ALBERT

Description: Key Points DLBCL patients carrying the HLA-B44 supertype have a worse progression-free and overall survival after R-CHOP-like treatment. The HLA-DRB1*01 allele increases the risk of DLBCL development.

Description: Introduction:SMM is an asymptomatic and heterogeneous plasma cell disorder. The Spanish Myeloma Group demonstrated that patients at high risk of progression benefit from early treatment with Rd. In addition, our preliminary results of the curative approach (GEM-CESAR) showed encouraging results (Mateos ASH 2017). Aim: The primary end-point was to evaluate the Minimal Residual Disease negative (MRD-ve) rate by next generation flow (NGF) after induction and ASCT and the sustained MRD-ve rate at 3 and 5 yrs after ASCT as secondary end-points. Our aim was to increase the MRD -ve rate from 34% (reported in NDMM patients after VTD and ASCT) to 50%. As all patients have completed induction and ASCT, we report the results of the primary end point, efficacy and safety after induction and ASCT. Methods: In this phase II single arm trial, 90 SMM patients at high-risk of progression (〉50% at 2 yrs), younger than 70 yrs and transplant candidates were included. The high risk was defined by the presence of both ≥PC 10% and MC ≥3g/dL (Mayo criteria) or ifonly one criterion was present, patients must have a proportionof aberrant PCs within the total PCsBM compartment by immunophenotypingof 95% plus immunoparesis (Spanish criteria). Asymptomatic MM patients with any of the three biomarkers recently included into the definition of active MM were allowed to be included. 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 at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2followed by 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 at dose of 20 mg weekly for up to 2 yrs Results: Between June 2015 and June 2017, the 90 SMM patients at high risk of progression were recruited. Twenty-eight pts (32%) shared at least one of the new biomarkers predicting imminent risk of progression to MM. The primary end point of the trial was met, since 55% of the patients who completed induction and ASCT achieved MRD -ve by NGF (sensitivity 3 x 10-6). Upon analyzing the results after induction, 88 patients completed the 6 induction cycles and were evaluable for response (two patients early discontinued): the ORR was 98% including 41% of ≥CR (32% sCR and 9% CR) and 41% of VGPR rate. Two patients were mobilization failures and one patient rejected ASCT. Two additional patients experienced biological progression before ASCT and went off the study. Eighty-three patients, therefore, proceeded to HDT-ASCT and were evaluable at day +100: the ORR was 100% including ≥CR in 63% of the patients (51% sCR and 12% CR) and VGPR rate in 23%. The MRD-ve rate increased from 31% after induction to 55% with the ASCT. No differences in outcome have been observed according neither to the definition of high risk (Mayo or Spanish model) nor ultra high risk SMM. Concerning toxicity, during induction, G3-4 neutropenia and thrombocytopenia were reported in 5 (6%) and 10 pts (11%), respectively. G3-4 infections were the most frequent non-hematological AE observed in 16 pts (18%), followed by skin rash in 8 pts (9%). One patient reported G1 atrial fibrillation and another cardiac failure secondary to respiratory infection. Three patients reported hypertension (G2 in two and G3 in one). Thirteen patients required lenalidomide dose reduction whilst carfilzomib was not reduced in any patient. In four patients, dexamethasone was reduced. In all but two of the pts, PBSC collection was successful with a median of 4.10 x 106/Kg CD34 cells collected. All patients engrafted. Consolidation and maintenance phases are ongoing. After a median follow-up of 17 months (5-36), 94% of patients remain alive and free of progression and 97% of them alive. Three patients experienced biological progression and discontinued the study: one of them was refractory to the rescue therapies and died and the other two are receiving rescue therapies. One additional patient died early during induction due to a massive ischemic stroke unrelated to the treatment. Conclusions: Although longer follow-up is required, this "curative strategy for high risk SMM" continues being encouraging with an acceptable toxicity profile. The study has met its primary endpoint. The depth of response improved over the treatment: 63% of patients who completed induction and ASCT achieved ≥CR with a MRD-ve rate of 55%. Disclosures Mateos: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rodriguez Otero:Takeda: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Clínica Universidad de Navarra: Employment. Ocio:AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Oriol:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rios:Amgen, Celgene, Janssen, and Takeda: Consultancy. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Alegre:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Puig:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. García Mateo:Binding Site: Research Funding; Amgen: Honoraria; Celgene: Honoraria. Bladé:Janssen: Honoraria. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Novartis: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Roche: Honoraria.

Description: Key Points Benefit from panobinostat-dexamethasone-bortezomib was greatest in patients who received ≥2 prior regimens including bortezomib and IMiDs.

Description: Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these “second-generation” PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade.

