Post ASH speaker abstracts 2018

Myeloma

Abstracts to support presentations from Graham Jackson and Ceri Bygrave

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

Result Type: Paper
Number: 401
Presenter: Michele Cavo
Program: Oral and Poster Abstracts
Session: 731. Clinical Autologous Transplantation: Results: Novel Conditioning & Maintenance Approaches

Michele Cavo, MD1*, Francesca Maria Gay2*, Francesca Patriarca, MD3*, Elena Zamagni, MD4*, Vittorio Montefusco, MD5*, Luca Dozza1*, Monica Galli, MD, PhD6*, Sara Bringhen7*, Nicoletta Testoni, BSc1*, Mariella Grasso, MD8*, Stelvio Ballanti, MD9*, Paola Tacchetti, MD1*, Giampietro Semenzato, MD10*, Anna Marina Liberati11*, Giulia Benevolo12*, Mauro Spriano, MD13*, Paolo Di Bartolomeo, M.D14, Tommaso Caravita di Toritto, MD15*, Angelo D. Palmas, MD16, Anna Maria Cafro, MD17*, Fortunato Morabito, MD18*, Pellegrino Musto, MD19, Rita Rizzi, MD20*, Antonio Palumbo, MD21 and Pieter Sonneveld, MD, PhD22

1Seragnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy
2Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
3Hematology, DAME, University of Udine, Udine, Italy
4Bologna University School of Medicine, Bologna, Italy
5Division of Hematology and Bone MarrowTransplant, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
6Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
7Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy
8Divisione di Ematologia, Ospedale Civico S. Croce e Carle, Cuneo, Italy
9Ospedale S. Maria della Misericordia, University of Perugia, Perugia, Italy
10Department of Medicine, Hematology and Clinical Immunology Section, Padua University School of Medicine, Padova, Italy
11University of Perugia, Azienda Ospedaliera S. Maria, Terni, Italy
12Division of Hematology, AOU Città della Salute e della Scienza, Torino, Italy
13Azienda Ospedaliera Universitaria S. Martino, Genova, Italy
14Department of Hematology, Transfusion Medicine and Biotecnology, ” Spirito Santo ” Civic Hospital, Pescara, Italy
15Ospedale S.Eugenio Roma, Roma, Italy
16Hematology, Ospedale San Francesco, Nuoro, ITA
17Department of Oncology/Hematology, Niguarda Ca’ Granda Hospital, Milan, Italy
18Hematology Unit, Department of Hemato-Oncology, Annunziata Hospital Cosenza, Cosenza, Italy
19IRCCS, Centro Di Riferimento Oncologico Della Basilicata, Rionero in Vulture, Italy
20Medicina Interna e Oncologia Clinica, Policlinico di Bari, Bari, Italy
21University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
22Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands

 

Background: The role of single vs double autologous stem cell transplantation (ASCT) for newly diagnosed (ND) multiple myeloma (MM) continues to be debated in the novel agent era.

Methods: The phase III EMN02/HO95 study was designed to administer 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy for NDMM and afterwards to randomize eligible patients to receive (randomization 1, R1) standard-dose intensification treatment with bortezomib-melphalan-prednisone (VMP) for four 42-day cycles or high-dose intensification treatment with melphalan at 200 mg/m(HDM) plus ASCT. A second randomization to receive or not receive consolidation therapy was planned after the intensification phase, followed by lenalidomide maintenance in both arms. In centers committed to a double ASCT policy, patients were randomized (1:1:1) to receive VMP or single ASCT (ASCT-1) or two sequential courses of HDM (administered 2 to 3 months apart) plus double ASCT (ASCT-2) in order to prospectively compare ASCT-1 vs ASCT-2, which was an additional study objective. For this purpose, and for consistency with the primary study end point, progression-free survival (PFS) from R1 was evaluated.

Results: A total of 1503 patients aged ≤65 years were registered and 1192 were eligible for R1. By study design, 618 patients who received the diagnosis of MM in centers with a double ASCT policy were randomly assigned to VMP (n=203) or ASCT-1 (n=208) or ASCT-2 (n=207). 415 of these patients who were randomized to receive ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 58 years for patients in the ASCT-1 group and 57 years for those in the ASCT-2 group. The frequency of ISS stage III was 19% in both groups. According to IMWG criteria, a high-risk (HiR) cytogenetic profile defined by t(4;14) ± t(14;16) ± del(17p) positivity (HiR-cyto-3) was detected in 26% and 21% of patients who were evaluable in ASCT-1 (80%) and ASCT-2 (86%) groups. The presence of amp(1q) ± del(1p) ± 1 or more of t(4;14), t(14;16) and del(17p) identified a HiR cytogenetic profile (HiR-cyto-5) which was detected in 55% of patients in ASCT-1 arm and 50% of those in ASCT-2 arm. Median follow-up from R1 was 38 (IQR: 29-47) months for the overall patient population (36 and 39 months for patients randomized to ASCT-1 and ASCT-2, respectively). On an intention-to-treat basis, 3-year estimate of PFS was 73% (95% CI=66-79) for ASCT-2 group vs 64% (CI=57-71) for ASCT-1 group (HR=0.70; CI=0.50-0.98; P=0.040), which represented a 30% reduced risk of progression or death in the ASCT-2 group compared with the ASCT-1 group (Fig. 1a). PFS benefit associated with ASCT-2 was confirmed in subgroups of patients with HiR-cyto-3 (HR=0.42; CI=0.21-0.84; P=0.014), revised ISS (R-ISS) stage II+III (HR=0.64; CI=0.43-0.97; P=0.034), age >55 years (HR=0.64; CI=0.43-0.96; P=0.033); HiR-cyto-5 (HR=0.65; CI=0.42-1.01; P=0.059) and best ≥VGPR (HR=0.64; CI=0.44-0.94; P=0.023). Importantly, ASCT-2 overcame the adverse prognosis conferred by HiR-cyto-3 (3-year PFS: 76% vs 69% for patients with standard-risk cytogenetic profile; P=0.482) (Fig. 1b). In particular, 3-year PFS estimate for patients randomized to ASCT-2 and carrying or lacking del(17p) was 72% vs 73%, respectively (P=0.534). The corresponding PFS values in the ASCT-1 group were 43% vs 67%, respectively (P=0.014). In a multivariate Cox regression analysis, randomization to ASCT-2 (HR=0.65; CI=0.44-0.95; P=0.029), R-ISS I (HR=0.60; CI=037-0.98; P=0.042), absence of HiR-cyto-5 (HR=0.35; CI=0.22-0.55; P<0.001) and best ≥VGPR (HR=0.27; CI=0.17-0.44; P<0.001) were the leading independent predictors of PFS. Overall survival (OS) from R1 was significantly prolonged with ASCT-2 as compared with ASCT-1 (3-year rate: 89% vs 82%; HR=0.52; CI=0.31-0.86; P=0.011) (Fig. 1c), a benefit also seen in subgroups of patients with adverse prognosis, including those with R-ISS stage II+III (HR=0.48; CI=0.27-0.86; P=0.013) and HiR-cyto-5 (HR=0.52; CI=0.28-0.98; P=0.042). Conclusions: Randomization to ASCT-2 was superior over ASCT-1 in terms of prolonged PFS and OS for the overall patient population and for poor prognosis subgroups of patients with advanced R-ISS disease stage and HiR cytogenetic profile. Incorporation of bortezomib into ASCT-2 abrogated the increased risk of progression or death imparted by t(4;14) ± t(14;16) ± del(17p), and in particular by del(17p) positivity.

Curative Strategy  for High-Risk Smoldering Myeloma (GEM-CESAR): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd

Result Type: Paper
Number: 402
Presenter: Maria-Victoria Mateos
Program: Oral and Poster Abstracts
Session: 731. Clinical Autologous Transplantation: Results: Novel Conditioning & Maintenance Approaches

Maria-Victoria Mateos, MD, PhD1, Joaquin Martinez Lopez2*, Paula Rodriguez-Otero, MD, PhD3*, Enrique M Ocio, MD4*, Marta Sonia Gonzalez, MD5*, Albert Oriol, MD6*, Norma Gutierrez, MD, PhD7*, Bruno Paiva, PhD8*, Rafael Rios9*, Laura Rosinol, MD, PhD10*, Miguel Angel Alvarez, MD11*, Maria Jose Calasanz, BSc, PhD12*, Joan Bargay, MD, PhD13*, Ana Pilar Gonzalez, PhD14*, Fernando Escalante, Dr.15*, Rafael Martínez16*, Noemi Puig, MD, PhD17*, Javier de la Rubia, MD18*, Ana Isabel Teruel, MD19*, Maria Teresa Teresa Cedena Romero20*, Felipe De Arriba, PhD21*, Luis Palomera22*, Miguel T Hernández23*, Javier Lopez Jimenez24*, Jesús Martín25*, Esther Piensa26*, Aránzazu García-Mateo27*, Veronica González17*, Joan Blade, MD28, Juan Jose Lahuerta29* and Jesus F. San Miguel, MD30

