ghobrial, I.M.; Schlossman, R.L.; et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010, 116, 679–686. [Google Scholar] [CrossRef] [Green Version]
- Gay, F.; Cerrato, C.; Petrucci, M.T.; Zambello, R.; Gamberi, B.; Ballanti, S.; Omedè, P.; Palmieri, S.; Troia, R.; Spada, S.; et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial. JCO 2019, 37, 8002. [Google Scholar] [CrossRef]
- Voorhees, P.M.; Kaufman, J.L.; Laubach, J.P.; Sborov, D.W.; Reeves, B.; Rodriguez, C.; Chari, A.; Silbermann, R.; Costa, L.J.; Anderson, L.D.; et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial. Blood 2020, 136, 936–945. [Google Scholar] [CrossRef]
- Moreau, P.; Attal, M.; Hulin, C.; Arnulf, B.; Belhadj, K.; Benboubker, L.; Béné, M.C.; Broijl, A.; Caillon, H.; Caillot, D.; et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study. Lancet 2019, 394, 29–38. [Google Scholar] [CrossRef]
- Stadtmauer, E.A.; Pasquini, M.C.; Blackwell, B.; Hari, P.; Bashey, A.; Devine, S.; Efebera, Y.; Ganguly, S.; Gasparetto, C.; Geller, N.; et al. Autologous Transplantation, Consolidation, and Maintenance Therapy in Multiple Myeloma: Results of the BMT CTN 0702 Trial. J. Clin Oncol 2019, 37, 589–597. [Google Scholar] [CrossRef] [PubMed]
- Cavo, M.; Gay, F.; Beksac, M.; Pantani, L.; Petrucci, M.T.; Dimopoulos, M.A.; Dozza, L.; van der Holt, B.; Zweegman, S.; Oliva, S.; et al. Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): A multicentre, randomised, open-label, phase 3 study. Lancet Haematol. 2020, 7, e456–e468. [Google Scholar] [CrossRef] [PubMed]
- Nooka, A.K.; Kaufman, J.L.; Muppidi, S.; Langston, A.; Heffner, L.T.; Gleason, C.; Casbourne, D.; Saxe, D.; Boise, L.H.; Lonial, S. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia 2014, 28, 690–693. [Google Scholar] [CrossRef]
- Facon, T.; Mary, J.Y.; Hulin, C.; Benboubker, L.; Attal, M.; Pegourie, B.; Renaud, M.; Harousseau, J.L.; Guillerm, G.; Chaleteix, C.; et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): A randomised trial. Lancet 2007, 370, 1209–1218. [Google Scholar] [CrossRef]
- San Miguel, J.F.; Schlag, R.; Khuageva, N.K.; Dimopoulos, M.A.; Shpilberg, O.; Kropff, M.; Spicka, I.; Petrucci, M.T.; Palumbo, A.; Samoilova, O.S.; et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N. Engl. J. Med. 2008, 359, 906–917. [Google Scholar] [CrossRef] [Green Version]
- Pawlyn, C.; Cairns, D.; Kaiser, M.; Striha, A.; Jones, J.; Shah, V.; Jenner, M.; Drayson, M.; Owen, R.; Gregory, W.; et al. The relative importance of factors predicting outcome for myeloma patients at different ages: Results from 3894 patients in the Myeloma XI trial. Leukemia 2020, 34, 604–612. [Google Scholar] [CrossRef] [Green Version]
- O’Donnell, E.K.; Laubach, J.P.; Yee, A.J.; Chen, T.; Huff, C.A.; Basile, F.G.; Wade, P.M.; Paba-Prada, C.E.; Ghobrial, I.M.; Schlossman, R.L.; et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br. J. Haematol. 2018, 182, 222–230. [Google Scholar] [CrossRef]
- Mateos, M.-V.; Dimopoulos, M.A.; Cavo, M.; Suzuki, K.; Jakubowiak, A.; Knop, S.; Doyen, C.; Lucio, P.; Nagy, Z.; Kaplan, P.; et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N. Engl. J. Med. 2018, 378, 518–528. [Google Scholar] [CrossRef]
