Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†

•This EHA-ESMO Clinical Practice Guideline provides key recommendations on the management of multiple myeloma.•Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe.•Key treatment recommendations are provided for both newly diagnosed myeloma patients and patients with relapsed/refractory disease.•Recommendations for the treatment of plasma cell leukaemia, solitary plasmacytoma and smouldering myeloma are also provided.•Key recommendations for myeloma complications, including bone disease and renal impairment, are included. Incidence and epidemiologyMultiple myeloma (MM) is a plasma cell neoplasm that accounts for 1%-1.8% of all cancers and is the second most common haematological malignancy with an estimated incidence in Europe of 4.5-6.0/100 000/year. Despite the significant improvement in patients' survival over the past 20 years, only 10%-15% of patients achieve or exceed expected survival compared with the matched general population.1Usmani S.Z. Hoering A. Cavo M. et al.Clinical predictors of long-term survival in newly diagnosed transplant eligible multiple myeloma - an IMWG Research Project.Blood Cancer J. 2018; 8: 123Crossref PubMed Scopus (55) Google ScholarDiagnosis and stagingIn 2017, ESMO published clinical practice guidelines for the diagnosis, staging and definitions of progressive disease, relapse and refractoriness to therapy, which have not changed and are summarised in Supplementary Tables S1-S3, available at https://doi.org/10.1016/j.annonc.2020.11.014.2Moreau P. San Miguel J. Sonneveld P. et al.Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv52-iv61Abstract Full Text Full Text PDF PubMed Scopus (451) Google ScholarThe recommendations for the tests that are required for the diagnosis, determination of prognosis and follow-up of MM are described in Table 1.Table 1Recommendations on examinations at diagnosis, response assessment, during follow-up and at relapse of MMAdapted with permission from Caers et al.85Caers J. Garderet L. Kortum K.M. et al.European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when.Haematologica. 2018; 103: 1772-1784Crossref PubMed Scopus (62) Google ScholarToolDiagnosisAt responseAt follow-upAt relapseBloodBlood count and blood smearObligatoryObligatoryObligatoryObligatorySerum electrophoresis and IFObligatoryObligatory (IF for CR confirmation)Obligatory (IF for CR patients)ObligatorySerum-free light chainObligatoryObligatory to confirm sCRObligatoryObligatorySerum immunoglobulin levelsObligatoryObligatoryObligatoryObligatoryRenal and liver function testsObligatoryObligatoryObligatoryObligatoryCalciumObligatoryObligatoryObligatoryObligatoryLactate dehydrogenaseObligatoryObligatoryObligatoryObligatoryAlbumin, β2mObligatoryNot requiredOptionalObligatoryFlow cytometryOptionalNot requiredNot requiredOptionalUrineUrine sample from 24 h urine collection to check for proteinuria and light-chain proteinuriaObligatoryObligatoryObligatoryObligatoryUrine electrophoresis and IF electrophoresisObligatoryObligatory (IF for CR confirmation)Obligatory (IF for CR patients)ObligatoryBone marrowBM cytology and biopsy to confirm plasmacytosis and monoclonalityObligatoryObligatory to confirm CR or for non-secretory MMNot requiredOptional (obligatory for non-secretory disease)NGF or NGS to detect clonal plasma cellsObligatoryObligatory to confirm MRD negativity in CR or sCR patientsEvery 12 months in CR and/or MRD-negative patientsaSustained MRD negativity is supported by IMWG guidelines,3 although it is not fully reimbursed in several countries. In a recent ‘Real-World’ study, MRD assessments were carried out in 139 patients before starting lenalidomide maintenance after ASCT and/or at the achievement of CR, while additional assessments were subsequently carried out on an annual basis until sustained MRD negativity was confirmed. In total, 34.3% of patients who were MRD-positive after induction treatment achieved MRD-negative status during maintenance and ultimately had improved PFS. Sequential MRD assessments identified patients with progressively decreasing MRD levels who also had better PFS outcomes, compared with patients not showing a decreasing pattern of MRD.90OptionalCytogenetics: karyotype and FISH for detection of del17p, t(4;14), t(14;16), ampl 1q/ gain 1q, t(11;14)ObligatoryNot requiredNot requiredObligatory for del17p, ampl 1q/ gain 1q and t(11;14)Advanced