1University Hospital of Salamanca, Salamanca, Spain
2Hospital Universitario 12 de Octubre, Madrid, Spain
3University Clinic of Navarra, Center for Applied Medical Research (CIMA), IDISNA, Pamplona, Spain
4Hospital Clinico Universitario de Salamanca, Salamanca, Spain
5Hospital Universitario de Santiago, Santiago de Compostela, Spain
6ICO Badalona, Hospital Germans Trias i Pujol, Badalona, Spain
7IBSAL, University Hospital of Salamanca, Salamanca, Spain
8Universidad de Navarra, Pamplona, Spain
9Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain
10Hospital Clinic i Provincial, Barcelona, Spain
11Hospital Universitario Reina Sofia, Cordoba, Spain
12Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), IDISNA, CIBERONC, Pamplona, Spain
13Hospital Sont LLatzer, Palma de Mallorca, Spain
14Hospital Central de Asturias, Oviedo, Spain
15Hospital Universitario de León, León, Spain
16Hospital Clínico San Carlos, Madrid, Spain
17IBSAL, Hospital Universitario de Salamanca, Salamanca, Spain
18Hematology Department, Universidad Católica de Valencia Hospital Dr. Peset, Valencia, Spain
19Hospital Clinico Universitario de Valencia, Valencia, Spain
20Hospital 12 de Octubre, Madrid, Spain
21Hospital Morales Meseguer, Murcia, Spain
22Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
23Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
24Hospital Ramon y Cajal, Madrid, Spain
25Hospital Universitario Virgen del Rocío, Sevilla, Spain
26Hospital de Mataró, Barcelona, Spain
27Hospital General de Segovia, Segovia, Spain
28Servicio de Onco-Hematología, Hospital Clínica de Barcelona, Barcelona, Spain
29Department of Hematology, Hospital 12 de Octubre, Madrid, Spain
30Centro de Investigación Médica Aplicada, University of Navarra, Clinica Universidad de Navarra, Pamplona, Spain

 

Introduction: Smoldering Multiple Myeloma (SMM) is an asymptomatic plasma cell disorder that includes patients with different risk of progression to Multiple Myeloma (MM). The Spanish Myeloma Group demonstrated that early treatment with Rd versus observation in SMM at high risk (HR) of progression resulted into a significant benefit in terms of progression to MM and overall survival. Our next step was to design this phase 2 trial with the potential goal of cure, defined by a sustained minimal residual disease (MRD) negativity for at least 5 years (yr).

Methods: In this phase 2 single-arm trial, 90 SMM patients (pts) at high-risk of progression (>50% at 2 yr), younger than 70 yr and transplant candidates were included. The HR was defined by the presence of both bone marrow plasma cells (PCs)≥ 10% and serum M-protein ≥3g/dL (Mayo) or if only one criterion was present, patients must have a proportion of aberrant PCs within the total PCs bone marrow compartment by immunophenotyping of 95% plus immunoparesis (Spanish). Asymptomatic MM patients with any of the three biomarkers that currently define active MM were allowed to be included, because the design of the trial was done before the publication (Lancet Oncol 2014). Induction therapy consisted on six 4-weeks cycles of KRd in which K was given at dose of 36 mg/m2twice per week plus R at dose of 25 mg on days 1-21 and dexamethasone (dex) at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2 followed by autologous stem-cell transplant (ASCT) was given as intensification therapy and three months later, patients received two KRd consolidation cycles followed by maintenance with R at dose of 10 mg on days 1-21 plus dex 20 mg weekly for up to 2 yr. MRD was evaluated by next-generation flow cytometry after induction, ASCT, consolidation and annually thereafter.

Results: the 90 planned patients were recruited between June 2015 and June 2017. Although 126 patients signed the informed consent (IC), there were 36 screening failures, including 21 (17%) pts due to the detection of lytic lesions by PET-CT or MRI (the most frequent exclusion criteria). The median age of the whole series was 59 yr. All pts were at HR according to the Mayo and/or Spanish models, including 28 pts (31%) that shared at least one of the new MM biomarkers (MDE).

Forty-three patients have completed the 6 induction cycles and are evaluable for response: the ORR was 98% including 46% of ≥CR (37% sCR and 9% CR) and 37% of VGPR. MRD by NGF was evaluated in 34 out of these 43 pts and was negative in 13 (38%). Twenty-nine patients have received ASCT and were evaluable at 3 months: the ORR was 100% including ≥CR in 69% of the patients (65% sCR and 3% CR) and VGPR rate in 21%. MRD was negative in 17 out of these 29 patients (58%). Nineteen patients have completed the two planned consolidation cycles and 85% of them are in ≥CR, including sCR in 74%, CR in 11% and VGPR in 16%.

As far as toxicity during induction is concerned, , G3-4 neutropenia and thrombocytopenia were reported in 4 (4%) and 2 pts (2%), respectively. G3-4 infections were the most frequent non-hematological adverse events (AE), observed in 9 pts (10%), followed by skin rash in 7 pts (8%). With regard to cardiovascular events, 1patient reported atrial fibrillation and another cardiac failure, both of G1, and 2 patients reported G2 arterial hypertension. In all but one of the pts, peripheral blood stem cell collection was successful, with a median number of CD34+ cells collected of 6,79 x 106/Kg. Engraftment occurred in all patients and the median number of CD34+ infused was 3.29 x 106/Kg. During consolidation, 2 pts developed G3-4 neutropenia, 3 pts G3-4 infections and 1 pt skin rash.

After a median f/u of 13 months (1-108), 98% of patients remain free of progression and alive. Three patients early discontinued: one withdrew the IC; and two treatment unrelated deaths, one during induction due to a massive ischemic stroke and the other one because of refractory disease after induction. No discontinuations due to related-AE have been reported.

Conclusions: Although longer follow-up is required, this “curative strategy for high-risk SMM” seems to be encouraging. The depth of response improved along with the duration of treatment, achieving up to 85% of ≥CR in patients who completed induction, ASCT and consolidation, with an acceptable safety profile. Interestingly, novel imaging techniques at screening allowed us to identify up to 17% of MM that would have been considered SMM with the conventional criteria.

Lenalidomide Maintenance Significantly Improves Outcomes Compared to Observation Irrespective of Cytogenetic Risk: Results of the Myeloma XI Trial

Result Type: Paper
Number: 436
Presenter: Graham Jackson
Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Upfront Therapy for Multiple Myeloma: Induction and Maintenance

Graham Jackson, MD, PhD1, Faith E Davies, MD2, Charlotte Pawlyn, BA, PhD, MBBChir, MRCP, FRCPath3, David Cairns, BSc, MSc, PhD4*, Alina Striha, MSc4*, Anna Hockaday4*, Inga Sakauskiene4*, John R Jones, MD5,6*, Bhuvan Kishore, MD7*, Mamta Garg, MD8*, Cathy Williams9*, Kamaraj Karunanithi10*, Jindriska Lindsay, MD11*, Matthew W Jenner12*, Gordon Cook, MD, PhD13*, Martin F Kaiser, MD5,6, Mark, T Drayson, MD, PhD14*, Roger G Owen, MD15*, Nigel H. Russell, MD16, Walter M Gregory, PhD4* and Gareth J. Morgan, MD, PhD17

1Department of Haematology, University of Newcastle, Newcastle Upon Tyne, United Kingdom

2Myeloma Institute, University of Arkansas, Little Rock, AR
3Institute of Cancer Research, Sutton, United Kingdom
4Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, Leeds, United Kingdom
5The Institute of Cancer Research, London, United Kingdom
6Department of Haematology, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom
7Heart of England Foundation Trust, Birmingham, United Kingdom
8Leicester Royal Infirmary – Haematology, Leicester, United Kingdom
9Centre for Clinical Haematology, Nottingham University Hospital, Nottingham, United Kingdom
10University Hospital of North Midlands, Stoke-on-Trent, United Kingdom
11Kent and Canterbury NHS Trust, Canterbury, United Kingdom
12Department of Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
13Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
14Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
15St James’s University Hospital, Leeds, United Kingdom

16Centre for Clinical Haematology, Nottingham University Hospital (City Hospital Campus), Nottingham, United Kingdom
17Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR

Background: Several studies and a meta-analysis have demonstrated the effectiveness of lenalidomide maintenance therapy post autologous stem cell transplant (ASCT) and in transplant non-eligible (TNE) myeloma patients. There are few studies examining whether this treatment strategy is effective in the subgroup of patients with high-risk myeloma, and indeed one study has suggested that it is ineffective. We will present an updated analysis of the Myeloma XI trial, the largest maintenance study performed to date, comparing the impact of lenalidomide to no maintenance. We will provide an in depth analysis of the role of tumour acquired risk variants on the effectiveness of maintenance. OS data for the study is due to mature in Sept 2017 and will be presented for the first time at the meeting.

Methods: The phase III NCRI Myeloma XI study recruited newly diagnosed myeloma patients from over 100 centers across the UK and in a maintenance randomization compared lenalidomide (Len) 10mg, days 1-21/28 until disease progression vs observation alone (Obs). There were pathways for transplant eligible (TE) and ineligible patients (TNE). The study was powered for both PFS and OS, with these being co-primary endpoints. Data for cytogenetic high-risk lesions including t(4;14), t(14;16), t(14;20), del(17p), gain(1q) as well as for B2M and LDH was collected. Cytogenetic high-risk was defined as the presence of at least one of the high-risk cytogenetic lesions, with ultra-high risk the presence of more than one. The International Staging System (ISS) and Revised ISS (R-ISS) scores were calculated.

1970 patients, 1247 TE and 723 TNE, median age 61 and 74 years, respectively, were randomized between lenalidomide (n=1136) and observation (n=834). The arms were well balanced for clinical and risk features. Cytogenetic data was available for 774 patients. The median follow up for this analysis was 28.7 months. 432/458 of the required overall survival events have been collected at July 2017.