- Facon, T.; Kumar, S.; Plesner, T.; Orlowski, R.Z.; Moreau, P.; Bahlis, N.; Basu, S.; Nahi, H.; Hulin, C.; Quach, H.; et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N. Engl. J. Med. 2019, 380, 2104–2115. [Google Scholar] [CrossRef]
- Kumar, S.K.; Dispenzieri, A.; Lacy, M.Q.; Gertz, M.A.; Buadi, F.K.; Pandey, S.; Kapoor, P.; Dingli, D.; Hayman, S.R.; Leung, N.; et al. Continued improvement in survival in multiple myeloma: Changes in early mortality and outcomes in older patients. Leukemia 2014, 28, 1122–1128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pozzi, S.; Marcheselli, L.; Bari, A.; Liardo, E.V.; Marcheselli, R.; Luminari, S.; Quaresima, M.; Cirilli, C.; Ferri, P.; Federico, M.; et al. Survival of multiple myeloma patients in the era of novel therapies confirms the improvement in patients younger than 75 years: A population-based analysis. Br. J. Haematol. 2013, 163, 40–46. [Google Scholar] [CrossRef] [PubMed]
- Gay, F.; Larocca, A.; Wijermans, P.; Cavallo, F.; Rossi, D.; Schaafsma, R.; Genuardi, M.; Romano, A.; Liberati, A.M.; Siniscalchi, A.; et al. Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: Analysis of 1175 patients. Blood 2011, 117, 3025–3031. [Google Scholar] [CrossRef] [PubMed]
- Shah, N.; Callander, N.; Ganguly, S.; Gul, Z.; Hamadani, M.; Costa, L.; Sengsayadeth, S.; Abidi, M.; Hari, P.; Mohty, M.; et al. Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Guidelines from the American Society for Blood and Marrow Transplantation. Biol. Blood Marrow Transplant. 2015, 21, 1155–1166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moreau, P.; San Miguel, J.; Sonneveld, P.; Mateos, M.V.; Zamagni, E.; Avet-Loiseau, H.; Hajek, R.; Dimopoulos, M.A.; Ludwig, H.; Einsele, H.; et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2017, 28, iv52–iv61. [Google Scholar] [CrossRef]
- Gay, F.; Engelhardt, M.; Terpos, E.; Wäsch, R.; Giaccone, L.; Auner, H.W.; Caers, J.; Gramatzki, M.; van de Donk, N.; Oliva, S.; et al. From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives. Haematologica 2018, 103, 197–211. [Google Scholar] [CrossRef] [PubMed]
- Jackson, G.H.; Davies, F.E.; Pawlyn, C.; Cairns, D.A.; Striha, A.; Collett, C.; Hockaday, A.; Jones, J.R.; Kishore, B.; Garg, M.; et al. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019, 20, 57–73. [Google Scholar] [CrossRef] [Green Version]
- Goldschmidt, H.; Mai, E.K.; Dürig, J.; Scheid, C.; Weisel, K.C.; Kunz, C.; Bertsch, U.; Hielscher, T.; Merz, M.; Munder, M.; et al. Response-adapted lenalidomide maintenance in newly diagnosed myeloma: Results from the phase III GMMG-MM5 trial. Leukemia 2020, 34, 1853–1865. [Google Scholar] [CrossRef]
- Kumar, S.; Paiva, B.; Anderson, K.C.; Durie, B.; Landgren, O.; Moreau, P.; Munshi, N.; Lonial, S.; Bladé, J.; Mateos, M.-V.; et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016, 17, e328–e346. [Google Scholar] [CrossRef]
- Landgren, O.; Devlin, S.; Boulad, M.; Mailankody, S. Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: A meta-analysis. Bone Marrow Transplant. 2016, 51, 1565–1568. [Google Scholar] [CrossRef] [Green Version]
- Munshi, N.C.; Avet-Loiseau, H.; Rawstron, A.C.; Owen, R.G.; Child, J.A.; Thakurta, A.; Sherrington, P.; Samur, M.K.; Georgieva, A.; Anderson, K.C.; et al. Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis. JAMA Oncol. 2017, 3, 28–35. [Google Scholar] [CrossRef] [PubMed]