Description: Multiple myeloma (MM) pathogenesis has been explained for many years by the cancer biology dogma introduced by Peter Nowell: first, a single plasma cell would be immortalized by an error in the immunoglobulin genes rearrangement process; then, a progressive stepwise acquisition of somatic cell mutations would induce a sequential selection and domination by the fittest clone. In line with this idea of “myeloma stability”, SNP arrays studies in diagnostic-relapse paired samples have revealed the presence of common clonal characteristics. Biologically, the M-protein remains usually constant across MM evolution and further, the variable domain of the rearranged immunoglobulin heavy chain genes (or CDR3 region) has been used as a patient-specific myeloma fingerprint in minimal residual disease (MRD) studies. However, massive genome studies with Next Generation Sequencing (NGS) have challenged this concept, showing a significant intraclonal heterogeneity at diagnosis with the possible presence of several clonal progenitors or tumor-initiating cells. In this study, we have characterized and compared the CDR3 region in 52-paired samples from 26 MM patients aiming: 1) to assess mono-clonality in MM evolution through the analysis of the CDR3 sequence and, 2) to validate ASO RQ-PCR approaches for MRD in MM, based on the constancy and specificity of the CDR3 region. Samples were obtained at diagnosis and progression (19 pairs) or at 2 different timepoints of progressive disease (7 pairs). Median time between sampling was 2 years. M-protein subtype remained stable in all pairs but 1, associated with a light-chain escape phenomenon. All samples proceeded from bone marrow (BM) except for 2 pairs, composed by BM and extramedullary disease (spleen and testes). Two major cytogenetic changes were identified: increased 13q14 deletion (from 7 to 54%) in 1 pair and increased 17p (p53) deletion (from 5 to 87%) in a further one. Treatments administered between sampling included most of the current approaches used in MM (data not shown). Genomic DNA isolation, PCR amplification and sequencing were performed following conventional methods. Germline VH, DH and JH segments were identified by comparison with public databases. CDR3 region was first identified in all samples and then compared between the two samples in the 26 pairs: the sequence of nucleotides was constantly identical in each pair, including those associated with major cytogenetic changes, a light-chain escape, extramedullar vs. BM infiltration and relapsed (and therefore, treatment selected) vs. refractory disease. Therefore, we can first conclude that the main tumor clone in MM retains a specific signature across all stages of disease evolution that allows the identification of samples as evolutionary related. This major clone signature is not modified by clinical or biological changes in the disease nor under different treatment pressures and would thus identify disease relapse and progression. Our results have also a clear impact on the validity of molecular MRD techniques. The high rate of complete responses (up to 50-60%) currently achieved in MM has prompted the use of new techniques for disease assessment. Today, ASO RQ-PCR, based on the use of specific primers and probes complementary of the VDJH rearrangement, continues to be the most sensitive approach. One pitfall of this technique would be the potential instability of PCR targets over time, which would induce false negative results. In B-cell precursor ALL, this is estimated to happen in 30-40% of cases but has not been deeply evaluated in MM yet. With the present study, we can also conclude that the junction region of the VDJH rearrangement in MM constantly identifies the myeloma cells responsible for relapse and therefore can be used as a reliable target for MRD assessment by ASO RQ-PCR and more recently, by NGS methods. If the CDR3 region remains stable, the novel concept of clonal tiding in MM should not be interpreted as a poly- or oligoclonal but subclonal. In MM, tides can be subclonal, but the ocean remains monoclonal. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Daratumumab (DARA) is a human IgGκ mAb targeting CD38 with both direct on-tumor and immunomodulatory mechanisms of action, and has been approved as monotherapy for RRMM and in combination with standard of care (SOC) regimens for RRMM and newly diagnosed MM (NDMM). Across three phase 3 DARA studies in RRMM and NDMM, DARA plus SOC reduced the risk of progression or death by ≥50%, enabled a doubling of CR rates, and elicited a ≥3-fold increase in MRD-negative rates. Among MRD-negative RRMM pts, pts treated with D-Rd or D-Vd rapidly achieved MRD negativity and demonstrated prolonged progression-free survival (PFS) vs MRD-positive pts (Avet-Loiseau H, et al. ASH 2016. Abstract 246). MRD assessment is being investigated as a potential surrogate for established endpoints such as overall survival (OS). When measured sequentially, sustained MRD-negativity provides an index of deep clinical responses that may provide a more robust assessment of disease control (Kumar S, et al. Lancet Oncol 2016. 17[8]:e328-e346). Here, we evaluate sustained MRD negativity with DARA plus SOC regimens and its association with PFS/OS outcomes in RRMM. Methods: Eligible pts in POLLUX and CASTOR received ≥1 prior line of therapy and were randomized (1:1) to receive SOC treatment regimens ± DARA. Pts in the POLLUX study were given lenalidomide (25 mg PO) on Days 1-21 and dexamethasone (40 mg) once per week in each 28-day cycle ± DARA (16 mg/kg IV) given weekly for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter. CASTOR pts received 8 cycles (21 d/cycle) of bortezomib (1.3 mg/m2 SC) on Days 1, 4, 8, and 11 and dexamethasone (20 mg) on Days 1, 2, 4, 5, 8, 9, 11, and 12 ± DARA (16 mg/kg IV) given weekly for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. MRD was assessed at the time of suspected CR and at 3 and 6 months following confirmed CR in POLLUX, and at time of suspected CR and 6 and 12 months following the first treatment dose in CASTOR. Additional MRD evaluation was required in both studies every 12 months post-CR. MRD was assessed via next generation sequencing using the clonoSEQ® assay V2.0 (Adaptive Biotechnologies, Seattle, WA). Sustained MRD negativity was defined as the maintenance of MRD negativity in the bone marrow confirmed ≥6 or ≥12 months apart and was evaluated in the intent-to-treat (ITT) population. Sustained MRD negativity was also evaluated among ≥CR pts to account for different sustained MRD negativity rates between treatment arms. Results: A total of 569 (D-Rd, n = 286; Rd, n = 283) pts in POLLUX and 498 pts (D-Vd, n = 251; Vd, n = 247) in CASTOR were randomized; median (range) number of prior lines received was 1 (1-11) and 2 (1-10), respectively. Median duration of follow up was 39.5 months in POLLUX and 31.3 months in CASTOR for this analysis. Using the ≥6-month sustained MRD cutoff, a significantly higher proportion of pts achieved sustained MRD negativity for ≥6 months when treated with D-Rd vs Rd (16% vs 0.7%; P

