1. Introduction
1.1. Multiple Myeloma Revolution: New Drugs
Multiple Myeloma (MM) is still considered an incurable disease in the current literature, although quite a “therapeutic and diagnostic revolution” has happened in last 20 years [ 1 , 2 , 3 ]. This revolution probably started after the pioneer study that found the drug thalidomide to be effective in relapsed/refractory MM patients (RRMM) [ 4 ]. Later, the antiapoptotic and immunomodulatory mechanisms of these drugs (IMIDs) were demonstrated [ 5 , 6 ]. A crucial new concept began to enter hematologists’ minds, i.e., the possibility of novel drugs that act differently from chemotherapy in MM. Drugs that can target not only the monoclonal plasma cell but also the bone marrow microenvironment have been shown to be of importance. Then, the proteasome inhibitor (PI) bortezomib, the second- and third-generation IMIDs lenalidomide and pomalidomide, the second-generation PI carfilzomib, and monoclonal antibodies against CD38, SLAM7, and BCMA were added to the therapeutic armamentarium [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. These drugs, combined in triplets and quadruplets, can increase the depth of response during induction therapy; this is subsequently consolidated with autologous stem cell transplant (ASCT), leading to complete responses (CR) in more than 80% of the newly diagnosed transplant-eligible patients (NDTE) [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Progression-free and overall survival (PFS and OS) have rapidly increased from a median of 2–3 years to 6–8 years [ 2 ]. In addition, particular forms of aggressive myeloma such as extramedullary or high-risk cytogenetic MM can partially benefit from new drugs [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ] and MGRS [ 35 ]. Patients with high-risk features, i.e., del 17p, t 4;14, and 14;16, may benefit from new compounds. These patients usually achieve CR after initial treatment, but they usually experience early relapse. Triplet and quadruplet combinations have demonstrated significative benefits when used in HR patients in many clinical trials [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Additionally, elderly patients can benefit from novel drugs that increase disease responses irrespective of age, but still have less eradicating potential than ASCT [ 36 , 37 , 38 , 39 , 40 , 41 ].
1.2. Minimal Residual Disease
The new concept of minimal residual disease (MRD) was introduced in MM by the Spanish group ten years ago with the intent of measuring, with high sensitivity, the disease after therapy [ 42 , 43 , 44 , 45 , 46 ]. It is not enough nowadays, even in clinical practice, to measure responses only using a bone marrow biopsy. Multi-parametric or Next-Generation Flow (NGF) and Next-Generation Sequencing (NGS) are tools recognized by the International Myeloma Working Group (IMWG) to better define CR [ 47 ]. Sensitivity has been set by the IMWG at 10 −5 but many clinical trials are now moving to 10 −6 . MRD has been proven to be the best surrogate for PFS and OS. All new clinical trials put MRD as an endpoint that can quickly measure the depth of response without the need to wait longer for a follow-up to measure PFS and OS. Sustained MRD negativity at 1 year after therapy is an even better prognosticator [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ]. A recent meta-analysis was reported on >8000 MM patients enrolled in 44 studies. MRD negativity, measured using NGF or NGS, was a surrogate for increased PFS and OS [ 59 ]. In this study, MRD was always predictive of survival at different sensitivity levels of 10 −4 , 10 −5 , and 10 −6 , but the best cut-off was set at 10 −6 . Outside clinical trials, the standard of care in NDTE patients in Europe has become daratumumab, which is associated with bortezomib thalidomide dexamethasone as an induction regimen to ASCT (Dara-VTD). The study CASSIOPEIA led to its approval. In this study, Dara-VTD was compared to VTD in 1086 patients, and MRD negativity was 64% vs. 44%, respectively [ 39 ]. PFS was not reached in the Dara arm vs. 46 months in the VTD arm. Novel triplets and quadruplets are being tested, as is the monoclonal anti-CD38 antibody associated with bortezomib lenalidomide (Dara-VRD, GRIFFIN study, with 51% MRD negativity reported) [ 60 ]. Additionally, in other studies MRD-driven therapy is being investigated, with the potential, in the future, to stop or resume therapy based on the absence or the presence of residual disease, respectively [ 61 ]. MRD is a predictor of survival irrespective of age. In fact, the best treatment regimen in clinical practice outside trials is now daratumumab plus lenalidomide and dexamethasone (Dara-Rd) from the MAIA trial, which showed MRD negativity in 31% vs. 10% in MM patients with Rd >65 years old who were not eligible for transplant. PFS is not reached at 50 months with Dara-Rd vs. 30 months with Rd [ 41 ]. Myeloma is often localized and patchy in the marrow, and limitations may derive from needle aspiration. In the future, peripheral blood could hopefully be considered as a “liquid biopsy” for MRD assessment using new methods such as circulating monoclonal plasma cells, tumor DNA, and mass-spectrometry [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ].