- Lahuerta, J.-J.; Paiva, B.; Vidriales, M.-B.; Cordón, L.; Cedena, M.-T.; Puig, N.; Martinez-Lopez, J.; Rosiñol, L.; Gutierrez, N.C.; Martín-Ramos, M.-L.; et al. Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials. J. Clin. Oncol. 2017, 35, 2900–2910. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chakraborty, R.; Muchtar, E.; Kumar, S.K.; Jevremovic, D.; Buadi, F.K.; Dingli, D.; Dispenzieri, A.; Hayman, S.R.; Hogan, W.J.; Kapoor, P.; et al. Impact of Post-Transplant Response and Minimal Residual Disease on Survival in Myeloma with High-Risk Cytogenetics. Biol. Blood Marrow Transplant. 2017, 23, 598–605. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Attal, M.; Lauwers-Cances, V.; Hulin, C.; Leleu, X.; Caillot, D.; Escoffre, M.; Arnulf, B.; Macro, M.; Belhadj, K.; Garderet, L.; et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N. Engl. J. Med. 2017, 376, 1311–1320. [Google Scholar] [CrossRef] [PubMed]
- Perrot, A.; Lauwers-Cances, V.; Corre, J.; Robillard, N.; Hulin, C.; Chretien, M.L.; Dejoie, T.; Maheo, S.; Stoppa, A.M.; Pegourie, B.; et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood 2018, 132, 2456–2464. [Google Scholar] [CrossRef] [Green Version]
- Goicoechea, I.; Puig, N.; Cedena, M.-T.; Burgos, L.; Cordón, L.; Vidriales, M.B.; Flores-Montero, J.; Gutierrez, N.; Calasanz, M.J.; Martin Ramos, M.-L.; et al. Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard and high risk myeloma. Blood 2020. [Google Scholar] [CrossRef]
- Costa, L.J.; Chhabra, S.; Godby, K.N.; Medvedova, E.; Cornell, R.F.; Hall, A.C.; Silbermann, R.W.; Innis-Shelton, R.; Dhakal, B.; DeIdiaquez, D.; et al. Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd) Induction, Autologous Transplantation and Post-Transplant, Response-Adapted, Measurable Residual Disease (MRD)-Based Dara-Krd Consolidation in Patients with Newly Diagnosed Multiple Myeloma (NDMM). Blood 2019, 134, 860. [Google Scholar] [CrossRef]
- Raje, N.; Berdeja, J.; Lin, Y.; Siegel, D.; Jagannath, S.; Madduri, D.; Liedtke, M.; Rosenblatt, J.; Maus, M.V.; Turka, A.; et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2019, 380, 1726–1737. [Google Scholar] [CrossRef]
- Moreau, P.; Zweegman, S.; Perrot, A.; Hulin, C.; Caillot, D.; Facon, T.; Leleu, X.; Belhadj, K.; Karlin, L.; Benboubker, L.; et al. Evaluation of the Prognostic Value of Positron Emission Tomography-Computed Tomography (PET-CT) at Diagnosis and Follow-up in Transplant-Eligible Newly Diagnosed Multiple Myeloma (TE NDMM) Patients Treated in the Phase 3 Cassiopeia Study: Results of the Cassiopet Companion Study. Blood 2019, 134, 692. [Google Scholar] [CrossRef]
- Mazzotti, C.; Buisson, L.; Maheo, S.; Perrot, A.; Chretien, M.-L.; Leleu, X.; Hulin, C.; Manier, S.; Hébraud, B.; Roussel, M.; et al. Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv. 2018, 2, 2811–2813. [Google Scholar] [CrossRef] [Green Version]
- Rodríguez-Otero, P.; Mateos, M.V.; Martínez-López, J.; Hernández, M.-T.; Ocio, E.M.; Rosiñol, L.; Martínez, R.; Teruel, A.-I.; Gutiérrez, N.C.; Bargay, J.; et al. Predicting long-term disease control in transplant-ineligible patients with multiple myeloma: Impact of an MGUS-like signature. Blood Cancer J. 2019, 9, 36. [Google Scholar] [CrossRef] [PubMed]