Description: Abstract 3989 Background: Treatment patterns of multiple myeloma (MM) vary across the globe, mostly dictated by the availability and patient access to different drug therapies. The outcomes of patients with MM, especially relapsed myeloma can be significantly affected by the availability of newer treatments, as well as potential biological differences related to ethnicity. We have previously shown that the outcome of patients relapsing after therapy with bortezomib (Bz) and one or more of the IMiDs remain poor with the currently available treatments and represent a difficult group of patients to treat. We undertook the current analysis on a set of patients from United States, several European countries and South Korea. Methods: We designed a multicenter, retrospective study that enrolled 294 patients with relapsed MM, from 14 sites (122 from Europe, 107 from US, and 65 from Korea). Patients were refractory to Bz, defined as no response to prior Bz-containing regimen or disease progression within 60 days of a Bz-containing regimen. Patients were also relapsed, refractory, intolerant, and/or ineligible, to treatment with an IMiD (thalidomide or lenalidomide). The date patients satisfied the above entry criteria was defined as time zero (T0). Clinical and laboratory data from diagnosis and individual relapses were collected along with details of all MM drug therapies before and after T0. Responses were assessed by IMWG or EBMT criteria. The goal of the study was to compare the characteristics of patients who satisfy the above inclusion criteria, the therapies employed prior to and after T0 and clinical outcome among these patients from different parts of the world. Results: The mean (median, range) time to reaching T0 from diagnosis was 4.5 (4.0, 12.8), 4.2 (3.2, 18.6), and 3.2 (2.8, 9.6) years from diagnosis for patients from US, Europe and Korea, respectively, P=0.021. The mean (median, range) number of therapies for the three groups were 8 (8, 13), 4 (4, 10), 5 (4, 7), respectively; P=PR) to the initial therapy at diagnosis were 56%, 77% and 49% respectively for the US, European and Korean cohorts. Overall 220 patients had at least one therapy after T0, and 114 (52%) had a novel agent (Bz, len or thal) containing regimen as their first treatment after T0. Patients in US were more likely to receive additional therapies after the first post-T0 therapy; 62%, 32%, and 12% of patients from US, Europe and Korea, respectively, began a second post-T0 regimen within 2 years following time zero. The median number of therapies post T0 was 2, 1, and 1 for patients in US, Europe and Korea respectively. The response rates to the first regimen after T0 were 15%, 33% and 19% for the US, European and Korean cohorts, and were similar between those receiving a regimen with one of the novel drugs compared to rest. Patients younger than 60 years and those with prior transplants were more likely to respond to post T0 regimens. The median time to progression or death from T0was similar for the three patient cohorts, 5 months (Figure 1A). The median overall survival (95% CI) from T0 was 13 months (10, 16), 7 (5,9) and 8 (4,9) respectively for the US, European and Korean cohorts (Figure 1B). Conventional prognostic factors, especially the ISS stage was predictive of OS post T0. Additionally, presence of extramedullary disease was associated with a shorter overall survival. Conclusion: The results of the current study demonstrate significant differences between different parts of the world in terms of the treatment patterns both in the setting of initial therapy as well as treatment of relapsed disease. Patients in the US were more likely to receive multiple regimens both before and after T0. This is likely a reflection of increasing numbers of new drugs that have gone into clinical trials and thus enhancing options. The study further highlights the poor outcome of patients who have relapsed after the new drugs, irrespective of the geographical location. Disclosures: Kumar: Merck: Consultancy, Honoraria; Genzyme: Consultancy; Celgene: Consultancy. Richardson:Millennium: ; Celgene: ; Johnson & Johnson: ; Novartis: ; Bristol Myers Squibb:. Moreau:Millennium Pharmaceuticals, Inc.: Advisory board, Honoraria; Janssen: Advisory board, Honoraria. Sonneveld:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Siegel:Merck: Honoraria; Millenium: Honoraria, Research Funding, Speakers Bureau. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees.