Adedayo, T

Braganca, N

Cavenagh, JD

Clifton-Hadley, L

Cook, G

Counsell, N

Crowe, J

De Tute, R

De-Silva, D

Koh, MBC

Morris, TC

Owen, R

Phillips, EH

Popat, R

Rabin, N

Roddie, C

Schey, S

Smith, P

Streetly, M

Yong, K

English

UCL Discovery

1  Title  Using depth of response to stratify patients to front line Autologous Stem Cell Transplant: Results of the phase II PADIMAC Myeloma Trial Author list:  Rakesh Popat,1,14 Nicholas Counsell,2 Ruth de Tute,3 Dunnya De-Silva,1 Elizabeth H Phillips,2,15 Jamie D Cavenagh,4 Toyin Adedayo,2 Nivette Braganca,2 Claire Roddie,1 Matthew Streetly,5 Steve Schey,6 Mickey BC Koh,7 Josephine Crowe,8 Treen C Morris,9 Gordon Cook,3  Paul Smith,2 Laura Clifton-Hadley,2 Neil Rabin,14 Roger Owen,3 Kwee Yong,1 for the PADIMAC investigators* Affiliations: 1UCL Cancer Institute, London, 2Cancer Research UK & UCL Cancer Trials Centre, London,  3Leeds Cancer Centre, Leeds Teaching Hospital NHS Trust, 4St. Bartholomew’s Hospital, London, 5Guy’s and St Thomas’ NHS Foundation Trust, London, 6Kings College Hospital, London, 7St George's University Hospitals NHS Foundation Trust,8Royal United Hospital, Bath, 9Belfast Trust, Belfast, 14University College London Hospitals NHS Foundation Trust, London, 15Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre,Manchester  *Collaborators: Shirley D’Sa (Mount Vernon Cancer Centre, Herts), Andres Virchis (Royal Free Hospital Foundation NHS Trust, London) , Michael Quinn (Belfast Trust), Charles Crawley (Addenbrookes Hospital, Cambridge), Guy Pratt (University Hospitals Birmingham NHS Foundation Trust, Birmingham), Mark Cook (University Hospitals Birmingham NHS Foundation Trust, Birmingham) Running title  Depth of response to stratify patients for ASCT in myeloma   2  Corresponding Author:  Prof Kwee Yong Email: kwee.yong@ucl.ac.uk Tel: 020 3447 8028 Fax: 020 3447 9911    Word count: 997 Figures: 2 Tables: 0   3   Autologous stem cell transplantation (ASCT) remains the standard of care for younger and fitter multiple myeloma (MM) patients; however highly effective induction combination regimens have questioned whether ASCT can be deferred. Trials randomising patients to ASCT or not have shown benefit for up-front ASCT. (1, 2) A response-stratified approach to treatment has not yet been reported, but is already being practised, mainly in the United States. (3)   The benefit of ASCT is related to an uplift in major response and minimal residual disease (MRD) negativity, associated with improved progression-free survival (PFS) and overall survival (OS). (4, 5) Achieving this with induction chemotherapy alone questions the additional benefit of upfront ASCT. This trial was designed to estimate the PFS of patients who, having achieved a major serological response (≥VGPR) to induction therapy, were stratified to receive no further treatment. Neither consolidation for those not proceeding to ASCT nor maintenance post ASCT were incorporated as these treatments were under evaluation at the time of this protocol and our primary goal was to investiagte outcomes using this approach to inform future studies. PADIMAC was a multi-centre phase II trial for newly diagnosed transplant eligible (NDTE) patients with MM (Supplementary materials Section 1). Patients received 4-6 cycles of PAD induction (6) followed by peripheral blood stem cell harvest (PBSCH).  Those achieving ≥VGPR post PBSCH received no further treatment and were observed until disease progression (‘VGPR-W&W’) when ASCT could be offered. Those achieving PR proceeded to high dose melphalan (as per institutional practice)  and ASCT with no further therapy until disease progression (‘PR-ASCT’). MRD was centrally assessed by multi-parametric flow cytometry (MPFC) with a detection threshold of 0.004% (7) at baseline, post-PBSCH and 100 days (D100) following PBSCH/ ASCT.  The primary endpoint was to estimate 2-year PFS by MRD status for the VGPR-W&W group. Secondary aims were to assess the response and toxicity of induction, MRD status following induction and at D100, PFS for PR-ASCT patients, PFS2, OS, and biomarkers of clinical outcomes.  4  The trial registered 153 patients (March 2011-January 2014, Supplementary Table S1; baseline characteristics: Table S2; consort diagram: Figure S1). All patients received ≥1 cycle of PAD induction and 139 (90.8%) received 4-6 cycles (adverse events: Tables S4 & S5). The overall response rate following induction was 82.4% (126/153) with 63 (41.2%) achieving ≥VGPR (Table S3, adverse events). Of the 126 patients achieving ≥PR and proceeding to PBSCH, 63 achieved ≥VGPR post-PBSCH. Of the remaining 63 patients, 17 did not proceed directly to PBSCH, and came off study (Table S6), 46 harvested (PR=44, PD=2) with 36 proceeding to ASCT (Table S7). After a median follow-up of 71.4m from PBSCH, median PFS was 17.0m (95% CI:10.5-23.2) for the VGPR-W&W group and 19.6m (95% CI:17.0-22.8) for the PR-ASCT group, 2-year PFS was 37.1% (95% CI:25.3-48.9) and 33.3% (95% CI:18.8-48.6) respectively (HR=1.23, 95% CI:0.79-1.92, p=0.36; Figure 1A). Within the VGPR-W&W group, by MRD status at D100, median PFS was 24.8m (95% CI:18.3-34.2) for MRD negative (N=18) and 9.9m (95% CI:5.8-23.2) for MRD positive (N=32) patients, 2-year PFS was 55.6% (95% CI:30.5-74.8) and 31.3% (95% CI:16.4-47.3) respectively (HR=0.74, 95% CI:0.40-1.37, p=0.33; Figure 1B). Consistent with their longer PFS, all 18 MRD negative patients post-PBSCH remained in ≥VGPR at D100, compared to 8 of 32 MRD positive patients whose response worsened (3 PR, 5 PD). Investigating PFS by MRD status irrespective of pathway (combining VGPR-W&W and PR-ASCT groups), MRD negative patients at D100 (n=25) generally had a longer median PFS (24.0m, 95% CI:19.2-41.6) than those who were MRD positive (n=52, 16.0m, 95% CI:10.4-20.1) (HR=0.59, 95% CI:0.35-1.01, p=0.05; Figure 1C).  Changes in MRD status from post-PBSCH to D100 by treatment are in Table S8. Within the VGPR-W&W group, 44 had standard risk and 12 adverse risk genetics.  There was no difference in PFS (Supplementary Figure S3).  Although small numbers, 1/8 MRD negative standard risk and 1/3 MRD negative adverse risk patients became MRD positive at D100; 4/24 MRD positive standard risk patients converted to MRD negative, whereas the only adverse risk patient remained positive at D100 (Table S9). 5  Of the 63 VGPR-W&W patients, 24 died (20: MM, 4: infection), 33 progressed and remain alive, 6 are alive without progression. For the VGPR-W&W group as a whole, 2-year OS was 91.9% (95% CI:81.6-96.5; Figure 2A); by MRD status at D100, 2-year OS was 100% (95% CI:81.5-100) for MRD negative and 90.5% (95% CI:73.4-96.8) for MRD positive patients (HR=0.28, 95% CI:0.08-0.97, p=0.04; Figure 2B). Combining the VGPR-W&W and PR-ASCT groups, the 2-year OS rates were 100% (95% CI:86.3-100, MRD negative) and 94.2% (95% CI:83.1-98.1, MRD positive) (HR=0.41, 95% CI:0.14-1.23, p=0.11), medians have not yet been reached (Figure 2C).  PFS2 and additional exploratory analyses, including by cytogenetic risk are presented in the Supplementary materials (Figures S2-5). PADIMAC was the first prospective trial to investigate whether a subgroup of patients can safely defer ASCT at front line therapy based on disease response.  Our findings suggest that using serological response alone was not adequate to stratify patients, as many in ≥VGPR remain MRD positive, with short PFS indicating that further cytoreductive therapy is required. Deferred ASCT may however be an option for standard risk MRD negative patients warranting further investigation. The numbers of adverse risk patients were too small to draw definitive conclusions, however published data shows that even after achieving a deep response, they are less likely to maintain it. (8)   We recommend MRD positive patients post-induction should receive ASCT as non-ASCT pathway outcomes were poor.  Dfferences in outcomes for MRD negative patients in PADIMAC, and those from the IFM and EMN02 studies, is likely attributable to the lack of maintenance therapy and/or the MRD detection threshold and timing of sampling. Consensus guidelines for clinical trials now recommend  MRD assessments to at least 10-5 .(9)  Future trials that employ MRD status and cytogenetic risk to stratify patients will help identify  patients that can safely be allocated a no-ASCT pathway. Such efforts are especially pertinent today where the risks associated with the COVID-19 pandemic highlight the need for such a pathway.     6  Acknowledgements  The authors acknowledge the research staff working across all sites, the patients and their carers. KY and RP are supported by the UCLH/ UCL NIHR Biomedical Research Centre. The trial was coordinated by the CRUK & UCL CTC.  Blood Cancer UK conducted an independent review of the study proposal and provided funding. Janssen LLC provided bortezomib free of charge, contributed to trial management costs, but had no involvement in the design, conduct, analysis or interpretation. All authors had full access to the data and the corresponding author was responsible for manuscript submission.   