Results: With longer follow up the previously reported significant reduction in risk of progression persists. This is demonstrated in all patients (HR 0.46 95%CI [0.40, 0.52], median PFS Len 39.1 months vs Obs 19.9, p<0.0001) and within both the TE (HR 0.47 95%CI [0.39, 0.57], median PFS Len 60.3 months vs Obs 30.1, p<0.0001) and TNE (HR 0.44 95%CI [0.37, 0.53], median PFS Len 25.7 months vs Obs 11.0, p<0.0001) pathways. The significant benefit of lenalidomide was seen irrespective of induction therapy received.

There was a consistent benefit for lenalidomide within each of the standard (HR 0.30 95%CI [0.19, 0.48]), high-risk (HR 0.30 95%CI [0.17, 0.51]) and ultra-high risk groups (HR 0.31 95%CI [0.15, 0.66], phet=0. 9339). The same pattern was also seen in all ISS groups (Stage I HR 0.39 95%CI [0.28, 0.46], Stage II HR 0.49 95%CI [0.36, 0.66], Stage III HR 0.47 95%CI [0.19, 0.48], phet=0. 6370) and R-ISS groups (Stage I too few events to quantify, Stage II HR 0.37 95%CI [0.25, 0.54], Stage III HR 0.56 95%CI [0.28, 1.13], phet=0.2340).

Analysis of patients using only t(4;14) and del17(p) as high-risk markers also demonstrated a benefit for lenalidomide maintenance. Those patients with del(17p) and/or t(4;14) present had a HR 0.31 95%CI [0.18, 0.53], median PFS Len 24.7 months vs Obs 10.5. Those patients without either del(17p) or t(4;14) had a HR 0.35 95%CI [0.25, 0.51], median PFS Len 60.4 months vs Obs 30.7 (phet=0.4871). Irrespective of how the high-risk population was defined there was a consistent benefit for lenalidomide maintenance with no significant heterogeneity between subgroups.

The impact of maintenance on OS and by risk status will be presented at the meeting.

Conclusion: The use of maintenance lenalidomide improves outcomes for newly diagnosed myeloma patients irrespective of risk status.

On behalf of the NCRI Haem-onc CSG

Thrombotic Events in Patients with Myeloma Treated with Immunomodulatory Drugs; Results of the Myeloma XI Study

Result Type: Paper
Number: 553
Presenter: Charlotte Bradbury
Program: Oral and Poster Abstracts
Session: 331. Pathophysiology of Thrombosis II

Charlotte A Bradbury, PhD, MD, FRCPath, FRCP, MSc1,2*, Matthew W Jenner3*, Alina Striha, MSc4*, Gordon Cook, MD, PhD5*, Charlotte Pawlyn, BA, PhD, MBBChir, MRCP, FRCPath6, John R Jones, MD6*, David Cairns, BSc, MSc, PhD4*, Anna Hockaday4*, Andrea Paterson7*, Mark T Drayson, MD, PhD8*, Roger G Owen, MD9*, Martin F Kaiser, MD6, Walter M Gregory, PhD4*, Faith E. Davies, MD10, Gareth J. Morgan, MD, PhD10 and Graham H Jackson, MD, PhD11

1Department of Cellular and Molecular Medicine, University of Bristol, Bristol, ENG, United Kingdom
2Bristol Haematology and Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, United Kingdom
3Department of Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
4Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, Leeds, United Kingdom
5Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
6The Institute of Cancer Research, London, United Kingdom
7Clinical Trials Research Unit, University of Leeds, Bristol, United Kingdom
8Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
9St James’s University Hospital, Leeds, United Kingdom
10Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR
11Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, United Kingdom

 

Background: Patients with Multiple Myeloma (MM) are at high risk of thrombosis due to a combination of disease, treatment and patient factors such as age and comorbidity. Newly diagnosed MM (NDMM) patients treated with regimes that include immunomodulatory drugs (IMiDs) and glucocorticoids are at highest risk.

Methods: Myeloma XI is a Phase III, UK-based, multicenter, open label, parallel group, randomized controlled trial for NDMM patients. Patients are initially randomised between a thalidomide or lenalidomide triplet combination with cyclophosphamide and dexamethasone. This IMiD triplet was continued for a minimum of 4 cycles (transplant eligible, TE, CTD vs CRD) or 6 attenuated dose cycles (transplant non-eligible, TNE, CTDa vs CRDa) and to maximum response. Patients with sub-optimal response were then randomised to receive CVD consolidation (cyclophosphamide, bortezomib and dexamethasone) or no consolidation (pre-transplant, if applicable). Patients were also randomised (post-transplant, if applicable) to receive lenalidomide maintenance, continued until disease progression vs observation. The protocol stipulated thrombosis risk assessment based on IMWG guidelines (Palumbo et al, Leukaemia 2008) and a minimum of 3 months thromboprophylaxis, with Low Molecular Weight Heparin (LMWH) recommended for high-risk patients and aspirin for low-risk or if LMWH is unsuitable. Here we present thrombosis outcome data from patients treated (n=3838) in the Myeloma XI trial.

Results: Overall, thrombotic events occurred in 11.8% of patients (569 events in 451 of 3838) of which 61.2% were male with a median age of 67y (range 37-89). Patients with and without thrombosis were not significantly different with respect to age, gender, performance status, ethnicity, paraprotein type, light chain type, or serum creatinine. Venous events were more frequent than reported arterial events (91.8% vs 8.2% of events). During induction, thrombosis occurred in 10.8% (524 events in 416 of 3838) at 6 months with no difference between cumulative incidence for CTD vs RCD (p=0.353) or CTDa vs RCDa (p=0.449). At the time of first thrombosis, 365 of 416 patients (87.7%) were receiving thromboprophylaxis (142 aspirin, 161 prophylactic LMWH, 24 treatment dose LMWH and 12 treatment dose warfarin). Out of patients with thrombosis, 55.0% (229/416) had been assessed as high-risk and of these, 203 (88.6%) were receiving thromboprophylaxis (31.0% aspirin (71/229), 44.1% prophylactic LMWH (101/229), 4.4% treatment dose LMWH (10/229) and 4.8% treatment dose warfarin (11/229)).

Patients with and without thrombosis did not have significantly different overall survival, but progression-free survival(PFS) appeared slightly reduced for TE patients who developed thrombosis (p=0.0472) (Figure 1).

During CVD consolidation, 4.5% of patients developed thrombosis at 12m compared with 2.4% with no treatment (p=0.023). During maintenance, 2.2% of patients on lenalidomide maintenance developed thrombosis at 36m compared to 0.2% on observation (p<0.001). Discussion: In Myeloma XI, the incidence of thrombosis was high (11.8%), consistent with previous smaller studies using similar IMiD combination regimes. Patients were at highest risk throughout the first 6m of treatment and it may be reasonable to recommend a minimum of 6m thromboprophylaxis for NDMM patients receiving similar treatment. Lenalidomide and thalidomide appear to be associated with a similar thrombotic risk. Although lenalidomide maintenance increased thrombotic risk, the absolute risk was small and far less than in induction. The association with a reduction in PFS for TE patients developing thrombosis may be due to clinicians making changes in myeloma directed treatment resulting from thrombosis. There is also likely to be morbidity and psychological impacts associated with thrombosis that have not been assessed in this study.

Contrary to guidance, 12.3% of patients were not on thromboprophylaxis during induction prior to the thrombosis event and 31.0% of high-risk patients were on aspirin rather than the recommended LMWH. This may be due to difficulties with daily injections or other patient/clinician reasons. However, thrombosis predominantly occurred in patients who were on thromboprophylaxis (87.7%) which suggests new thrombosis prevention strategies are needed, particularly in the first 6m of treatment, and should be explored in future studies.

Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy

Result Type: Paper
Number: 740
Presenter: James Kochenderfer
Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation I

Jesus G. Berdeja, MD1, Yi Lin, MD, PhD2, Noopur Raje, MD3, Nikhil Munshi, MD4, David Siegel, MD, PhD5, Michaela Liedtke, MD6, Sundar Jagannath, MD7, Marcela V. Maus, MD, PhD3, Ashley Turka8*, Lyh Ping Lam, PharmD, RPh8*, Kristen Hege, MD9, Richard A. Morgan, PhD8, Michael Travis Quigley8* and James N. Kochenderfer, MD10

1Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN
2Division of Hematology, Mayo Clinic, Rochester, MN
3Massachusetts General Hospital Cancer Center, Boston, MA
4Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
5John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
6Department of Medicine, Stanford University School of Medicine, Stanford, CA
7Mount Sinai Hospital, New York, NY
8bluebird bio, Inc., Cambridge, MA
9Celgene Corporation, San Francisco, CA
10National Cancer Institute, National Institutes of Health Clinical Center, Bethesda, MD

 

Introduction: Chimeric antigen receptor (CAR) T cell therapies have demonstrated robust and sustained clinical responses in several hematologic malignancies. Data suggest that achieving acceptable benefit:risk profiles depends on several factors, including the specificity of the antigen target and characteristics of the CAR itself, including on-target, off-tumor activity. To test the safety and efficacy of CAR T cells in relapsed and/or refractory multiple myeloma (RRMM), we have designed a second-generation CAR construct targeting B cell maturation antigen (BCMA) to redirect T cells to MM cells. BCMA is a member of the tumor necrosis factor superfamily that is expressed primarily by malignant myeloma cells, plasma cells, and some mature B cells. bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB costimulatory motif and a CD3-zeta T cell activation domain.