techniques: GEP, NGSFor clinical trials use onlyFor clinical trials use onlyFor clinical trials use onlyFor clinical trials use onlyImagingWBLD-CTObligatoryNot requiredWhen symptomatic (or CT of the symptomatic area)ObligatoryPET-CTOptional (it may be carried out instead of WBLD-CT if available)Obligatory to confirm imaging MRDEvery 12 months in bone marrow MRD-negative patientsbRecommended based on panel consensus in order to confirm extramedullary MRD negativity in patients who are MRD-negative in the bone marrow.OptionalWhole-body MRIObligatory in WBLD-CT-negative cases and if PET-CT is not carried outNot requiredWhen symptomaticOptionalASCT, autologous stem cell transplantation; β2m, beta-2 microglobulin; BM, bone marrow; CR, complete response; CT, computed tomography; FISH, fluorescent in situ hybridisation; GEP, gene expression profiling; IF, immunofixation; IMWG, International Myeloma Working Group; MM, multiple myeloma; MRD, minimal residual disease; MRI, magnetic resonance imaging; NGF, next-generation flow cytometry; NGS, next-generation sequencing; PET, positron emission tomography; PFS, progression-free survival; sCR, stringent complete response; WBLD-CT, whole-body low-dose computed tomography.a Sustained MRD negativity is supported by IMWG guidelines,3Kumar S. Paiva B. Anderson K.C. et al.International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.Lancet Oncol. 2016; 17: e328-e346Abstract Full Text Full Text PDF PubMed Scopus (1265) Google Scholar although it is not fully reimbursed in several countries. In a recent ‘Real-World’ study, MRD assessments were carried out in 139 patients before starting lenalidomide maintenance after ASCT and/or at the achievement of CR, while additional assessments were subsequently carried out on an annual basis until sustained MRD negativity was confirmed. In total, 34.3% of patients who were MRD-positive after induction treatment achieved MRD-negative status during maintenance and ultimately had improved PFS. Sequential MRD assessments identified patients with progressively decreasing MRD levels who also had better PFS outcomes, compared with patients not showing a decreasing pattern of MRD.90Alonso R. Cedena M.T. Wong S. et al.Prolonged lenalidomide maintenance therapy improves the depth of response in multiple myeloma.Blood Adv. 2020; 4: 2163-2171Crossref PubMed Scopus (12) Google Scholarb Recommended based on panel consensus in order to confirm extramedullary MRD negativity in patients who are MRD-negative in the bone marrow. Open table in a new tab Response criteria to anti-myeloma therapyOne of the most significant improvements in the response criteria is the introduction of minimal residual disease (MRD) both in the bone marrow (BM) [using either next-generation sequencing or next-generation flow cytometry (NGF)] and outside the BM [using positron emission tomography-computed tomography (PET-CT); imaging MRD].3Kumar S. Paiva B. Anderson K.C. et al.International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma.Lancet Oncol. 2016; 17: e328-e346Abstract Full Text Full Text PDF PubMed Scopus (1265) Google Scholar MRD negativity in the BM in patients who have achieved conventional complete response (CR) consistently correlates with prolonged progression-free survival (PFS) and overall survival (OS) in both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients.4Perrot A. Lauwers-Cances V. Corre J. et al.Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma.Blood. 2018; 132: 2456-2464Crossref PubMed Scopus (216) Google Scholar,5Munshi N.C. Avet-Loiseau H. Rawstron A.C. et al.Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis.JAMA Oncol. 2017; 3: 28-35Crossref PubMed Scopus (325) Google ScholarMRD negativity in the BM, defined as the absence of tumour plasma cells within 1 000 000 BM cells (<10−6) shows the best results for the prediction of both PFS and OS compared with higher cut-off values (i.e. 10−5).4Perrot A. Lauwers-Cances V. Corre J. et al.Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma.Blood. 2018; 132: 2456-2464Crossref PubMed Scopus (216) Google Scholar Outside the BM, PET-CT is able to recognise hypermetabolic areas in approximately 15%-20% of patients with MRD negativity in the BM and is considered the best method for imaging MRD to date.6Cavo M. Terpos E. Nanni C. et al.Role of (18)F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group.Lancet Oncol. 