- Chapman, M.A.; Lawrence, M.S.; Keats, J.J.; Cibulskis, K.; Sougnez, C.; Schinzel, A.C.; Harview, C.L.; Brunet, J.-P.; Ahmann, G.J.; Adli, M.; et al. Initial genome sequencing and analysis of multiple myeloma. Nature 2011, 471, 467–472. [Google Scholar] [CrossRef] [PubMed]
- Bolli, N.; Avet-Loiseau, H.; Wedge, D.C.; Van Loo, P.; Alexandrov, L.B.; Martincorena, I.; Dawson, K.J.; Iorio, F.; Nik-Zainal, S.; Bignell, G.R.; et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat. Commun. 2014, 5, 2997. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lohr, J.G.; Stojanov, P.; Carter, S.L.; Cruz-Gordillo, P.; Lawrence, M.S.; Auclair, D.; Sougnez, C.; Knoechel, B.; Gould, J.; Saksena, G.; et al. Widespread genetic heterogeneity in multiple myeloma: Implications for targeted therapy. Cancer Cell 2014, 25, 91–101. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Aparicio, S.A.J.R.; Behjati, S.; Biankin, A.V.; Bignell, G.R.; Bolli, N.; Borg, A.; Børresen-Dale, A.-L.; et al. Signatures of mutational processes in human cancer. Nature 2013, 500, 415–421. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Corre, J.; Cleynen, A.; Robiou du Pont, S.; Buisson, L.; Bolli, N.; Attal, M.; Munshi, N.; Avet-Loiseau, H. Multiple myeloma clonal evolution in homogeneously treated patients. Leukemia 2018, 32, 2636–2647. [Google Scholar] [CrossRef] [PubMed]
- Walker, B.A.; Mavrommatis, K.; Wardell, C.P.; Ashby, T.C.; Bauer, M.; Davies, F.E.; Rosenthal, A.; Wang, H.; Qu, P.; Hoering, A.; et al. Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma. Blood 2018, 132, 587–597. [Google Scholar] [CrossRef] [PubMed]
- Andrulis, M.; Lehners, N.; Capper, D.; Penzel, R.; Heining, C.; Huellein, J.; Zenz, T.; von Deimling, A.; Schirmacher, P.; Ho, A.D.; et al. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013, 3, 862–869. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Weinhold, N.; Ashby, C.; Rasche, L.; Chavan, S.S.; Stein, C.; Stephens, O.W.; Tytarenko, R.; Bauer, M.A.; Meissner, T.; Deshpande, S.; et al. Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood 2016, 128, 1735–1744. [Google Scholar] [CrossRef] [PubMed]
- Yordanova, A.; Hose, D.; Neben, K.; Witzens-Harig, M.; Gütgemann, I.; Raab, M.-S.; Moehler, T.; Goldschmidt, H.; Schmidt-Wolf, I.G.H. Sorafenib in patients with refractory or recurrent multiple myeloma. Hematol. Oncol. 2013, 31, 197–200. [Google Scholar] [CrossRef] [PubMed]
- Srkalovic, G.; Hussein, M.A.; Hoering, A.; Zonder, J.A.; Popplewell, L.L.; Trivedi, H.; Mazzoni, S.; Sexton, R.; Orlowski, R.Z.; Barlogie, B. A phase II trial of BAY 43-9006 (sorafenib) (NSC-724772) in patients with relapsing and resistant multiple myeloma: SWOG S0434. Cancer Med. 2014, 3, 1275–1283. [Google Scholar] [CrossRef] [PubMed]
- Udi, J.; Schüler, J.; Wider, D.; Ihorst, G.; Catusse, J.; Waldschmidt, J.; Schnerch, D.; Follo, M.; Wäsch, R.; Engelhardt, M. Potent in vitro and in vivo activity of sorafenib in multiple myeloma: Induction of cell death, CD138-downregulation and inhibition of migration through actin depolymerization. Br. J. Haematol. 2013, 161, 104–116. [Google Scholar] [CrossRef] [PubMed]