Methods: CRB-401 (NCT02658929) is a multi-center phase 1 dose escalation trial of bb2121 in patients with RRMM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥ 50% BCMA expression on malignant cells. Peripheral blood mononuclear cells are collected via leukapheresis and shipped to a central facility for transduction, expansion, and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days then receive 1 infusion of bb2121. The study follows a standard 3+3 design with planned dose levels of 50, 150, 450, 800, and 1,200 x 10CAR+ T cells. The primary outcome measure is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional outcome measures were quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for Multiple Myeloma, evaluation of minimal residual disease (MRD), overall and progression-free survival, quantification of bb2121 in blood, and quantification of circulating soluble BCMA over time.

Results: As of May 4, 2017, 21 patients (median 58 [37 to 74] years old) with a median of 5 (1 to 16) years since MM diagnosis, had been infused with bb2121, and 18 patients were evaluable for initial (1-month) clinical response. Patients had a median of 7 prior lines of therapy (range 3 to 14), all with prior autologous stem cell transplant; 67% had high-risk cytogenetics. Fifteen of 21 (71%) had prior exposure to, and 6 of 21 (29%) were refractory to 5 prior therapies (Bort/Len/Car/Pom/Dara). Median follow-up after bb2121 infusion was 15.4 weeks (range 1.4 to 54.4 weeks). As of data cut-off, no DLTs and no treatment-emergent Grade 3 or higher neurotoxicities similar to those reported in other CAR T clinical studies had been observed. Cytokine release syndrome (CRS), primarily Grade 1 or 2, was reported in 15 of 21 (71%) patients: 2 patients had Grade 3 CRS that resolved in 24 hours and 4 patients received tocilizumab, 1 with steroids, to manage CRS. CRS was more common in the higher dose groups but did not appear related to tumor burden. One death on study, due to cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history, was observed while the patient was in sCR and was assessed as unrelated to bb2121. The overall response rate (ORR) was 89% and increased to 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. No patients treated with doses of 150 x 106 CAR+ T cells or higher had disease progression, with time since bb2121 between 8 and 54 weeks (Table 1). MRD negative results were obtained in all 4 patients evaluable for analysis. CAR+ T cell expansion has been demonstrated consistently and 3 of 5 patients evaluable for CAR+ cells at 6 months had detectable vector copies. A further 5 months of follow up on reported results and initial data from additional patients will be presented.

Conclusions: bb2121 shows promising efficacy at dose levels above 50 x 10CAR+ T cells, with manageable CRS and no DLTs to date. ORR was 100% at these dose levels with 8 ongoing clinical responses at 6 months and 1 patient demonstrating a sustained response beyond one year. These initial data support the potential of CAR T therapy with bb2121 as a new treatment paradigm in RRMM.

CT.gov study NCT02658929, sponsored by bluebird bio and Celgene

Tackling Early Morbidity and Mortality in Myeloma (TEAMM): Assessing the Benefit of Antibiotic Prophylaxis and Its Effect on Healthcare Associated Infections in 977 Patients

Result Type: Paper
Number: 903
Presenter: Mark Drayson
Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation II

Mark T Drayson, MD, PhD1*, Stella Bowcock, MD, BA, FRCP, FRCPath, MA2*, Tim Planche, MD PhD3*, Gulnaz Iqbal, PhD4*, Jill Wood, MPH4*, Kerry Raynes, MSc4*, Guy Pratt5, Kwee Yong, PhD6*, Peter Hawkey, FRCPath7*, Helen Higgins, MSc4* and Janet Dunn, PhD4*

1Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
2Department of Haematological Medicine, Queen Mary’s Sidcup NHS Trust, Sidcup, United Kingdom
3St George’s University Hospitals NHS Trust, London, United Kingdom
4University of Warwick, Warwick Clinical Trials Unit, Coventry, United Kingdom
5Centre for Clinical Haematology, University Hospital Birmingham, Birmingham, United Kingdom
6Department of Haematology, UCL Cancer Institute, United Kingdom
7Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom

 

Background: TEAMM (Tackling EArly Morbidity and Mortality in Myeloma) was a randomised, double-blind, placebo-controlled multi-centre phase III clinical trial assessing the benefits of antibiotic prophylaxis and its effect on healthcare associated infections. Infection in the first 12 weeks is the biggest cause of the high early death rate in myeloma. Levofloxacin is a quinolone antibiotic that is effective against the common bacterial infections in myeloma and taken once daily has proven efficacy as prophylaxis during therapy for other cancers. There has however been concern about the development of antibiotic resistance. We randomised the use of levofloxacin or placebo for 12 weeks to see if levofloxacin reduces febrile episodes and death in patients with newly diagnosed myeloma. Subjects were regularly screened for carriage of resistant organisms to detect if levofloxacin increases their carriage.

Methods: Patients were eligible if >21 years old with newly diagnosed symptomatic myeloma, intention to treat myeloma actively, and were +/- 14 days into a programme of anti-myeloma treatment. Patients were randomised to receive 500 mg levofloxacin or placebo tablets once daily for 12 weeks, dose adjusted for renal function. Patients were permitted to continue routine non-bacterial antimicrobial prophylaxis, including thrice weekly sulfamethoxazole-trimethoprim (SMZ-TMP) for pneumocystis. Faecal and throat samples were taken every 4 weeks to detect carriage of Clostridium difficile, MRSA and faecal ESBL-positive Gram-negative bacteria (ESBLGnB). The primary endpoint was the number of febrile episodes (defined as an oral temperature of ≥38°C treated with anti-infectives) and or death by any cause suffered in the first 12 weeks obtained using Kaplan-Meier curves censored at 12 weeks. Secondary outcomes included death, the number of clinically documented total infections, episodes of severe sepsis and suspected infections. Occurrence of febrile episodes was captured at clinic visits every 4 weeks up to 12 weeks. All patients were included in an intention to treat analyses.

Results: TEAMM recruited 977 patients between August 2012 and April 2016 from 92 centres within the UK. Median age was 67 years, 63% male, 76% had eGFR>50 ml/min, 54% had planned high dose chemotherapy with autologous-stem cell transplantation, 93% were ECOG performance status 0 to 2, 71% presented with bone disease. The primary endpoint showed a significant benefit for the use of levofloxacin with 134 of 488 patients (27%) on placebo reporting events (112 febrile episodes; 15 deaths; 7 febrile episodes and death) versus 95 of 489 patients (19%) on levofloxacin (87 febrile episodes; 4 deaths; 4 febrile episodes and death); hazard ratio (HR) 1.52 (95%CI 1.17-1.97) p=0.002, see figure 1. After 52 weeks there was no survival benefit between arms (p=0.94). Of the 586 total infections, there were 329 infections from 214 patients on the placebo arm and 257 infections from 189 patients on the Levofloxacin arm (chi-square=7.55,P-trend=0.006) with differences emerging after 4 weeks. C. difficilecarriage at baseline was uncommon (7 of 785 subjects). Levofloxacin significantly reduced the number of recoded invasive gram-negative infections, but not the number of reported Gram positive infections. SMZ-TMP (315 patients) significantly reduced the number of febrile episodes and deaths and the effect of SMZ-TMP was additive with the effects of levofloxacin. Cox regression adjusting for baseline factors showed levofloxacin treatment (HR=1.47, 95%CI=1.10-1.96, p=0.009) and prophylactic SMZ-TMP (HR=1.75 (95%CI=1.26-2.43, p=0.0008) to be significant predictors for reduction of febrile episodes or death within the first 12 weeks of starting trial treatment, see table 1. There was no significant difference between the 2 arms for carriage or infection with C. difficile, MRSA and ESBLGnB.

Conclusion: Prophylactic use of 12 weeks levofloxacin for patients undergoing treatment for active myeloma significantly reduces febrile episodes and deaths without increasing healthcare associated infections or carriage of key nosocomial pathogens. The value of adding SMZ-TMP to levofloxacin and for periods greater than 12 weeks needs to be explored in future trials.

Funding: Project funded by NIHR HTA programme (08/116/69). Views expressed are those of the authors and not those of the HTA programme, NIHR, NHS or the Department of Health.

Minimal Residual Disease in the Maintenance Setting in Myeloma: Prognostic Significance and Impact of Lenalidomide

Result Type: Paper
Number: 904
Presenter: Ruth De Tute
Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation II

Ruth M De Tute, BSc, MSc1*, David Cairns, BSc, MSc, PhD2*, Andy Rawstron, PhD3*, Charlotte Pawlyn, BA, PhD, MBBChir, MRCP, FRCPath4, Faith E. Davies, MD5,6, John R Jones, MD6*, Martin F Kaiser, MD6, Anna Hockaday2*, Alina Striha, MSc2*, Rowena Henderson, PhD2*, Gordon Cook, PhD7*, Nigel H. Russell, MD8, Mark T Drayson, MD, PhD9*, Matthew W Jenner10*, Walter M Gregory, PhD2*, Graham Jackson, MBBS, FRCP, FRCPath, MA, DM11, Gareth J. Morgan, MD, PhD5 and Roger G. Owen, MD3*

1Institute of Oncology, Leeds, United Kingdom
2Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, Leeds, United Kingdom
3Haematological Malignancy Diagnostic Service, St. James’s University Hospital, Leeds, United Kingdom
4Institute of Cancer Research, Sutton, United Kingdom
5Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR
6The Institute of Cancer Research, London, United Kingdom
7St James’s University Hospital, Leeds, United Kingdom
8Centre for Clinical Haematology, Nottingham University Hospital (City Hospital Campus), Nottingham, United Kingdom
9Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
10Department of Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
11Department of Haematology, NCCC Freeman Road Hospital, Newcastle Upon Tyne, United Kingdom

 

Introduction: Minimal residual disease (MRD) is a powerful predictor of outcome in multiple myeloma (MM). A recent meta-analysis has confirmed this and demonstrated a hazard ratio for PFS of 0.41; 95% CI, 0.36-0.48; P < .001 (Munshi et al, JAMA Oncol, Jan 2017). We have previously demonstrated the prognostic impact of MRD both following ASCT in transplant-eligible (TE) patients and following induction in transplant non-eligible (TNE) patients. There is more limited data on the applicability and significance of MRD assessment in the maintenance setting, largely as a consequence of high rates of drop-off historically within myeloma trials but improved outcomes have seen larger numbers of participants with samples at later timepoints. Patients and Methods: This analysis aims to assess the impact of MRD on PFS amongst patients receiving maintenance or no further therapy in the NCRI Myeloma XI trial. In this study patients were randomised between thalidomide (CTD) and lenalidomide (RCD) based induction therapies. For patients with a sub-optimal response to initial therapy, induction was supplemented with sequenced bortezomib-based induction (CVD). Intensively treated patients then proceeded to an autologous transplant and then responding patients from both intensive and non-intensive arms were subsequently randomised to maintenance with lenalidomide monotherapy, lenalidomide and vorinostat or no further therapy. Bone marrow aspirates were obtained prior to maintenance randomisation (100 days post ASCT for TE and at the end of (sequenced-) induction treatment for TNE) and 6 months post maintenance randomisation. This analysis represents a subset of 389 patients (median age 63.5 years) with an informative post maintenance randomisation bone marrow aspirate. MRD was assessed using flow cytometry (sensitivity 0.004%) with a minimum of 500,000 cells evaluated with six- or eight-colour antibody combinations including CD138/CD38/CD45/CD19/CD56/CD27 in all cases and CD81/CD117 added latterly.

Results:Taking the group as a whole, MRD-negativity was demonstrated in 206/389 (55.8%) and this was associated with a significant outcome advantage as the median PFS was >50 months versus 20 months for MRD-positive patients (Fig.1(a), p<0.0001, HR 0.2, 95% CI 0.11-0.37). When the pre-maintenance MRD result was also taken into account, outcome was best for patients achieving negativity post ASCT/end of treatment and remaining MRD-negative and worst for those patients who were MRD-positive post ASCT/end of treatment and remained so (Fig 1(b), p<0.0001). Conversions to MRD-negativity were seen in 32% of MRD-positive patients on maintenance compared to 4% of patients randomised to no further therapy (p=0.0045). This conversion is associated with some improvement in outcome, but this group still have inferior outcome relative to those patients achieving MRD-negativity earlier in protocol treatment. Conversions to MRD-positivity were also seen in 24 (9.5%) of 252 patients and the outcome for this patient group was similar to that of the patients who remain MRD-positive throughout (Fig. 1(b)). For those patients that remained MRD-positive, a benefit from maintenance could be demonstrated by a lower level of residual disease relative to those patients on observation (median level of neoplastic plasma cells 0.15% on maintenance vs 0.39%, p=0.04). Conclusions: We would conclude that MRD is a particularly powerful predictor of outcome in the maintenance setting and is clearly a desirable therapeutic goal in this patient group. The hazard ratio of 0.2 demonstrated here appears superior to those demonstrated in previous studies examining post induction or ASCT time-points. Approximately one third of MRD-positive patients receiving maintenance became MRD-negative and maintenance therapy also results in a decrease in disease levels in those patients remaining positive. These results support the role of MRD monitoring in assessment of the efficacy of different maintenance/consolidation strategies within clinical trials. In the longer term, a stratified approach to treatment based on sequential MRD assessments is feasible. The predictive ability of MRD during maintenance will be assessed with respect to overall survival when the primary endpoint matures in September 2017 and presented at the meeting.

Factors Predicting Poor Outcomes for Myeloma Patients at Different Ages: Results from 3894 Patients in the Myeloma XI Trial

Result Type: Paper
Number: 3040
Presenter: Charlotte Pawlyn
Program: Oral and Poster Abstracts
Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster II

Charlotte Pawlyn, BA, PhD, MBBChir, MRCP, FRCPath1,2, Martin F Kaiser, MD2,3, David Cairns, BSc, MSc, PhD4*, Alina Striha, MSc4*, John R Jones, MD2,3*, Vallari Shah, MBBS2*, Matthew W Jenner5*, Mark T Drayson, MD, PhD6*, Roger G Owen, MD7*, Walter M Gregory, PhD4*, Gordon Cook, MD, PhD8*, Graham Jackson, MBBS, FRCP, FRCPath, MA, DM9, Gareth J. Morgan, MD, PhD10 and Faith E Davies, MD11

1Institute of Cancer Research, Sutton, United Kingdom
2The Institute of Cancer Research, London, United Kingdom
3Department of Haematology, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom
4Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, Leeds, United Kingdom
5Department of Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
6Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
7St James’s University Hospital, Leeds, United Kingdom
8Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
9Department of Haematology, NCCC Freeman Road Hospital, Newcastle Upon Tyne, United Kingdom
10Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR
11Myeloma Institute, University of Arkansas, Little Rock, AR

 

 

Background: Phenotypically, high-risk myeloma is characterized by early progression and death. In younger patients this is known to correlate with a number of tumour acquired genetic changes such as the cytogenetic lesions t(4;14) and del(17p). Outcomes in older patients are further nuanced by features such as age, physical function and comorbidities, which play a role in treatment tolerability, dose intensity, duration and response. In this work we studied both patient-specific and tumour acquired variables and how these were impacted by age and their effect on outcome across patients of all ages in the NCRI Myeloma XI study.

Methods: Myeloma XI recruited 3894 patients and compared a triplet combination of cyclophosphamide, lenalidomide and dexamethasone to a similar combination with thalidomide (CRD vs CTD). At maximum response a maintenance randomization compared lenalidomide till disease progression vs observation. We summarise important variables by age group (<=50 n=311, 51-60 n=671, 71-80 n=1247, >80 n=247). A multivariate Cox regression analysis was performed within each age group to identify the variables with the greatest effect on outcome. Adverse cytogenetic lesions were defined as t(4;14), t(14;16), t(14;20), del(17p) and gain(1q). Standard risk was defined as the absence of any of these lesions, High-risk one lesion and Ultra High-risk >1 lesion.

Results: Neither progression-free (PFS) nor overall survival (OS) differed between patients aged <=50 years vs 51-60 but both significantly deteriorated with each additional decade of life thereafter (Figure 1). The proportion of patients with impaired performance status increased significantly with age (p<0.0001) and changes in biomarkers of frailty such as low albumin were also seen (p=0.048). There was a significant increase in the time from presentation to initial randomisation with age (p<0.001), potentially reflecting access to healthcare. There was no statistically significant difference across ages in tumour burden at presentation with a similar proportion of patients having >20% plasma cells on bone marrow biopsy and no significant difference in LDH. There was a significant increase in B2M with age (p<0.0001) but this may reflect renal function rather than disease burden, supported by a significant increase in both urea (p<0.0001) and creatinine (p<0.0001). The biological and genetic features of disease changed significantly across age groups. The youngest patient group (<=50) had an increased proportion of IgA subtype and decreased proportion of light chain only patients. In contrast the light chain type did not differ with age. The proportion of patients with each of the cytogenetic risk lesions t(4;14) and del(17p) fell significantly with age whilst those with gain(1q) increased. Therefore, despite these changes the proportion of patients classified as High-risk or Ultra High-risk did not change but the spectrum of lesions responsible for the classification did. Using multivariate Cox regression analysis of factors affecting PFS and OS we show that with advancing age cytogenetic based risk stratification has a lesser influence on outcome compared to other factors. Performance status had a clear impact on outcomes at all ages suggesting that physical frailty might be a more important driver of outcome that age itself. Conclusions: The spectrum and relative importance of patient-specific and tumour acquired biological and genetic features change significantly across age-groups of myeloma patients. This is important to understand as we design disease segmentation strategies to deliver personalized treatment approaches to improve patient outcomes. Whereas the focus in younger patients should be on targeting high-risk disease biology, approaches to improve outcomes for older patients will require a focus on clinical variables and treatment modification strategies.

Molecular Characterisation of TP53 Aberrations in 1,777 Myeloma Trial Patients

Result Type: Paper
Number: 4331
Presenter: Vallari Shah
Program: Oral and Poster Abstracts
Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster III

Vallari Shah, MBBS1*, Amy L Sherborne, PhD2*, Sidra Ellis1,3*, David C. Johnson, PhD1*, Farzana Begum1*, Jack Kendall1*, Brian A Walker, PhD4, John R Jones, MD3*, Charlotte Pawlyn, BA, PhD, MBBChir, MRCP, FRCPath5, Suvi Savola6*, Matthew W Jenner7*, Mark T Drayson, MD, PhD8*, Roger G. Owen, MD9*, David Cairns, BSc, MSc, PhD10*, Walter M Gregory, PhD10*, Richard S Houlston, MD, PhD1*, Faith E Davies, MD11, Gordon Cook, MD, PhD, FRCP, FRCPath12*, Gareth J. Morgan, MD, PhD4, Graham Jackson, MBBS, FRCP, FRCPath, MA, DM13 and Martin F Kaiser, MD1

1The Institute of Cancer Research, Sutton, United Kingdom
2Molecular Pathology, The Institute of Cancer Research, London, United Kingdom
3The Institute of Cancer Research, London, United Kingdom
4Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR
5Institute of Cancer Research, Sutton, United Kingdom
6MRC-Holland, Amsterdam, Netherlands
7Department of Haematology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
8Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
9Haematological Malignancy Diagnostic Service, St. James’s University Hospital, Leeds, United Kingdom
10Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, Leeds, United Kingdom
11Myeloma Institute, University of Arkansas, Little Rock, AR
12Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
13Department of Haematology, NCCC Freeman Road Hospital, Newcastle Upon Tyne, United Kingdom

 

Introduction: Aberrations of TP53 remain the most important adverse genetic prognostic factor in multiple myeloma (MM), even in the context of novel biologic combination therapies. However, there is still no consensus approach on how to assess this molecular marker in daily practice and within clinical trials. Main controversies exist in A) methods used to assess TP53 aberrations, B) definition of the optimal cut-off for calling TP53 deletions, C) whether heterozygous alterations have independent prognostic impact. Here, we report on comprehensive TP53 profiling of 1,777 myeloma patients from the UK NCRI Myeloma XI trial to inform the discussion towards a consensus regarding these questions.

Patients and methods: In the phase III multicenter Myeloma XI trial newly diagnosed patients with MM were randomised between thalidomide (CTD) or lenalidomide (CRD) based induction, a response-dependent bortezomib (CVD) intensification and lenalidomide +/- vorinostat maintenance or no maintenance. Transplant eligible patients received high dose melphalan+ ASCT after induction. The data cut-off for this analysis was July 2016 with a median follow-up of 36 months.

DNA from CD138-purified (>95%) bone marrow MM cells from 1,777 Myeloma XI patients was used for copy-number aberration (CNA) profiling with the MLPA P425 probemix (MRC Holland), which assays 3 representative exons of TP53 (Shah V, et al, Leukemia 2017). 1,178 patient tumors were further analysed with probemix X073, covering all exons of TP53. Previously published exome sequencing data was available for 422 patients (Walker B, et al, JCO 2015). Survival analyses were performed in R 3.4.1, C-statistics were used for evaluating adequacy of risk prediction.

Results: We systematically tested different clonal fraction cut-off thresholds for calling TP53 deletions and confirmed an optimal cut-off of <0.75 by MLPA, equivalent to a 20% cut-off by iFISH (Boyle EM, et al, GenChromCanc 2015), identifying 9% of patients with a hazard ratio (HR) for OS of 2.4 (CI: 1.9-3.1; P=1.1x10-12; C-statistics 0.55). Increasing stringency of the cut-off resulted in a loss of sensitivity, e.g. a cut-off of <0.55 by MLPA (equivalent to 60% by iFISH) identified 3.4% of patients with a HR for OS of 2.3 (CI: 1.6-3.5; P=3.3x10-6; C-statistics 0.52). Accordingly, a less stringent cut-off of <0.85 by MLPA (10% clonal fraction) decreased specificity with a HR for OS of only 1.6 (CI: 1.3-2.0; P=1.29x10-6; C-statistics of 0.54). Results were consistent for progression free survival (PFS).

We next examined the impact of homozygous and heterozygous alterations of TP53 on outcome. Seven of 1,178 MM tumors (0.6%) carried homozygous deletions of at least one exon of TP53. Homozygous deletions were associated with very short median OS of 22.4 months and a HR for OS of 4.0 (CI: 1.7-9.7; P=0.002). Heterozygous deletions were detected in 8.1% of cases and were also clearly associated with shorter survival (median OS 33.5 vs. 60.3 months without deletion) and a HR for OS of 2.2 (CI: 1.7-3.0; P=8.4x10-8(Figure 1). The association with outcome for homo- and heterozygous deletions was independent of ISS, gain of 1q and adverse translocations by multivariable analysis. Results were consistent in the sub-group of patients receiving intensive therapy.

In the 422 patients assessed for TP53 deletions and mutations, bi-allelic loss (e.g. deletion and mutation) was found in 1.9% (n=8) and mono-allelic loss in 8.3% (n=35) of tumors. Again, both bi- and mono-allelic TP53 loss were associated with inferior survival, with median OS of 12.2 months (HR 5.2; CI: 2.4-11.5; P=2.6x10-5) for bi-allelic loss vs. 31.0 months for mono-allelic loss (HR 2.1; CI: 1.3-3.3; P=0.002) vs. 60.3 months in the group with normal TP53 status (Figure 1).

Conclusion: With this detailed analysis of TP53 aberrations in 1,777 trial patients from a single trial, we confirm the independent prognostic significance of mono-allelic TP53 alterations. Our data establish MLPA with a cut-off at <0.75, equivalent to 20% by iFISH, as a suitable molecular method for TP53 CNA detection that can be readily applied in standard diagnostic laboratories. Harmonisation of TP53 assessment is highly warranted for consistent outcome reporting and to facilitate meta-analyses, inside and outside of clinical trials.[/et_pb_text][et_pb_image src="http://www.post-ash.co.uk/wp-content/uploads/2018/01/4331.jpg" _builder_version="3.0.92"][/et_pb_image][et_pb_text _builder_version="3.0.92"]

Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible for Transplant (ALCYONE)

Result Type: Paper
Number: LBA-4
Presenter: Maria-Victoria Mateos
Program: General Sessions
Session: Late-Breaking Abstracts Session

Maria-Victoria Mateos, MD, PhD1, Meletios A. Dimopoulos2, Michele Cavo, MD3*, Kenshi Suzuki4*, Andrzej J. Jakubowiak, MD5, Stefan Knop, MD6*, Chantal Doyen, MD7, Paulo Lucio8*, Zsolt Nagy, MD, PhD9*, Polina Kaplan10*, Ludek Pour, Doc, MD, PhD11*, Mark Cook, MBChB, PhD12, Sebastian Grosicki, MD, PhD13, Andre H Crepaldi, MD14*, Anna Marina Liberati15*, Philip Campbell, MBBS, FRACP, FRCPA16, Tatiana Shelekhova17*, Sung-Soo Yoon, MD, PhD18*, Genadi Iosava19*, Tomoaki Fujisaki, MD20*, Mamta Garg, MD21*, Christopher Chiu, PhD22, Jianping Wang23*, Robin Carson, MD, BA24, Wendy Crist, BA22*, William Deraedt25*, Marie Nguyen23*, Ming Qi22* and Jesus F. San-Miguel, MD26

1University Hospital of Salamanca/IBSAL, Salamanca, Spain
2National and Kapodistrian University of Athens, Athens, Greece
3Institute of Hematology Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
4Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
5University of Chicago Medical Center, Chicago, IL
6Würzburg University Medical Center, Würzburg, Germany
7Université catholique de Louvain, CHU UCL Namur, Namur, Belgium
8Champalimaud Foundation, Lisbon, Portugal
9Semmelweis Egyetem, Budapest, Hungary
10Dnepropetrovsk City Clinical Hospital #4, Dnepropetrovsk, Ukraine
11Department of Internal Medicine, Haematooncology and Oncology, University Hospital Brno, Brno, Czech Republic
12University Hospitals Birmingham NHS Trust, Birmingham, United Kingdom
13Department of Cancer Prevention, School of Public Health, Silesian Medical University in Katowice, Katowice, Poland
14Clinica de Tratamento E, Cuiaba, Brazil
15Azienda Ospedaliera “Santa Maria, Terni, Italy
16Andrew Love Cancer Centre, Geelong, Australia
17Clinic of Professional Pathology, Saratov, RUS
18Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea, Republic of (South)
19LTD “Medinvent” Institute of Health, Tbilisi, Georgia
20Matsuyama Red Cross Hospital, Matsuyama, Japan
21Leicester Royal Infirmary – Haematology, Leicester, United Kingdom
22Janssen Research & Development, Spring House, PA
23Janssen Research & Development, Raritan, NJ
24Janssen Biotech, Horsham, PA
25Janssen Research & Development, Beerse, Belgium
26Clínica Universidad de Navarra-CIMA, IDISNA, Pamplona, Spain

 

Introduction: VMP is a standard of care (SOC) for transplant ineligible NDMM. Daratumumab (D), a human IgGκ anti-CD38 monoclonal antibody with a direct on-tumor and multifaceted immunomodulatory mechanism of action significantly improves PFS and depth of response in combination with SOC in relapsed MM. Treatment-naïve pts may benefit greatly with the addition of D to SOC regimens. Here we report the results from the ALCYONE study, where D is added to VMP in transplant ineligible NDMM.

Methods: Pts ≥65 years or otherwise ineligible for high-dose chemotherapy with autologous stem cell transplantation were randomized 1:1 to VMP ± D and stratified by International Staging System (ISS [I, II, III]), region (Europe vs other) and age (<75 vs ≥75 years). All pts received up to a maximum of nine 6-week cycles of VMP. V: 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, 32 (Cycle 1) and Days 1, 8, 22, and 29 (Cycles 2-9); M: 9 mg/m2 PO and P: 60 mg/m2PO on Days 1-4 (Cycles 1-9). In the D-VMP arm, D was given at 16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ (post VMP-treatment phase) until disease progression. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), rate of very good partial response (VGPR) or better, rate of complete response (CR) or better, minimal residual disease (MRD)–negativity rate (10-5 threshold, Adaptive clonoSEQ® Assay), overall survival (OS), and safety.