1.3. Imaging
Imaging is very important for disease assessment in MM. In fact, it is essential to detect residual disease outside the bone marrow (extramedullary disease). PET-CT and whole-body MRI have been demonstrated as prognosticators for long-term PFS and OS and have become important tools in routine practice after non-Hodgkin lymphomas lessons [ 71 , 72 , 73 , 74 , 75 , 76 , 77 ]. MM plasma cells can persist after therapy as focal lesions or as diffuse infiltration in the bone representing an incomplete response to therapy. This residual disease could also be a cause of relapse in MM patients. It is recommended by the IMWG criteria to evaluate imaging after therapy to assess the response [ 78 ]. FDG-PET is a functional imaging technique that detects bone disease in MM, and it is optimal for assessing MRD. Imaging combined with MRD detection using NGF or NGS in the bone marrow can provide an even better prognosis. In fact, these techniques combined, when negative, were independent predictors of longer PFS and OS in different randomized clinical trials. Standardization is needed both for PET-CT and MRI and new recommendations have been proposed [ 78 ]. However, new tracers and more sensitive imaging methods are needed since pitfalls may exist.
1.4. Immunotherapy: Bispecific Antibodies and CART
MM is characterized by a high propensity for infections. This is due to a humorally and cellularly defective immune system [ 79 ]. Immune response is also determinant in antitumor activity, and novel therapies are being developed, and some approved, for the treatment of multiple myeloma. Bispecific antibodies (BITEs) that bind myeloma antigens and T-cells have shown significant responses in patients and are multi-refractory to other treatments (PI, IMIDs, and CD38). The anti-BCMA antigen teclistamab, given subcutaneously weekly, led to more than very good partial responses (>VGPR) in 55% of the patients treated with acceptable toxicity [ 80 ]. Erlanatamab is another BITE-targeting BCMA and CD3 that led to overall responses in 83% of RRMM patients who were heavily pretreated [ 81 ]. Talquetamab is an anti-GPRC5D BITE that has been evaluated and gave VGPR in 53% of the patients treated [ 82 ]. CART cell therapy is a new cellular immunotherapy that specifically binds to a myeloma antigen (BCMA) and led to a high overall response rate (64–97%) in heavily pretreated MM patients. Manufacturing time and failures of CART infusion are limitations that need to be ameliorated. Strategies that also consider the timing of CART infusion are being studied [ 83 , 84 , 85 ].
2. Conclusions
The survival progress in MM is evident and patients’ quality of life is being ameliorated. A large number of patients are reaching MRD negativity after therapy. How long this MRD negative status will last is an open question. New therapies and new flow and molecular methods for residual disease detection and imaging will help to better manage patients. Immunotherapies such as BITEs and CART are the new “Kids on the block” and promise to help reach and maintain deep responses. Altogether, these tools will help MM patients to become disease-free and, hopefully, cured.
Acknowledgments
We acknowledge all the patients and staff at the department of Hematology, University of Siena.
Author Contributions
A.G., conceptualization and writing; M.B., writing and supervision. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Funding Statement
This research received no external funding.
Footnotes
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
1. Brenner H., Gondos A., Pulte D. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood. 2008;111:2521–2526. doi: 10.1182/blood-2007-08-104984.
2. Kumar S.K., Rajkumar S.V., Dispenzieri A., Lacy M.Q., Hayman S.R., Buadi F.K., Zeldenrust S.R., Dingli D., Russell S.J., Lust J.A., et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516–2520. doi: 10.1182/blood-2007-10-116129.