- Heuck, C.J.; Jethava, Y.; Khan, R.; van Rhee, F.; Zangari, M.; Chavan, S.; Robbins, K.; Miller, S.E.; Matin, A.; Mohan, M.; et al. Inhibiting MEK in MAPK pathway-activated myeloma. Leukemia 2016, 30, 976–980. [Google Scholar] [CrossRef] [PubMed]
- Khoo, K.H.; Hoe, K.K.; Verma, C.S.; Lane, D.P. Drugging the p53 pathway: Understanding the route to clinical efficacy. Nat. Rev. Drug Discov. 2014, 13, 217–236. [Google Scholar] [CrossRef]
- Touzeau, C.; Maciag, P.; Amiot, M.; Moreau, P. Targeting Bcl-2 for the treatment of multiple myeloma. Leukemia 2018, 32, 1899–1907. [Google Scholar] [CrossRef] [PubMed]
- Dingli, D.; Ailawadhi, S.; Bergsagel, P.L.; Buadi, F.K.; Dispenzieri, A.; Fonseca, R.; Gertz, M.A.; Gonsalves, W.I.; Hayman, S.R.; Kapoor, P.; et al. Therapy for Relapsed Multiple Myeloma: Guidelines From the Mayo Stratification for Myeloma and Risk-Adapted Therapy. Mayo Clin. Proc. 2017, 92, 578–598. [Google Scholar] [CrossRef] [Green Version]
- Moreau, P.; Chanan-Khan, A.; Roberts, A.W.; Agarwal, A.B.; Facon, T.; Kumar, S.; Touzeau, C.; Punnoose, E.A.; Cordero, J.; Munasinghe, W.; et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood 2017, 130, 2392–2400. [Google Scholar] [CrossRef] [Green Version]
- Kumar, S.; Harrison, S.J.; Cavo, M.; De La Rubia, J.; Popat, R.; Gasparetto, C.J.; Hungria, V.; Salwender, H.J.; Suzuki, K.; Kim, I.; et al. A Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. Clin. Lymphoma Myeloma Leuk. 2019, 19, E31. [Google Scholar] [CrossRef]
- Avet-Loiseau, H.; Leleu, X.; Roussel, M.; Moreau, P.; Guerin-Charbonnel, C.; Caillot, D.; Marit, G.; Benboubker, L.; Voillat, L.; Mathiot, C.; et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2010, 28, 4630–4634. [Google Scholar] [CrossRef]
- Abdallah, N.; Rajkumar, S.V.; Greipp, P.; Kapoor, P.; Gertz, M.A.; Dispenzieri, A.; Baughn, L.B.; Lacy, M.Q.; Hayman, S.R.; Buadi, F.K.; et al. Cytogenetic abnormalities in multiple myeloma: Association with disease characteristics and treatment response. Blood Cancer J. 2020, 10, 82. [Google Scholar] [CrossRef]
- Perrot, A.; Lauwers-Cances, V.; Tournay, E.; Hulin, C.; Chretien, M.-L.; Royer, B.; Dib, M.; Decaux, O.; Jaccard, A.; Belhadj, K.; et al. Development and Validation of a Cytogenetic Prognostic Index Predicting Survival in Multiple Myeloma. J. Clin. Oncol. 2019, 37, 1657–1665. [Google Scholar] [CrossRef] [PubMed]
- Avet-Loiseau, H.; Bahlis, N.J.; Chng, W.-J.; Masszi, T.; Viterbo, L.; Pour, L.; Ganly, P.; Palumbo, A.; Cavo, M.; Langer, C.; et al. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood 2017, 130, 2610–2618. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Leleu, X.; Karlin, L.; Macro, M.; Hulin, C.; Garderet, L.; Roussel, M.; Arnulf, B.; Pegourie, B.; Kolb, B.; Stoppa, A.M.; et al. Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood 2015, 125, 1411–1417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hose, D.; Rème, T.; Hielscher, T.; Moreaux, J.; Messner, T.; Seckinger, A.; Benner, A.; Shaughnessy, J.D.; Barlogie, B.; Zhou, Y.; et al. Proliferation is a central independent prognostic factor and target for personalized and risk-adapted treatment in multiple myeloma. Haematologica 2011, 96, 87–95. [Google Scholar] [CrossRef] [Green Version]