2017; 18: e206-e217Abstract Full Text Full Text PDF PubMed Scopus (286) Google ScholarMRD has been found to be a surrogate endpoint for PFS in patients receiving first-line treatment.7Avet-Loiseau H. Ludwig H. Landgren O. et al.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-e37Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Therefore, MRD may be used as an endpoint to accelerate drug development. The use of MRD to drive treatment decisions is under investigation, e.g. whether maintenance/continuous therapy in MRD-negative patients can be stopped or whether treatment needs to be changed in MRD-positive patients, especially in high-risk MM. The results of several phase III trials in the field will clarify the role of MRD in making decisions about therapy in MM.Front-line therapySmouldering MMPatients with standard- or intermediate-risk smouldering MM (SMM; see Supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2020.11.014) do not need immediate therapy. Myeloma treatment should be initiated according to the International Myeloma Working Group (IMWG) recommendations.8Rajkumar S.V. Dimopoulos M.A. Palumbo A. et al.International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.Lancet Oncol. 2014; 15: e538-548Abstract Full Text Full Text PDF PubMed Scopus (2424) Google Scholar Regarding high-risk SMM, which is recently defined by the ‘20-20-20’ rule (Supplementary Table S4, available at https://doi.org/10.1016/j.annonc.2020.11.014),9Rajkumar S.V. Landgren O. Mateos M.V. Smoldering multiple myeloma.Blood. 2015; 125: 3069-3075Crossref PubMed Scopus (159) Google Scholar two randomised, phase III studies have shown that lenalidomide plays a significant role in prolonging PFS. In the first study, 119 patients with high-risk SMM (before the introduction of the new criteria for the definition of myeloma)8Rajkumar S.V. Dimopoulos M.A. Palumbo A. et al.International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.Lancet Oncol. 2014; 15: e538-548Abstract Full Text Full Text PDF PubMed Scopus (2424) Google Scholar were randomly assigned either to receive treatment with the combination of lenalidomide plus dexamethasone (Rd) for 9 cycles followed by lenalidomide maintenance or to observation. At a median follow-up of 75 months, Rd improved both PFS [median PFS (mPFS) not reached versus 23 months; P < 0.0001] and OS compared with observation [hazard ratio (HR) 0.43; P = 0.024].10Mateos M.V. Hernandez M.T. Giraldo P. et al.Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.N Engl J Med. 2013; 369: 438-447Crossref PubMed Scopus (371) Google Scholar,11Mateos M.V. Hernandez M.T. Giraldo P. et al.Lenalidomide plus dexamethasone versus observation in patients with high-risk smouldering multiple myeloma (QuiRedex): long-term follow-up of a randomised, controlled, phase 3 trial.Lancet Oncol. 2016; 17: 1127-1136Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar However, this study was conducted several years ago and enrolled a number of patients who are considered as having MM according to the revised definition. In the second study,12Lonial S. Jacobus S. Fonseca R. et al.Randomized trial of lenalidomide versus observation in smoldering multiple myeloma.J Clin Oncol. 2020; 38: 1126-1137Crossref PubMed Scopus (98) Google Scholar 182 patients with intermediate- or high-risk SMM were randomly assigned either to receive lenalidomide monotherapy or to observation. At a median follow-up of 35 months, PFS was longer with lenalidomide (HR 0.28; P = 0.002); this result was driven mainly by the high-risk SMM group.12Lonial S. Jacobus S. Fonseca R. et al.Randomized trial of lenalidomide versus observation in smoldering multiple myeloma.J Clin Oncol. 2020; 38: 1126-1137Crossref PubMed Scopus (98) Google Scholar This study has not reported OS advantage for the lenalidomide arm to date. Several phase II studies using daratumumab (Dara) monotherapy,13Landgren C.O. Chari A. Cohen Y.C. et al.Daratumumab monotherapy for patients with intermediate-risk or high-risk smoldering multiple myeloma: a randomized, open-label, multicenter, phase 2 study (CENTAURUS).Leukemia. 