3. Gozzetti A., Candi V., Papini G., Bocchia M. Therapeutic Advancements in Multiple Myeloma. Front. Oncol. 2014;4:241. doi: 10.3389/fonc.2014.00241.
4. Singhal S., Mehta J., Desikan R., Ayers D., Roberson P., Eddlemon P., Munshi N., Anaissie E., Wilson C., Dhodapkar M., et al. Antitumor Activity of Thalidomide in Refractory Multiple Myeloma. N. Engl. J. Med. 1999;341:1565–1571. doi: 10.1056/nejm199911183412102.
5. Zhu Y.X., Braggio E., Shi C.-X., Bruins L.A., Schmidt J.E., Van Wier S., Chang X.-B., Bjorklund C.C., Fonseca R., Bergsagel P.L., et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood. 2011;118:4771–4779. doi: 10.1182/blood-2011-05-356063.
6. Zhu Y.X., Braggio E., Shi C.-X., Kortuem K.M., Bruins L.A., Schmidt J.E., Chang X.-B., Langlais P., Luo M., Jedlowski P., et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood. 2014;124:536–545. doi: 10.1182/blood-2014-02-557819.
7. Hideshima T., Richardson P., Chauhan D., Palombella V.J., Elliott P.J., Adams J., Anderson K.C. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 2001;61:3071–3076.
8. Orlowski R.Z., Stinchcombe T.E., Mitchell B.S., Shea T.C., Baldwin A.S., Stahl S., Adams J., Esseltine D.-L., Elliott P.J., Pien C.S., et al. Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies. J. Clin. Oncol. 2002;20:4420–4427. doi: 10.1200/jco.2002.01.133.
9. Hideshima T., Chauhan D., Hayashi T., Akiyama M., Mitsiades N., Mitsiades C., Podar K., Munshi N.C., Richardson P.G., Anderson K.C. Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene. 2003;22:8386–8393. doi: 10.1038/sj.onc.1207170.
10. Ocio E.M., Richardson P.G., Rajkumar S.V., Palumbo A., Mateos M.V., Orlowski R., Kumar S., Usmani S., Roodman D., Niesvizky R., et al. New drugs and novel mechanisms of action in multiple myeloma in 2013: A report from the International Myeloma Working Group (IMWG) Leukemia. 2014;28:525–542. doi: 10.1038/leu.2013.350.
11. Palumbo A., Falco P., Falcone A., Benevolo G., Canepa L., Gay F., Larocca A., Magarotto V., Gozzetti A., Luraschi A., et al. Melphalan, Prednisone, and Lenalidomide for Newly Diagnosed Myeloma: Kinetics of Neutropenia and Thrombocytopenia and Time-to-Event Results. Clin. Lymphoma Myeloma. 2009;9:145–150. doi: 10.3816/clm.2009.n.035.
12. Durie B.G.M., Hoering A., Abidi M.H., Rajkumar S.V., Epstein J., Kahanic S.P., Thakuri M., Reu F., Reynolds C.M., Sexton R., et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet. 2017;389:519–527. doi: 10.1016/s0140-6736(16)31594-x.
13. 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. doi: 10.1056/nejmoa1114138.
14. McCarthy P.L., Owzar K., Hofmeister C.C., Hurd D.D., Hassoun H., Richardson P.G., Giralt S., Stadtmauer E.A., Weisdorf D.J., Vij R., et al. Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma. N. Engl. J. Med. 2012;366:1770–1781. doi: 10.1056/nejmoa1114083.
15. Avet-Loiseau H., Ludwig H., Landgren O., Paiva B., Morris C., Yang H., Zhou K., Ro S., Mateos M.-V. Minimal Residual Disease Status as a Surrogate Endpoint for Progression-free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis. Clin. Lymphoma Myeloma Leuk. 2020;20:e30–e37. doi: 10.1016/j.clml.2019.09.622.
16. Gandolfi S., Prada C.P., Richardson P.G. How I treat the young patient with multiple myeloma. Blood. 2018;132:1114–1124. doi: 10.1182/blood-2017-05-693606.
17. Touzeau C., Moreau P., Dumontet C. Monoclonal antibody therapy in multiple myeloma. Leukemia. 2017;31:1039–1047. doi: 10.1038/leu.2017.60.
18. Gozzetti A., Bacchiarri F., Sammartano V., Defina M., Sicuranza A., Mecacci B., Zappone E., Cencini E., Fabbri A., Raspadori D., et al. Long-Term Safety of Rapid Daratumumab Infusions in Multiple Myeloma Patients. Front. Oncol. 2020;10:570187. doi: 10.3389/fonc.2020.570187.
19. Korde N., Roschewski M., Zingone A., Kwok M., Manasanch E.E., Bhutani M., Tageja N., Kazandjian D., Mailankody S., Wu P., et al. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol. 2015;1:746–754. doi: 10.1001/jamaoncol.2015.2010.
20. Lonial S., Anderson K.C. Association of response endpoints with survival outcomes in multiple myeloma. Leukemia. 2014;28:258–268. doi: 10.1038/leu.2013.220.
21. 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. doi: 10.1056/nejmoa1505654.
22. Palumbo A., Chanan-Khan A., Weisel K., Nooka A.K., Masszi T., Beksac M., Spicka I., Hungria V., Munder M., Mateos M.V., et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N. Engl. J. Med. 2016;375:754–766. doi: 10.1056/nejmoa1606038.
23. 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. doi: 10.1056/NEJMoa1411321.
24. Attal M., Lauwers-Cances V., Hulin C., Leleu X., Caillot D., Escoffre M., Arnulf B., Macro M., Belhadj K., Garderet L., et al. IFM 2009 Study. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N. Engl. J. Med. 2017;376:1311–1320. doi: 10.1056/NEJMoa1611750.
25. Luoma S., Anttila P., Säily M., Lundan T., Heiskanen J., Siitonen T., Kakko S., Putkonen M., Ollikainen H., Terävä V., et al. RVD induction and autologous stem cell transplantation followed by lenalidomide maintenance in newly diagnosed multiple myeloma: A phase 2 study of the Finnish Myeloma Group. Ann. Hematol. 2019;98:2781–2792. doi: 10.1007/s00277-019-03815-7.
26. Roussel M., Lauwers-Cances V., Robillard N., Hulin C., Leleu X., Benboubker L., Marit G., Moreau P., Pegourie B., Caillot D., et al. Front-Line Transplantation Program With Lenalidomide, Bortezomib, and Dexamethasone Combination As Induction and Consolidation Followed by Lenalidomide Maintenance in Patients With Multiple Myeloma: A Phase II Study by the Intergroupe Francophone du Myélome. J. Clin. Oncol. 2014;32:2712–2717. doi: 10.1200/jco.2013.54.8164.
27. 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. doi: 10.1016/s2352-3026(20)30099-5.
28. Gozzetti A., Cerase A., Lotti F., Rossi D., Palumbo A., Petrucci M.T., Patriarca F., Nozzoli C., Cavo M., Offidani M., et al. GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) Myeloma Working Party. Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: A retrospective survey of 50 patients. Cancer. 2012;118:1574–1584. doi: 10.1002/cncr.26447.
29. Gozzetti A., Cerase A. Novel Agents in CNS Myeloma Treatment. Central Nerv. Syst. Agents Med. Chem. 2014;14:23–27. doi: 10.2174/1871524914999140818111514.
30. Sammartano V., Cerase A., Venanzi V., Mazzei M.A., Vangone B.E., Gentili F., Chiarotti I., Bocchia M., Gozzetti A. Central Nervous System Myeloma and Unusual Extramedullary Localizations: Real Life Practical Guidance. Front. Oncol. 2022;12:934240. doi: 10.3389/fonc.2022.934240.
31. Castillo J.J., Jurczyszyn A., Brozova L., Crusoe E., Czepiel J., Davila J., Dispenzieri A., Eveillard M., Fiala M.A., Ghobrial I.M., et al. IgM myeloma: A multicenter retrospective study of 134 patients. Am. J. Hematol. 2017;92:746–751. doi: 10.1002/ajh.24753.