- Montesinos, P.; Beckermann, B.M.; Catalani, O.; Esteve, J.; Gamel, K.; Konopleva, M.Y.; Martinelli, G.; Monnet, A.; Papayannidis, C.; Park, A.; et al. MIRROS: A randomized, placebo-controlled, Phase III trial of cytarabine ± idasanutlin in relapsed or refractory acute myeloid leukemia. Future Oncol. 2020, 16, 807–815. [Google Scholar] [CrossRef]
- Vadakekolathu, J.; Lai, C.; Reeder, S.; Church, S.E.; Hood, T.; Lourdusamy, A.; Rettig, M.P.; Aldoss, I.; Advani, A.S.; Godwin, J.; et al. TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. Blood Adv. 2020, 4, 5011–5024. [Google Scholar] [CrossRef]
- Heaney, J.L.J.; Campbell, J.P.; Iqbal, G.; Cairns, D.; Richter, A.; Child, J.A.; Gregory, W.; Jackson, G.; Kaiser, M.; Owen, R.; et al. Characterisation of immunoparesis in newly diagnosed myeloma and its impact on progression-free and overall survival in both old and recent myeloma trials. Leukemia 2018, 32, 1727–1738. [Google Scholar] [CrossRef]
- Roussel, M.; Hebraud, B.; Hulin, C.; Perrot, A.; Caillot, D.; Stoppa, A.-M.; Macro, M.; Escoffre, M.; Arnulf, B.; Belhadj, K.; et al. Health-related quality of life results from the IFM 2009 trial: Treatment with lenalidomide, bortezomib, and dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma. Leuk. Lymphoma 2020, 61, 1323–1333. [Google Scholar] [CrossRef]
- Attal, M.; Lauwers-Cances, V.; Marit, G.; Caillot, D.; Moreau, P.; Facon, T.; Stoppa, A.M.; Hulin, C.; Benboubker, L.; Garderet, L.; et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 2012, 366, 1782–1791. [Google Scholar] [CrossRef] [Green Version]
- Dimopoulos, M.A.; Gay, F.; Schjesvold, F.; Beksac, M.; Hajek, R.; Weisel, K.C.; Goldschmidt, H.; Maisnar, V.; Moreau, P.; Min, C.K.; et al. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): A double-blind, randomised, placebo-controlled phase 3 trial. Lancet 2019, 393, 253–264. [Google Scholar] [CrossRef] [Green Version]
- Hulin, C.; Hansen, T.; Heron, L.; Pughe, R.; Streetly, M.; Plate, A.; Perkins, S.; Morgan, K.; Tinel, A.; Rodrigues, F.; et al. Living with the burden of relapse in multiple myeloma from the patient and physician perspective. Leuk. Res. 2017, 59, 75–84. [Google Scholar] [CrossRef] [PubMed]
Clinical–biological presentation | Plasma cell leukemia |
Extramedullary presentation | |
Plasmablastic cytomorphology | |
Cytogenetics | del17p |
t(4;14) | |
t(14;16) | |
t(14;20) | |
del(1p32) | |
Gain of 1q21 (three or more copies) | |
Mutations | TP53 |
Prognostic scores | R-ISS |
IFM multiparametric score | |
mSMART |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Cazaubiel, T.; Mulas, O.; Montes, L.; Schavgoulidze, A.; Avet-Loiseau, H.; Corre, J.; Perrot, A. Risk and Response-Adapted Treatment in Multiple Myeloma. Cancers 2020, 12, 3497. https://doi.org/10.3390/cancers12123497
Cazaubiel T, Mulas O, Montes L, Schavgoulidze A, Avet-Loiseau H, Corre J, Perrot A. Risk and Response-Adapted Treatment in Multiple Myeloma. Cancers. 2020; 12(12):3497. https://doi.org/10.3390/cancers12123497
Chicago/Turabian StyleCazaubiel, Titouan, Olga Mulas, Lydia Montes, Anaïs Schavgoulidze, Hervé Avet-Loiseau, Jill Corre, and Aurore Perrot. 2020. "Risk and Response-Adapted Treatment in Multiple Myeloma" Cancers 12, no. 12: 3497. https://doi.org/10.3390/cancers12123497