Frontline therapy in multiple myeloma: fast start for a long game
Authors: Francesca Patriarca
Journal: The Lancet Haematology (2019)

Survival after diagnosis of multiple myeloma has been substantially improved in the past two decades owing to the availability of effective drugs administered in sequential phases, such as induction, autologous stem cell transplantation (ASCT) for eligible patients, maintenance, and salvage treatments at relapse. The bulk of evidence suggests that depth of response, regardless of how it is measured (either by standard response criteria based on serum or urine monoclonal protein detection or by more sensitive flowcytometric and molecular techniques in bone marrow), is correlated with subsequent clinical outcomes.1van de Velde HJ Liu X Chen G et al.Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma.Haematologica. 2007; 92: 1399-1406Crossref PubMed Scopus (248) Google Scholar, 2Munshi NC Avet-Loiseau H Rawstron AC 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 (333) Google Scholar Moreover, minimal residual disease assessment has been recognised as a clinical and regulatory endpoint in clinical trials. Prospective studies comparing ASCT with therapies at conventional doses, tandem with single ASCT, and consolidation with no consolidation3Palumbo A Cavallo F Gay F et al.Autologous transplantation and maintenance therapy in multiple myeloma.N Engl J Med. 2014; 371: 895-905Crossref PubMed Scopus (567) Google Scholar, 4Cavo M Gay FM 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 (abstr).: 401Google Scholar, 5Stadtmauer EA Pasquini MC 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 (142) Google Scholar have clearly confirmed the positive effect of late treatment intensification on clinical outcomes in transplant-eligible patients. However, the clinical value of maximising response during induction has not been extensively explored. The Myeloma XI trial reported in The Lancet Haematology by Graham H Jackson and colleagues6Jackson GH Davies FE Pawlyn C et al.Response-adapted intensification with cyclophosphamide, bortezomib and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.Lancet Haematol. 2019; (published online Oct 14)https://doi.org/10.1016/S2352-3026(19)30167-XSummary Full Text Full Text PDF Scopus (32) Google Scholar has helped to fill this knowledge gap. The Myeloma XI trial is a large, national study done in the UK including 3894 patients with newly diagnosed multiple myeloma. Jackson and colleagues6Jackson GH Davies FE Pawlyn C et al.Response-adapted intensification with cyclophosphamide, bortezomib and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial.Lancet Haematol. 2019; (published online Oct 14)https://doi.org/10.1016/S2352-3026(19)30167-XSummary Full Text Full Text PDF Scopus (32) Google Scholar report one of the three randomisation stages evaluating the clinical value of a response-adapted approach to induction therapy in this setting. The authors show a significant improvement of progression-free survival in patients who achieved partial or minimal response after first-line treatment with cyclophosphamide, lenalidomide or thalidomide, and dexamethasone and were then switched to an intensified induction with bortezomib, cyclophosphamide, and dexamethasone. This improvement in progression-free survival was observed in both, transplantation-eligible and ineligible patients. After bortezomib, cyclophosphamide, and dexamethasone, 123 (43%) of 289 patients improved depth of response, with 10 (3%) achieving complete response and 113 (39%) achieving very good partial response. Unfortunately, remission was evaluated only by standard serological criteria, and minimal residual disease data reporting is postponed by the authors to a subsequent publication. The benefit of bortezomib, cyclophosphamide, and dexamethasone was independent on age, International Staging System stage, and cytogenetic risk group and was persistent after ASCT in transplant-eligible patients. Toxicity was mainly haematological and manageable in all patients. No advantage in overall survival was observed 3 years after randomisation in the intensified induction group, probably due to the efficacious subsequent treatments patients received (eg, maintenance or salvage at relapse). Although designed a decade ago, this study provides further insight for the design of future studies. The authors themselves admit that the immunomodulatory drug-based inductions used in Myeloma XI were proposed in 2010 and should not be regarded as current standard of care, although median progression-free survival of patients treated with bortezomib, cyclophosphamide, and dexamethasone after suboptimal response with cyclophosphamide, lenalidomide or thalidomide, and dexamethasone was comparable with that reported by studies employing proteosome inhibitors upfront, at least in the transplant-eligible group. However, 302 patients withdrew consent before intensification randomisation, suggesting a potential patient or physician reluctance or a somewhat low feasibility of the proposed response-adapted approach. Given that prospective randomised studies showed superiority of bortezomib, thalidomide, and dexamethasone induction over thalidomide and dexametahasone or bortezomib, cyclophosphamide, and dexamethasone in transplant-eligible patients,7Cavo M Tacchetti P Patriarca F et al.Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3.Lancet. 2010; 376: 2075-2085Summary Full Text Full Text PDF PubMed Scopus (721) Google Scholar, 8Moreau 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 (194) Google Scholar the principle of maximising response supports a standard of care induction that includes a proteosome inhibitor with an immunomodulatory agent upfront before transplantation, at least in high risk patients. The Myeloma XI study also suggests some potential mechanisms of resistance and methods to overcome it. Given the high clonal heterogeneity of multiple myeloma, it can be hypothesised that drugs with different mechanism of action, administered either in combination upfront or in sequence based on previous response, could block different clones and overcome resistance. This concept is further supported by studies showing improved outcomes with the addition of, the anti-CD38 monoclonal antibody, daratumumab to standard first-line treatments in older patients, with manageable toxicity,9Mateos MV Dimopoulos MA Cavo M et al.Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma.N Engl J Med. 2018; 378: 518-528Crossref PubMed Scopus (601) Google Scholar, 10Facon T Kumar SK Plesner T et al.Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA).Blood. 2018; 132 (LBA–2 (abstr).)Google Scholar and by the investigation of upfront quadruplets that include most available effective drugs (immunomodulatory agent plus one proteosome inhibitor plus monoclonal antibody plus dexamethasone) in transplant-eligible patients. The benefit of the response-adapted intensification was also observed in patients with advanced International Staging System stage and high-risk fluorescence in-situ hybridisation cytogenetics, although these were small patient subsets, which might suggest that clonal heterogeneity is a key mechanism of resistance in high-risk disease as well and might be overcome by drug combinations encompassing different mechanisms of action. Once a molecular risk stratification that surpasses conventional prognostication tools and reflects the entire biological heterogeneity of multiple myeloma is designed, we can envisage personalised treatment strategies at diagnosis, with more intense and complex induction regimens in high-risk patients and less toxic schemes in standard-risk patients. I have received speaker's honoraria from Celgene, Takeda, and Janssen-Cilag. Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trialIntensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK. Full-Text PDF Open Access