Results: Of 706 pts randomized (350 D-VMP; 356 VMP), median (range) age was 71 (40-93) years; 29.9% were ≥75 years; 46.3% were male. 74.9% of pts had ECOG scores ≥1, and 19.3%, 42.4%, and 38.4% were ISS stage I, II, and III, respectively. Of 616 pts evaluable for FISH/karyotyping cytogenetic analysis, 84.1% and 15.9% were standard and high risk (positive for del17p, t[14;16], t[4;14]), respectively. At the timepoint of the prespecified analysis after 231 PFS events on 12 June 2017, pts had received a median (range) of 12 (1-24) vs 9 (1-9) treatment cycles for D-VMP vs VMP, respectively. 80% of pts in the D-VMP arm completed 9 treatment cycles of VMP vs 62% of pts in the VMP arm. Median (range) cumulative bortezomib doses were 46.9 (1.3-55.3) mg/m2 vs 42.2 (2.6-55.0) mg/m2 for D-VMP vs VMP, respectively.

At a median follow-up of 16.5 months, the hazard ratio for PFS (D-VMP vs VMP) was 0.50 (95% confidence interval, 0.38-0.65, P <0.0001), representing a 50% reduction in the risk of progression or death in pts treated with D-VMP (Figure). Median PFS was not reached vs 18.1 months for D-VMP vs VMP. The PFS treatment benefit of D-VMP vs VMP was consistent across all pre-specified subgroups, including age ≥75 years, ISS stage III, and high-risk cytogenetics. ORR (90.9% vs 73.9%), ≥VGPR (71.1% vs 49.7%), ≥CR (42.6% vs 24.4%) and MRD-negativity rate (22.3% vs 6.2%) were significantly higher for D-VMP vs VMP (all < 0.0001; Table). OS data were immature after 93 deaths (45 vs 48 deaths for D-VMP vs VMP). The most common (≥20%) all-grade treatment emergent adverse events (TEAE; D-VMP/VMP) were neutropenia (49.7%/52.5%), thrombocytopenia (48.8%/53.7%), anemia (28.0%/37.6%), peripheral sensory neuropathy (28.3%/34.2%), upper respiratory tract infection (26.3%/13.8%), diarrhea (23.7%/24.6%), pyrexia (23.1%/20.9%), and nausea (20.8%/21.5%). Most common (≥10%) grade 3/4 TEAEs (D-VMP/VMP) were neutropenia (39.9%/38.7%), thrombocytopenia (34.4%/37.6%), anemia (15.9%/19.8%), and pneumonia (11.3%/4.0%). Only 1 pt in each arm discontinued treatment due to pneumonia. The rates of grade 3/4 infections were 23.1% vs 14.7% and treatment discontinuations due to infections were 0.9% vs 1.4% for D-VMP vs VMP. D-associated infusion-related reactions (27.7%) mostly were grade 1/2 (grade 3/4, 4.3%/0.6%) and most (92.7%) occurred during the first infusion. Tumor lysis syndrome occurred in <1% of pts in each arm. Second primary malignancy occurred in 2.3% vs 2.5% pts in D-VMP vs VMP. Conclusion: The combination of D with VMP in transplant ineligible NDMM pts doubled the PFS (HR 0.50), which was driven by more pts achieving deep responses, including significantly higher ≥CR rate and tripling of the MRD-negativity rate. No new safety signals were observed when combining D with VMP. Three phase 3 studies have now demonstrated a consistent doubling of PFS and more than threefold increase in MRD-negativity rate when combining D with SOC regimens. These results support the use of a D-based combination, D-VMP, in transplant ineligible NDMM.

Impact of Bortezomib- or Lenalidomide-Based Induction Treatment on High Risk Cytogenetic Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Enrolled in the Gimema-MM-03-05 and EMN01 Trials

Result Type: Paper
Number: 744
Presenter: Alessandra Larocca
Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation I

Alessandra Larocca1*, Massimo Offidani, MD2, Pellegrino Musto, MD2, Francesca Patriarca, MD2*, Lorenzo De Paoli, MD2*, Paolo Corradini, MD2, Marco Salvini, MD1*, Clotilde Cangialosi, MD2*, Tommasina Guglielmelli, MD2*, Giovannino Ciccone3*, Fausto Dore, MD2*, Angelo Belotti, MD2*, Mattia D’Agostino, MD1*, Felicetto Ferrara, MD2*, Daniela Oddolo1*, Riccardo Centurioni, MD2*, Fabrizio Ciambelli, MD2*, Stefano Spada1*, Donatella Iolanda Vincelli, MD2*, Michele Cavo, MD2*, Nicola Giuliani, MD, PhD2, Alberto Bosi, MD2*, Concetta Conticello, MD2*, Roberto Ria, MD2*, Maria Teresa Petrucci, MD2* and Mario Boccadoro1

1Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy
2Italian Multiple Myeloma Network, GIMEMA, Italy
3Unit of Cancer Epidemiology, University of Torino and CPO Piemonte, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy

 

Introduction: Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment.

Methods: In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)).

Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR).

Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value.

Results: 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p<0.001), ISS3 20% vs 27% (P=0.65), HiR patients were 29% vs 26%, StR patients were 71% vs 74% (p=0.32) and the median follow-up was 72.3 and 63.6 months, respectively. In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B). BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A). Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02. BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A). In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045. Conclusions: BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetic

Daratumumab, Lenalidomide, and Dexamethasone (DRd) Versus Lenalidomide and Dexamethasone (Rd) in Relapsed or Refractory Multiple Myeloma (RRMM): Updated Efficacy and Safety Analysis of Pollux

Result Type: Paper
Number: 739
Presenter: Meletios Dimopoulos
Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation I

Meletios A. Dimopoulos1, Darrell J. White, MD2, Lofti Benboubker, MD3*, Gordon Cook, MD, PhD4*, Merav Leiba5*, James Morton6*, P. Joy Ho, MBBS, DPhil, FRACP, FRCPA, FFSc(RCPA)7*, Kihyun Kim8*, Naoki Takezako, MD, PhD9, Sonali Trivedi10*, Kaida Wu10, Tineke Casneuf11*, Christopher Chiu10, Jordan Schecter12* and Philippe Moreau13*

1National and Kapodistrian University of Athens, Athens, Greece
2Dalhousie University and QEII Health Sciences Centre, Halifax, NS, Canada
3Service d’Hématologie et Thérapie Cellulaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire (CHRU), Tours, France
4St James’s Institute of Oncology, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, United Kingdom
5Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center,Tel Hashomer, Ramat Gan, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
6Icon Cancer Care, South Brisbane, QLD, Australia
7Institute of Haematology Royal Prince Alfred Hospital, Camperdown, NSW, Australia
8Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of (South)
9National Hospital Organization Disaster Medical Center, Tokyo, Japan
10Janssen Research & Development, Spring House, PA
11Janssen Research & Development, Beerse, Belgium
12Janssen Research & Development, LLC, Raritan, NJ
13Hematology, University Hospital Hôtel-Dieu, Nantes, France

 

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Daratumumab induces rapid, deep, and durable responses in combination with a proteasome inhibitor (bortezomib) or an immunomodulatory drug (lenalidomide or pomalidomide) in patients with RRMM (Palumbo A, et al. N Engl J Med 2016. 375(8):754-766; Dimopoulos MA, et al. N Engl J Med 2016.375(14):1319-1331; Chari A, et al. Blood 2017. Epub ahead of print). At the time of the pre-specified interim analysis of the phase 3 study POLLUX (median follow-up of 13.5 months), DRd reduced the risk of disease progression or death by 63% and significantly improved the overall response rate (ORR) compared with Rd alone (92.9% vs 76.4%; <0.001). This analysis reports updated efficacy and safety data in POLLUX based on longer follow-up. Methods: Patients (pts) who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide: 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone: 40 mg PO per week) with or without daratumumab (16 mg/kg IV weekly for Cycles 1 and 2, q2w for Cycles 3-6, then q4w until disease progression). The primary endpoint was progression free survival (PFS). Minimal residual disease (MRD) was assessed on bone marrow aspirate samples at the time of suspected complete response (CR) and at 3 and 6 months after suspected CR at sensitivity thresholds of 10–4, 10–5, and 10–6 via the clonoSEQTM next-generation sequencing assay (V.1.3; Adaptive Biotechnologies, Seattle, WA). For PFS on subsequent line of therapy (PFS2; defined as time from randomization to progression after next line of subsequent therapy or death) was examined as an exploratory endpoint.

Results: Pts in both treatment groups (DRd, n=286; Rd, n=283) received a median of 1 prior line of therapy and 18% of patients received prior treatment with lenalidomide. After a median follow-up of 25.4 months, PFS was significantly prolonged with DRd vs Rd (median, not reached [NR] vs 17.5 months; HR, 0.41; 95% CI, 0.31-0.53; P<0.0001; Figure 1A). A higher ORR was observed with DRd compared with Rd (93% vs 76%; P<0.0001), including significantly higher rates of ≥very good partial response (79% vs 48%; P<0.0001) and ≥CR (51% vs 21%; P<0.0001; Figure 1B). DRd prolonged the duration of response compared with Rd (median, NR vs 26.0 months).