7  Authorship contributions KY, RP, JC and RO conceived the study; NC, RP, RD, RO, CR, DDS, EP, TA, NB,  PS, LCH, KY analysed the data; RP, JC, GC, MS, SS, MK, JC, MQ, SDS, AV, CC, GP, MC, JL, NR performed the research; RP, NC, KY wrote the manuscript; all authors reviewed and approved the manuscript  Conflict of Interests:  RP: Janssen Honoraria and Travel support for meetings outside the submitted work; RT: nothing to disclose; NC: grants from Blood Cancer UK, grants and other from Janssen,  during the conduct of the study; DDS: nothing to disclose; EP: nothing to disclose; JC: Janssen Honoraria outside the submitted work; TA: grants from Blood Cancer UK, grants and other from Janssen,  during the conduct of the study; NB: grants from Blood Cancer UK, grants and other from Janssen,  during the conduct of the study; MS: Janssen Honoraria outside the submitted work; SS: nothing to disclose; MK: consultancy and honoraria from Gilead and Alexion; JC: nothing to disclose; MQ: nothing to disclose; TCM: nothing to disclose; SDS: Janssen Cilag Consultancy, Honoraria, Education grant and Research Funding outside the submitted work; AV: nothing to disclose; GC: grants and personal fees from Janssen outside the submitted work; CC: nothing to disclose; GP: grants and personal fees from Janssen outside the submitted work; MC: grants and personal fees from Celgene, personal fees and non-financial support from Takeda, personal fees and non-financial support from Abbvie, personal fees and non-financial support from Amgen, personal fees from Chugai, personal fees from Jazz Pharmaceuticals, personal fees and non-financial support from Janssen UK,  outside the submitted work; PS: grants from Blood Cancer UK, grants and other from Janssen,  during the conduct of the study; LCH: grants from Blood Cancer UK, grants and other from Janssen,  during the conduct of the study; NR: Janssen Consultancy, travel support for meetings and Speakers Bureau outside the submitted work; RO: Janssen Consultancy travel support outside the submitted work; KY: Janssen Honoraria and Research Funding.   8  References  1. Cavo M, Gay F, Beksac M, Pantani L, Petrucci MT, Dimopoulos MA, 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(6):e456-e68. 2. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017;376(14):1311-20. 3. Joseph NS, Kaufman JL, Dhodapkar MV, Hofmeister CC, Almaula DK, Heffner LT, 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(17):1928-37. 4. Dingli D, Pacheco JM, Nowakowski GS, Kumar SK, Dispenzieri A, Hayman SR, et al. Relationship between depth of response and outcome in multiple myeloma. J Clin Oncol. 2007;25(31):4933-7. 5. Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, et al. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012;97(3):442-50. 6. Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946-55. 7. Rawstron AC, Child JA, de Tute RM, Davies FE, Gregory WM, Bell SE, 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(20):2540-7. 8. Lahuerta JJ, Paiva B, Vidriales MB, Cordon L, Cedena MT, Puig N, et al. Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials. J Clin Oncol. 2017;35(25):2900-10. 9. Costa LJ, Derman BA, Bal S, Sidana S, Chhabra S, Silbermann R, et al. International harmonization in performing and reporting minimal residual disease assessment in multiple myeloma trials. Leukemia. 2021;35(1):18-30.    9  Figure Legends: Figure 1. Kaplan-Meier plots of progression-free survival (PFS) by: (A) post-PBSCH response; (B) post-PBSCH response and MRD status at Day 100; (C) MRD status at Day 100. Figure 2. Kaplan-Meier plots of overall survival by: (A) post-PBSCH response; (B) post-PBSCH response and MRD status at Day 100; (C) MRD status at Day 100.    10     FIGURE 11A                                                                                                          1B1CFIGURE 22A                                                                                                       2B2C

Using depth of response to stratify patients to front line Autologous Stem Cell Transplant: results of the phase II PADIMAC Myeloma Trial

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Using depth of response to stratify patients to front line Autologous Stem Cell Transplant: results of the phase II PADIMAC Myeloma Trial

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