32. Jurczyszyn A., Olszewska-Szopa M., Hungria V., Crusoe E., Pika T., Delforge M., Leleu X., Rasche L., Nooka A.K., Druzd-Sitek A., et al. Cutaneous involvement in multiple myeloma: A multi-institutional retrospective study of 53 patients. Leuk. Lymphoma. 2015;57:2071–2076. doi: 10.3109/10428194.2015.1128542.
33. Jurczyszyn A., Radocha J., Davila J., Fiala M.A., Gozzetti A., Grzasko N., Robak P., Hus I., Waszczuk-Gajda A., Kazimierczak R.G., et al. Prognostic indicators in primary plasma cell leukaemia: A multicentre retrospective study of 117 patients. Br. J. Haematol. 2018;180:831–839. doi: 10.1111/bjh.15092.
34. Avivi I., Cohen Y.C., Suska A., Shragai T., Mikala G., Garderet L., Seny G.M., Glickman S., Jayabalan D.S., Niesvizky R., et al. Hematogenous extramedullary relapse in multiple myeloma—A multicenter retrospective study in 127 patients. Am. J. Hematol. 2019;94:1132–1140. doi: 10.1002/ajh.25579.
35. Gozzetti A., Guarnieri A., Zamagni E., Zakharova E., Coriu D., Bittrich M., Pika T., Tovar N., Schutz N., Ciofini S., et al. Monoclonal gammopathy of renal significance (MGRS): Real-world data on outcomes and prognostic factors. Am. J. Hematol. 2022;97:877–884. doi: 10.1002/ajh.26566.
36. Martín-Mateos M.-L., Oriol A., Martinez-Lopez J., Teruel A.-I., De La Guía A.L., López J., Bengoechea E., Pérez M., Martínez R., Palomera L., et al. GEM2005 trial update comparing VMP/VTP as induction in elderly multiple myeloma patients: Do we still need alkylators? Blood. 2014;124:1887–1893. doi: 10.1182/blood-2014-05-573733.
37. Spencer A.U., Lentzsch S., Weisel K., Avet-Loiseau H., Mark T.M., Spicka I., Masszi T., Lauri B., Levin M.-D., Bosi A. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: Updated analysis of CASTOR. Haematologica. 2018;103:2079–2087. doi: 10.3324/haematol.2018.194118.
38. Dimopoulos M.A., San-Miguel J., Belch A., White D., Benboubker L., Cook G., Leiba M., Morton J., Ho P.J., Kim K., et al. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: Updated analysis of POLLUX. Haematologica. 2018;103:2088–2096. doi: 10.3324/haematol.2018.194282.
39. 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. doi: 10.1016/S0140-6736(19)31240-1.
40. Mills J.R., Barnidge D.R., Dispenzieri A., Murray D.L. High sensitivity blood-based M-protein detection in sCR patients with multiple myeloma. Blood Cancer J. 2017;7:e590. doi: 10.1038/bcj.2017.75.
41. 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. doi: 10.1056/NEJMoa1817249.
42. Paiva B.D.L., Gutierrez N., Rosiñol L., Vidriales M.-B., Montalbán M., Martínez-López J., Mateos M.-V., Cibeira M.-T., Cordón L., Oriol A., et al. High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 2012;119:687–691. doi: 10.1182/blood-2011-07-370460.
43. Flores-Montero J., Sanoja-Flores L., Paiva B., Puig N., García-Sánchez O., Böttcher S., Van Der Velden V.H.J., Pérez-Morán J.-J., Vidriales M.-B., García-Sanz R., et al. Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. 2017;31:2094–2103. doi: 10.1038/leu.2017.29.
44. Arroz M., Came N., Lin P., Chen W., Yuan C., Lagoo A., Monreal M., de Tute R., Vergilio J.-A., Rawstron A.C., et al. Consensus guidelines on plasma cell myeloma minimal residual disease analysis and reporting. Cytom. Part B Clin. Cytom. 2015;90:31–39. doi: 10.1002/cyto.b.21228.
45. Gozzetti A., Raspadori D., Bacchiarri F., Sicuranza A., Pacelli P., Ferrigno I., Tocci D., Bocchia M. Minimal Residual Disease in Multiple Myeloma: State of the Art and Applications in Clinical Practice. J. Pers. Med. 2020;10:120. doi: 10.3390/jpm10030120.
46. Landgren O., Rajkumar S.V. New Developments in Diagnosis, Prognosis, and Assessment of Response in Multiple Myeloma. Clin. Cancer Res. 2016;22:5428–5433. doi: 10.1158/1078-0432.CCR-16-0866.
47. 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. doi: 10.1016/S1470-2045(16)30206-6.
48. Bai Y., Orfao A., Chim C. Molecular detection of minimal residual disease in multiple myeloma. Br. J. Haematol. 2018;181:11–26. doi: 10.1111/bjh.15075.
49. Yao Q., Bai Y., Orfao A., Chim C. Standardized Minimal Residual Disease Detection by Next-Generation Sequencing in Multiple Myeloma. Front. Oncol. 2019;9:449. doi: 10.3389/fonc.2019.00449.
50. Korde N., Mailankody S., Roschewski M., Faham M., Kotwaliwale C., Moorhead M., Kwok M.L., Manasanch E.E., Bhutani M., Tageja N., et al. Minimal Residual Disease (MRD) Testing in Newly Diagnosed Multiple myeloma (MM) Patients: A Prospective Head-to-Head Assessment of Cell-Based, Molecular, and Molecular-Imaging Modalities. Blood. 2014;124:2105. doi: 10.1182/blood.V124.21.2105.2105.
51. 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. doi: 10.1182/blood-2018-06-858613.
52. Avet-Loiseau H., Bene M.C., Wuilleme S., Corre J., Attal M., Arnulf B., Garderet L., Macro M., Stoppa A.-M., Delforge M., et al. Concordance of Post-consolidation Minimal Residual Disease Rates by Multiparametric Flow Cytometry and Next-generation Sequencing in CASSIOPEIA. Clin. Lymphoma Myeloma Leuk. 2019;19:e3–e4. doi: 10.1016/j.clml.2019.09.005.
53. Martinez-Lopez J., Lahuerta J.J., Pepin F., González M., Barrio S., Ayala R., Puig N., Montalban M.A., Paiva B.D.L., Weng L., et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014;123:3073–3079. doi: 10.1182/blood-2014-01-550020.
54. Rawstron A.C., Orfao A., Beksac M., Bezdickova L., Brooimans R.A., Bumbea H., Dalva K., Fuhler G., Gratama J., Hose D., et al. European Myeloma Network. Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders. Haematologica. 2008;93:431–438. doi: 10.3324/haematol.11080.
55. Gupta R., Bhaskar A., Kumar L., Sharma A., Jain P. Flow Cytometric Immunophenotyping and Minimal Residual Disease Analysis in Multiple Myeloma. Am. J. Clin. Pathol. 2009;132:728–732. doi: 10.1309/AJCP1GYI7EHQYUYK.
56. Sanoja-Flores L., Flores-Montero J., Puig N., Contreras-Sanfeliciano T., Pontes R., Corral-Mateos A., García-Sánchez O., Díez-Campelo M., De Magalhães R.J.P., García-Martín L., et al. Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy. Blood. 2019;134:2218–2222. doi: 10.1182/blood.2019002610.
57. Garcés J.J., Cedena M.T., Puig N., Burgos L., Perez J.J., Cordon L., Flores-Montero J., Sanoja-Flores L., Calasanz M.J., Ortiol A., et al. Circulating Tumor Cells for the Staging of Patients With Newly Diagnosed Transplant-Eligible Multiple Myeloma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2022 doi: 10.1200/JCO.21.01365.
58. Oberle A., Brandt A., Voigtlaender M., Thiele B., Radloff J., Schulenkorf A., Alawi M., Akyüz N., März M., Ford C.T., et al. Monitoring multiple myeloma by next-generation sequencing of V(D)J rearrangements from circulating myeloma cells and cell-free myeloma DNA. Haematologica. 2017;102:1105–1111. doi: 10.3324/haematol.2016.161414.
59. 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. doi: 10.1001/jamaoncol.2016.3160.
60. 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., Jr., et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial. Blood. 2020;136:936–945. doi: 10.1182/blood.2020005288.
61. Landgren O., Giralt S. MRD-driven treatment paradigm for newly diagnosed transplant eligible multiple myeloma patients. Bone Marrow Transplant. 2016;51:913–914. doi: 10.1038/bmt.2016.24.
62. Biancon G., Gimondi S., Vendramin A., Carniti C., Corradini P. Noninvasive Molecular Monitoring in Multiple Myeloma Patients Using Cell-Free Tumor DNA: A pilot study. J. Mol. Diagn. 2018;20:859–870. doi: 10.1016/j.jmoldx.2018.07.006.
63. 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. doi: 10.1182/bloodadvances.2018025197.
64. Landgren O., Owen R.G. Better therapy requires better response evaluation: Paving the way for minimal residual disease testing for every myeloma patient. Cytom. Part B Clin. Cytom. 2016;90:14–20. doi: 10.1002/cyto.b.21273.
65. Munshi N.C., Anderson K.C. Minimal Residual Disease in Multiple Myeloma. J. Clin. Oncol. 2013;31:2523–2526. doi: 10.1200/JCO.2013.49.2124.
66. Mailankody S., Korde N., Lesokhin A.M., Lendvai N., Hassoun H., Stetler-Stevenson M., Landgren O. Minimal residual disease in multiple myeloma: Bringing the bench to the bedside. Nat. Rev. Clin. Oncol. 2015;12:286–295. doi: 10.1038/nrclinonc.2014.239.
67. Rawstron A.C., De Tute R.M., Haughton J., Owen R.G. Measuring disease levels in myeloma using flow cytometry in combination with other laboratory techniques: Lessons from the past 20 years at the Leeds Haematological Malignancy Diagnostic Service. Cytom. Part B Clin. Cytom. 2015;90:54–60. doi: 10.1002/cyto.b.21271.
68. Rawstron A.C., Child J.A., De Tute R.M., Davies F.E., Gregory W.M., Bell S.E., Szubert A.J., Navarro-Coy N., Drayson M.T., Feyler S., et al. Minimal Residual Disease Assessed by Multiparameter Flow Cytometry in Multiple Myeloma: Impact on Outcome in the Medical Research Council Myeloma IX Study. J. Clin. Oncol. 2013;31:2540–2547. doi: 10.1200/JCO.2012.46.2119.
69. Chapman J.R., Thoren K.L. Tracking of low disease burden in multiple myeloma: Using mass spectrometry assays in peripheral blood. Best Pract. Res. Clin. Haematol. 2020;33:101142. doi: 10.1016/j.beha.2020.101142.
70. Usmani S.Z., Mitchell A., Waheed S., Crowley J., Hoering A., Petty N., Brown T., Bartel T., Anaissie E., Van Rhee F., et al. Prognostic implications of serial 18-fluoro-deoxyglucose emission tomography in multiple myeloma treated with total therapy 3. Blood. 2013;121:1819–1823. doi: 10.1182/blood-2012-08-451690.
71. Bartel T.B., Haessler J., Brown T.L.Y., Shaughnessy J.D., Jr., van Rhee F., Anaissie E., Alpe T., Angtuaco E., Walker R., Epstein J., et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114:2068–2076. doi: 10.1182/blood-2009-03-213280.
72. Li H., Li F., Zhou X., Mei J., Song P., An Z., Zhao Q., Guo X., Wang X., Zhai Y. Achieving minimal residual disease-negative by multiparameter flow cytometry may ameliorate a poor prognosis in MM patients with high-risk cytogenetics: A retrospective single-center analysis. Ann. Hematol. 2019;98:1185–1195. doi: 10.1007/s00277-019-03609-x.
73. Jamet B., Zamagni E., Nanni C., Bailly C., Carlier T., Touzeau C., Michaud A.-V., Moreau P., Bodet-Milin C., Kraeber-Bodere F. Functional Imaging for Therapeutic Assessment and Minimal Residual Disease Detection in Multiple Myeloma. Int. J. Mol. Sci. 2020;21:5406. doi: 10.3390/ijms21155406.
74. Zamagni E., Patriarca F., Nanni C., Zannetti B., Englaro E., Pezzi A., Tacchetti P., Buttignol S., Perrone G., Brioli A., et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011;118:5989–5995. doi: 10.1182/blood-2011-06-361386.
75. Moreau P., Attal M., Caillot D., Macro M., Karlin L., Garderet L., Facon T., Benboubker L., Escoffre-Barbe M., Stoppa A.-M., et al. Prospective Evaluation of MRI and PET-CT at Diagnosis and Before Maintenance Therapy in Symptomatic Patients with Multiple Myeloma Included in the IFM/DFCI 2009 Trial. J. Clin. Oncol. 2017;35:2911–2918. doi: 10.1200/JCO.2017.72.2975.
76. Zinzani P.L., Zompatori M., Bendandi M., Battista G., Fanti S., Barbieri E., Gherlinzoni F., Rimondi M.R., Frezza G., Pisi P., et al. Monitoring Bulky Mediastinal Disease with Gallium-67, CT-Scan and Magnetic Resonance Imaging in Hodgkin’s Disease and High-Grade Non-Hodgkin’s Lymphoma. Leuk. Lymphoma. 1996;22:131–135. doi: 10.3109/10428199609051740.
77. Zamagni E., Nanni C., Dozza L., Carlier T., Bailly C., Tacchetti P., Versari A., Chauvie S., Gallamini A., Gamberi B., et al. Standardization of 18F-FDG–PET/CT According to Deauville Criteria for Metabolic Complete Response Definition in Newly Diagnosed Multiple Myeloma. J. Clin. Oncol. 2021;39:116–125. doi: 10.1200/JCO.20.00386.
78. Raje N.S., Anaissie E., Kumar S.K., Lonial S., Martin T., Gertz M.A., Krishnan A., Hari P., Ludwig H., O’Donnell E., et al. Consensus guidelines and recommendations for infection prevention in multiple myeloma: A report from the International Myeloma Working Group. Lancet Haematol. 2022;9:e143–e161. doi: 10.1016/S2352-3026(21)00283-0.
79. Moreau P., Usmani S.Z., Garfall A.L., van de Donk N.W., Nahi H., San-Miguel J., Oriol A., Nooka A.K., Martin T., Rosinol L., et al. Updated Results from MajesTEC-1: Phase 1/2 Study of Teclistamab, a B-Cell Maturation Antigen x CD3 Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma. Blood. 2021;138((Suppl. S1)):896. doi: 10.1182/blood-2021-147915.
80. Sebag M., Raje N.S., Bahlis N.J., Costello C., Dholaria B., Solh M., Levy M.Y., Tomasson M.H., Dube H., Damore M.A., et al. Elranatamab (PF-06863135), a B-Cell Maturation Antigen (BCMA) Targeted CD3-Engaging Bispecific Molecule, for Patients with Relapsed or Refractory Multiple Myeloma: Results from Magnetismm-1. Blood. 2021;138((Suppl. S1)):895. doi: 10.1182/blood-2021-150519.
81. Chari A., Berdeja J.G., Oriol A., Van De Donk N.W.C.J., Rodriguez P., Askari E., Mateos M.-V., Minnema M.C., Verona R., Girgis S., et al. A Phase 1, First-in-Human Study of Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) x CD3 Bispecific Antibody, in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM) Blood. 2020;136:40–41. doi: 10.1182/blood-2020-133873.
82. 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. doi: 10.1056/NEJMoa1817226.
83. Munshi N.C., Anderson L.D., Jr., Shah N., Madduri D., Berdeja J., Lonial S., Raje N., Lin Y., Siegel D., Oriol A., et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N. Engl. J. Med. 2021;384:705–716. doi: 10.1056/NEJMoa2024850.
84. Berdeja J.G., Madduri D., Usmani S.Z., Jakubowiak A., Agha M., Cohen A.D., Stewart A.K., Hari P., Htut M., Lesokhin A. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b/2 open-label study. Lancet. 2021;398:314–324. doi: 10.1016/S0140-6736(21)00933-8.
85. McLellan A.D., Rad S.M.A.H. Chimeric antigen receptor T cell persistence and memory cell formation. Immunol. Cell Biol. 2019;97:664–674. doi: 10.1111/imcb.12254.
Associated Data
Data Availability Statement
Not applicable.