MRD-negative rates were >3-fold higher with DRd vs Rd at all sensitivity thresholds evaluated. At a sensitivity threshold of 10–5, MRD-negative rates were 26% with DRd vs 6% for Rd (P<0.0001) and pts with MRD-negative status accumulated more rapidly with DRd vs Rd. Regardless of treatment group, PFS was prolonged in pts who achieved MRD-negative status compared with MRD-positive status. PFS2 was significantly improved with DRd vs Rd in the intent to treat (ITT) population (HR, 0.55; 95% CI, 0.40-0.76; P=0.0002; Figure 2A). Among MRD-negative (10–5) pts who received DRd (n=75) or Rd (n=18), no significant differences in PFS2 were observed between treatment groups (Figure 2B). Time to next therapy was also significantly prolonged with DRd vs Rd in the ITT population (median, NR vs 22.7 months; HR, 0.34; 95% CI, 0.25-0.46; P<0.0001). The most common (≥10%) grade 3/4 TEAEs included neutropenia (54% vs 40%), anemia (16% vs 21%), thrombocytopenia (14% vs 16%), and pneumonia (12% vs 9%), in pts treated with DRd vs Rd, respectively. The incidence of TEAE-related treatment discontinuations was similar between groups, occurring in 12% of pts in both treatment groups. No differences in the incidence of secondary primary malignancies were observed between treatment groups (16 [6%] patients in each group). Updated data will be presented at the meeting. Conclusion: This updated analysis reveals that DRd continues to demonstrate a significant PFS benefit compared with Rd alone, and pt responses continue to deepen with DRd with longer follow up. Pts who receive DRd demonstrated longer time to next therapy and responded more favorably to subsequent therapy as evidenced by prolonged PFS2, suggesting that patients continue to observe clinical benefit from prior daratumumab treatment. Importantly, the favorable safety profile was maintained with longer follow-up. These data support the addition of daratumumab to standard of care regimens in RRMM.

Impact of Next-Generation Flow (NGF) Minimal Residual Disease (MRD) Monitoring in Multiple Myeloma (MM): Results from the Pethema/GEM2012 Trial

Result Type: Paper
Number: 905
Presenter: Bruno Paiva
Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation II

Bruno Paiva, PhD1*, Noemi Puig, MD, PhD2*, Maria Teresa Teresa Cedena Romero3*, Lourdes Cordon4*, Maria-Belen Vidriales5*, Leire Burgos6*, Juan Flores-Montero7*, Lucía Lopez-Anglada3*, Norma Gutierrez, MD, PhD8*, Maria Jose Calasanz, BSc, PhD9*, Maria Luisa Martin-Ramos3*, Ramon Garcia-Sanz, MD, PhD10*, Joaquin Martinez-Lopez, MD, PhD11*, Albert Oriol, MD12*, M Jesús Blanchard13*, Rafael Rios14*, Jesús Martín15*, Rafael Martínez16*, Josep Sarra17*, Miguel T Hernández18*, Javier de la Rubia, MD19*, Isabel Krsnik20*, Jose M Moraleda21*, Luis Palomera22*, Juan Bargay23*, Alberto Orfao, MD, PhD24, Laura Rosinol, MD, PhD25*, Maria-Victoria Mateos, MD, PhD26, Juan-José Lahuerta27*, Joan Bladé, MD, PhD28 and Jesus F. San Miguel, MD29

1Centro de Investigación Médica Aplicada, University of Navarra, Clínica Universidad de Navarra, Pamplona, Spain
2IBSAL, Hospital Universitario de Salamanca, Salamanca, Spain
3Hospital 12 de Octubre, Madrid, Spain
4Hospital Universitario La Fe, Valencia, Spain
5Hospital Universitario Salamanca, Salamanca, Spain
6Clinica Universidad de Navarra, Pamplona, Spain
7Servicio de Citometría de flujo de la Universidad de Salamanca, Salamanca, Spain

8IBSAL, University Hospital of Salamanca, Salamanca, Spain
9Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada (CIMA), IDISNA, CIBERONC, Pamplona, Spain

10University Hospital of Salamanca, Salamanca, ESP
11Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain
12ICO Badalona, Hospital Germans Trias i Pujol, Badalona, Spain
13Hospital Ramón y Cajal, Madrid, Spain

14Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain
15Hospital Universitario Virgen del Rocío, Sevilla, Spain

16Hospital Clínico San Carlos, Madrid, Spain
17ICO L’HOSPITALET, Barcelona, Spain
18Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
19Hematology Department, Universidad Católica de Valencia Hospital Dr. Peset, Valencia, Spain
20Hospital Puerta de Hierro, Madrid, ESP
21Hospital Virgen de la Arrixaca, El Palmar, Spain
22Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain

23Hospital Son Llatzer, Palma de Mallorca, Spain
24Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), University of Salamanca; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain
25Hospital Clinic i Provincial, Barcelona, Spain
26University Hospital of Salamanca, Salamanca, Spain
27Hospital 12 de Octubre, CIBERONC, Madrid, Spain
28Servicio de Onco-Hematología, Hospital Clínica de Barcelona, Barcelona, Spain

29Centro de Investigación Médica Aplicada, University of Navarra, Clinica Universidad de Navarra, Pamplona, Spain

 

Background:MRD is an established biomarker to evaluate treatment efficacy, define patients at risk based on persistent MRD, and eventually, act as surrogate for prolonged survival based on sensitive MRD-negative definitions. Accordingly, the IMWG has developed criteria for MRD-negativity defined by next-generation sequencing, NGF or PET/CT, and has recommended their inclusion in clinical trials. Notwithstanding, most flow cytometry results have been obtained using less sensitive methods and in fact, there is no data about the impact of NGF-based MRD assessment in clinical trials.

Aim: To define the feasibility, sensitivity and clinical impact of NGF-based MRD assessment in the phase III PETHEMA/GEM2012 trial.

Methods: A total of 458 patients were enrolled into the PETHEMA/GEM2012 trial. MRD was predefined to be prospectively assessed at three time-points: after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), after HDT/ASCT, and after two courses of consolidation with VRD. MRD monitoring was performed blinded for clinical outcomes in four PETHEMA/GEM laboratory cores, and data was centralized for MRD analyses. MRD assessment was performed following EuroFlow SOPs in a total of 1,134 bone marrow (BM) samples from 419 patients. The 39 cases without MRD assessment had suboptimal response to induction and were thus considered as MRD+ for intention-to-treat analyses. Noteworthy, in 14 BM samples with undetectable MRD, B-cell precursors, erythroblasts and mast cells represented <0.01% of BM cells, and these samples were thus considered as hemodiluted and inadequate for MRD assessment. The limit of detection (LOD) was determined for each of the 1,117 BM samples representative for MRD assessment, according to the formula: (20/nucleated viable cells) x 100; the median LOD achieved by NGF in the PETHEMA/GEM2012 trial was of 3x10-6.

Results: Overall, 225/458 (49%) patients had undetectable MRD at the latest time-point in which MRD was assessed and were thus classified as MRD-. Conversely, 233/458 (51%) cases remained MRD+: 28% with ≥10-4MRD, 12% with 10-5 MRD, and 11% with 10-6 MRD. Detailed analyses of MRD kinetics in 320 patients with available MRD results at all three time-points, showed that the percentage of MRD- patients increased from 35% into 54% and 58% after induction, HDT/ASCT and consolidation, respectively. Furthermore, a restricted analysis among MRD+ patients showed that whereas after induction only 8% of them had MRD levels as low as 10-6, subsequent intensification with HDT/ASCT and consolidation could reduce MRD levels down to 10-6 in 32% of MRD+ cases.

Progression-free survival (PFS) rates at 3-years were of 92%, 70%, 54% and 44% for patients being MRD-negative, MRD+ 10-6, 10-5 and ≥10-4, respectively (P<.001; Figure). Thus far, only 6/225 (3%) MRD- patients have relapsed; strikingly, all 6 cases had extramedullary plasmacytomas at diagnosis, all relapsed with extramedullary plasmacytomas, and only 2 had concomitant serological relapse. The favorable outcome of MRD- patients encouraged us to investigate the impact of MRD negativity in both standard- and high-risk patients defined by FISH [i.e.: t(4;14), t(14;16), and/or del(17p)]. Even though MRD- rates were significantly inferior in patients with high- vs standard-risk FISH (37% vs 50%, respectively; P=.03), 3-year PFS rates were similar between patients with high- and standard-risk FISH reaching MRD-negativity (94% and 91%, respectively; P=.56); by contrast, MRD+ cases with high- and standard- risk FISH had median PFS of 27 and 35 months, respectively (P=.025). Conclusions: This is the largest study of MRD monitoring in MM based on the total number of samples analyzed (n=1,134). Our results show that NGF-based MRD assessment is feasible in large multicenter clinical trials, is highly-sensitive, and allows the identification of hemodiluted BM samples inadequate for MRD assessment. Risk of relapse among MRD-negative patients was remarkably reduced (3%), and was particularly related to the reappearance of extramedullary plasmacytomas, which urges the need for combined cellular and imaging MRD monitoring in these patients; by contrast, even MRD levels as low as 10-5 and 10-6 conferred significantly inferior PFS. Overall, this study defines MRD-negativity as the most relevant clinical endpoint for both standard- and high-risk transplant-eligible MM patients.