2020; 34: 1840-1852Crossref PubMed Scopus (40) Google Scholar isatuximab (Isa) monotherapy or other Rd-based regimens [with elotuzumab (EloRd), or with ixazomib] have shown encouraging results.All the above data suggest that high-risk SMM patients should be encouraged to participate in randomised phase III trials to reveal the best treatment that offers OS advantage. To date, no treatment has been approved for SMM.Newly diagnosed patients who are eligible for high-dose therapy and autologous transplantationFor fit NDMM patients, aged <70 years, without comorbidities, induction followed by high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) and lenalidomide maintenance is the recommended treatment. Two recent phase III trials comparing the use or not of upfront ASCT, after triplet novel agent-based induction, showed that PFS was improved in the upfront ASCT arm.14Cavo M. Gay F. Patriarca F. et al.Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study.Blood. 2017; 130: 401Google Scholar, 15Attal M. Lauwers-Cances V. Hulin C. et al.Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med. 2017; 376: 1311-1320Crossref PubMed Scopus (668) Google Scholar, 16Cavo M. Gay F. Beksac M. 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-e468Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar The first study was conducted by the French Myeloma Study Group and included 700 patients who were randomised to receive induction therapy with 3 cycles of bortezomib, lenalidomide and dexamethasone (VRd) and then consolidation therapy with either 5 additional cycles of VRd or high-dose melphalan (HDM) plus ASCT followed by 2 additional cycles of VRd. Patients in both groups received maintenance therapy with lenalidomide for 1 year. After a median follow-up of 44 months in the VRd-alone group and 43 months in the ASCT group, the mPFS was longer in the ASCT group (50 versus 36 months; P < 0.001). This benefit was observed across all patient subgroups, including advanced Revised International Staging System (R-ISS) and high-risk cytogenetics. OS at 4 years was not different between the ASCT and the non-ASCT groups.15Attal M. Lauwers-Cances V. Hulin C. et al.Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med. 2017; 376: 1311-1320Crossref PubMed Scopus (668) Google ScholarThe second study was conducted by the European Myeloma Network (EMN)—EMN02/HO95 trial—and included 1503 patients who received an induction therapy with 3-4 cycles of bortezomib, cyclophosphamide and dexamethasone (VCD) followed by the first randomisation between bortezomib, melphalan and prednisone (VMP) versus ASCT. A second randomisation to consolidation therapy (2 cycles of VRd) versus no consolidation was carried out after intensification therapy, to be followed by lenalidomide maintenance until progression or toxicity in both arms. With a median follow-up from the first randomisation of 60.3 months, the mPFS was improved with ASCT compared with VMP (56.7 versus 41.9 months; P = 0.0001).16Cavo M. Gay F. Beksac M. 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-e468Abstract Full Text Full Text PDF PubMed Scopus (142) Google ScholarInduction regimenA three-drug combination, including at least bortezomib and dexamethasone, has been the standard of care.2Moreau P. San Miguel J. Sonneveld P. et al.Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2017; 28: iv52-iv61Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar,17Sonneveld P. Goldschmidt H. Rosinol L. et al.Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials.J Clin Oncol. 2013; 31: 3279-3287Crossref PubMed Scopus (203) Google Scholar Bortezomib, thalidomide, dexamethasone (VTD) induction showed better response rates over VCD at the expense of a higher rate of peripheral neuropathy.18Moreau P. Hulin C. Macro M. et al.VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.Blood. 2016; 127: 2569-2574Crossref PubMed Scopus (187) Google Scholar VCD and bortezomib, doxorubicin and dexamethasone (PAd) were equally effective in terms of response but VCD was less toxic.19Mai E.K. Bertsch U. Durig J. et al.Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma.Leukemia. 2015; 29: 1721-1729Crossref PubMed Scopus (109) Google Scholar In single-arm studies, VRd produced high very good partial response (VGPR), CR and MRD negativity rates, as well as prolonged PFS.4Perrot A. Lauwers-Cances V. Corre J. et al.Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma.Blood. 2018; 132: 2456-2464Crossref PubMed Scopus (216) Google Scholar,15Attal M. Lauwers-Cances V. Hulin C. et al.Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med. 2017; 376: 1311-1320Crossref PubMed Scopus (668) Google Scholar,20Rosinol L. Oriol A. Rios R. et al.Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma.Blood. 2019; 134: 1337-1345Crossref PubMed Scopus (106) Google Scholar, 21Voorhees P.M. Kaufman J.L. Laubach J.P. et al.Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.Blood. 2020; 136: 936-945Crossref PubMed Scopus (235) Google Scholar, 22Joseph N.S. Kaufman J.L. Dhodapkar M.V. et al.Long-term follow-up results of lenalidomide, bortezomib, and dexamethasone induction therapy and risk-adapted maintenance approach in newly diagnosed multiple myeloma.J Clin Oncol. 2020; 38: 1928-1937Crossref PubMed Scopus (75) Google Scholar However, there is no direct comparison between VTD with VRd induction before ASCT. There is only an integrated analysis of three randomised trials, presented in abstract form, which showed that VRd produces higher VGPR and MRD negativity rates compared with VTD.23Rosinol L. Hebraud B. Oriol A. et al.Integrated analysis of bortezomib- lenalidomide-dexamethasone vs bortezomib-thalidomide-dexamethasone in transplant-eligible newly diagnosed myeloma.Clin Lymphoma Myeloma Leuk. 2019; 19: E1-E2Abstract Full Text Full Text PDF PubMed Google ScholarThe introduction of monoclonal antibodies (mAbs), and especially of Dara, in the front-line setting has changed the treatment landscape in MM. In the phase III CASSIOPEIA trial, 4 cycles of induction with VTD (n = 542) were compared with 4 cycles of VTD plus Dara (DaraVTD) (n = 543); patients then received a single ASCT followed by consolidation and maintenance.24Moreau P. Attal M. Hulin C. 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: 29-38Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar PFS at 18 months showed the superiority of DaraVTD over VTD (93% versus 85%, P < 0.0001).25Moreau P. Attal M. Hulin C. et al.Phase 3 randomized study of daratumumab + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible newly diagnosed multiple myeloma: CASSIOPEIA Part 1 results.J Clin Oncol. 2019; 37: 8003Crossref Google Scholar The combination of Dara with VRd (DaraVRd) had better results. In the randomised phase II GRIFFIN study, 207 patients were randomly assigned to receive VRd ± Dara induction (4 cycles), ASCT, VRd ± Dara consolidation (2 cycles) and lenalidomide ± Dara maintenance (26 cycles). The 24-month PFS rates were 95.8% for DaraVRd and 89.8% for VRd.21Voorhees P.M. Kaufman J.L. Laubach J.P. et al.Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.Blood. 2020; 136: 936-945Crossref PubMed Scopus (235) Google ScholarThe substitution of bortezomib with the second-generation proteasome inhibitor (PI) carfilzomib (K) resulted in high sustained MRD negativity rate in carfilzomib, lenalidomide and dexamethasone (KRd) compared with VRd, especially in patients with advanced R-ISS.26Gay F. Cerrato C. Petrucci M. 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.J Clin Oncol. 2019; 37: 8002Crossref Google Scholar There is no direct comparison between VRd and KRd in NDMM patients who are eligible for ASCT; however, in the ENDURANCE trial (see Elderly patients' section), which included <30% of patients who received an ASCT, there was no PFS difference between the two regimens.Based on the above data, VRd is likely to offer the best risk-benefit profile to date among triplet combinations [II, B]. The four-drug combination DaraVTD is more efficacious than VTD [I, A] but comparisons are lacking versus DaraVRd or VRd [these regimens have not been approved by the European Medicines Agency (EMA)]. The EMA approval of DaraVTD makes it a new standard of care for induction before ASCT. Novel studies that are ongoing compare DaraVRd versus VRd, DaraVCD versus VTD, or combinations with novel mAbs such as IsaVRd, IsaKRd or EloVRd will reveal the best induction regimen in the future.Conditioning regimen before ASCTHDM (200 mg/m2) remains the standard conditioning regimen before ASCT for NDMM patients. The addition of busulfan to melphalan has not shown OS benefit over HDM.27Blanes M. Lahuerta J.J. Gonzalez J.D. et al.Intravenous busulfan and melphalan as a conditioning regimen for autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: a matched comparison to a melphalan-only approach.Biol Blood Marrow Transplant. 2013; 19: 69-74Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar,28Blanes M. Lorenzo J.I. Ribas P. et al.Intravenous busulfan plus melphalan versus melphalan alone as conditioning regimen for patients with multiple myeloma.Ann Hematol. 2019; 98: 2013-2015Crossref PubMed Scopus (8) Google Scholar The addition of bortezomib to HDM did not improve the efficacy of the conditioning regimen and had higher toxicity.29Roussel M. Hebraud B. Lauwers-Cances V. et al.Bortezomib and high-dose melphalan vs. high-dose melphalan as conditioning regimen before autologous stem cell transplantation in de novo multiple myeloma patients: a phase 3 study of the Intergroupe Francophone Du Myelome (IFM 2014-02).Blood. 2017; 130: 398Google ScholarConsolidation therapyThe EMN02/HO95 study showed that at a median follow-up of 42 months, consolidation therapy with 2 cycles of VRd improved mPFS compared with no consolidation (58.9 versus 45.5 months; P = 0.014).16Cavo M. Gay F. Beksac M. 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-e468Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar It must be noted that induction treatment in this study included 4 cycles of VCD and not VRd or DaraVTD.The use of a second planned ASCT as consolidation has also been tested in clinical trials. In the EMN02/HO95 study, in centres with a policy of double ASCT, patients were assigned to receive VMP, single ASCT (ASCT-1) or two planned ASCTs (administered 2-3 months apart; ASCT-2) to prospectively compare ASCT-1 with ASCT-2. Patients who received ASCT-2 had a prolonged PFS compared with those who received ASCT-1: the 3-year PFS probability was 53.5% for ASCT-2 versus 44.9% for ASCT-1 group (P = 0.036), which represented a 26% reduced risk of progression or death in the ASCT-2 group. Importantly, ASCT-2 significantly improved the outcome of patients with high-risk cytogenetics (mPFS: 46 and 26.7 months for ASCT-2 and ASCT-1, respectively; HR 0.59; P = 0.062).14Cavo M. Gay F. Patriarca F. et al.Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study.Blood. 2017; 130: 401Google Scholar In the same study, OS from the first randomisation was significantly prolonged with ASCT-2 compared with ASCT-1 (3-year rate: 89% versus 82%; HR 0.52; P = 0.011); this benefit was also reported in patients with R-ISS II + III (HR 0.48; P = 0.013) and with high-risk cytogenetics (HR 0.52; P = 0.042).14Cavo M. Gay F. Patriarca F. et al.Double autologous stem cell transplantation significantly prolongs progression-free survival and overall survival in comparison with single autotransplantation in newly diagnosed multiple myeloma: an analysis of phase 3 EMN02/HO95 study.Blood. 2017; 130: 401Google ScholarThe phase III StaMINA study randomised 758 patients who received induction therapy for up to 12 cycles, followed by one ASCT versus tandem ASCT versus ASCT-1 followed by 4 subsequent cycles of VRd; all treatment groups received lenalidomide maintenance until disease progression.30Stadtmauer E.A. Pasquini M.C. Blackwell B. et al.Autologous transplantation, consolidation, and maintenance therapy in multiple myeloma: results of the BMT CTN 0702 trial.J Clin Oncol. 2019; 37: 589-597Crossref PubMed Scopus (128) Google Scholar The 6-year PFS in high-risk patients was 43.6% and 26% for tandem ASCT and ASCT-1, respectively (P = 0.03).31Hari P. Pasquini M. Stadtmauer E. et al.Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM).J Clin Oncol. 2020; 38: 8506Crossref Google ScholarFinally, a study which compared tandem ASCTs with ASCT-1 followed by allogeneic SCT (allo-SCT) has recently reported the 10-year median follow-up results. In both standard-risk (n = 625) and high-risk patients (n = 85), there was no PFS or OS difference.32Giralt S. Costa L.J. Maloney D. et al.Tandem autologous-autologous versus autologous-allogeneic hematopoietic stem cell transplant for patients with multiple myeloma: long-term follow-up results from the Blood and Marrow Transplant Clinical Trials Network 0102 Trial.Biol Blood Marrow Transplant. 2020; 26: 798-804Abstract Full Text Full Text PDF PubMed Scopus (21) Google ScholarMaintenance therapyTreatment with lenalidomide maintenance after ASCT offers PFS and OS benefits over placebo as reported in two large randomised trials.33Attal M. Lauwers-Cances V. Marit G. et al.Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012; 366: 1782-1791Crossref PubMed Scopus (888) Google Scholar,34McCarthy P.L. Owzar K. Hofmeister C.C. et al.Lenalidomide after stem-cell transplantation for multiple myeloma.N Engl J Med. 2012; 366: 1770-1781Crossref PubMed Scopus (898) Google Scholar A meta-analysis including more than 1200 patients, with a median follow-up of