Background Combined therapy with carfilzomib, bendamustine, and dexamethasone was evaluated in this multicenter phase 1/2 trial conducted within the European Myeloma Network (EMN09 trial). Methods Sixty-three patients with relapsed/refractory multiple myeloma who had received >= 2 lines of prior therapy were included. The phase 1 portion of the study determined the maximum tolerated dose of carfilzomib with bendamustine set at 70 mg/m(2) on days 1 and 8. After 8 cycles, responding patients received maintenance therapy with carfilzomib and dexamethasone until progression. Results On the basis of the phase 1 results, the recommended phase 2 dose for carfilzomib was 27 mg/m(2) twice weekly in weeks 1, 2, and 3. Fifty-two percent of patients achieved a partial response or better, and 32% reached a very good partial response or better. The clinical benefit rate was 93%. After a median follow-up of 21.9 months, the median progression-free survival was 11.6 months, and the median overall survival was 30.4 months. The reported grade >= 3 hematologic adverse events (AEs) were lymphopenia (29%), neutropenia (25%), and thrombocytopenia (22%). The main nonhematologic grade >= 3 AEs were pneumonia, thromboembolic events (10%), cardiac AEs (8%), and hypertension (2%). Conclusions In heavily pretreated patients who have relapsed/refractory multiple myeloma, combined carfilzomib, bendamustine, and dexamethasone is an effective treatment option administered in the outpatient setting. Infection prophylaxis and attention to patients with cardiovascular predisposition are required.

Aggregation of human wild-type transthyretin (hTTR), a homo-tetrameric plasma protein, leads to acquired senile systemic amyloidosis (SSA), recently recognised as a major cause of cardiomyopathies in 1–3% older adults. Fragmented hTTR is the standard composition of amyloid deposits in SSA, but the protease(s) responsible for amyloidogenic fragments generation in vivo is(are) still elusive. Here, we show that subtilisin secreted from Bacillus subtilis , a gut microbiota commensal bacterium, translocates across a simulated intestinal epithelium and cleaves hTTR both in solution and human plasma, generating the amyloidogenic fragment hTTR(59–127), which is also found in SSA amyloids in vivo. To the best of our knowledge, these findings highlight a novel pathogenic mechanism for SSA whereby increased permeability of the gut mucosa, as often occurs in elderly people, allows subtilisin (and perhaps other yet unidentified bacterial proteases) to reach the bloodstream and trigger generation of hTTR fragments, acting as seeding nuclei for preferential amyloid fibrils deposition in the heart.

Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).

Background:Multiple myeloma (MM) is a clinically heterogeneous disease and several classification systems have been developed to stratify patients in low, intermediate or high risk. Tumor Circulating Plasma Cells (TCPC) are considered a marker of high‐risk disease in all plasma cell disorders. To date, different methods are available to detect TCPC in peripheral blood, but they are barely reproducible and time consuming.Aims:For the first time the amount of TCPC was quantified in newly diagnosed MM patients with a single platform flow cytometric method and was evaluated their correlation with patients‘ baseline characteristics.Methods:Whole peripheral blood (PB) samples from 413 newly diagnosed young MM patients enrolled in the UNITO‐MM‐01/FORTE trial were included in the study. For the single platform technique, the antibody combination CD38PC7/CD138PC5.5/CD45KO/ CD56PE/CD19PB was mixed with 100 μL of EDTA PB, dispensed with reverse pipetting, and incubated for 15 min at RT, added with 500 μL of lysing solution and, after 15 min, 100 μL of flow count fluorospheres were dispensed with reverse pipetting and cells acquired with Navios flow cytometer. Intracytoplasmic kappa and lambda were tested to confirm the TCPC clonality.Results:Circulating Plasma Cells (CPC) were found in 390 out of 413 samples (94.4%), with median values of 0.03% (range: 0%>51%) and 2.37/mm3 (range: 0/mm3–6272/mm3). White blood cells were 5710/mm3 (range: 1752/mm3–26102/mm3); median CPC events 58 (range: 0–441.000); cellular events acquired were 190.000 (range: 4.428–1.300.000).TCPC were found in 272 samples (66%) with a median value of 1.24/mm3 (range 0.06/mm3 ‐ 6272/mm3).Patients were stratified according to different baseline characteristics and median values of absolute TCPC were compared. The most significant statistical differences (p < 0.001) were: Hb <10 (12.9/mm3) vs ≥10 (0.81/mm3); ISS I (0.30/mm3) vs ISS II (2.85/mm3) vs ISS III (5.14/mm3); R‐ISS I (0.25/mm3) vs II (2.76/mm3) vs III (5.14/mm3); Albumin <3.5 g/dL (2.76/mm3) vs ≥3.5 g/dL (1.05/mm3); β2‐microglobulin <3.5 mg/dL (0.67/mm3) vs 3.5 mg/dL‐5.5 mg/dL (3.88/mm3) vs >5.5 mg/dL (16.47/mm3); LDH ≤upper limit (1.14/mm3) vs >upper limit (7.36/mm3); PC in biopsy <60% (0.60/mm3) vs ≥60% (2.76/mm3); with 1q gain (3.18/mm3) vs without (1.18/mm3); Morgan risk Standard (1.16/mm3) vs High (3.00/mm3) (presence of del17 and/or t(4;14) and/or t(14;16) and/or 1q gain).Moreover, the TCPC were sorted in quartiles according to the absolute values (0/mm3–0/mm3, 0/mm3–1.24/mm3, 1.24/mm3–8.3/mm3, 8.3/mm3–6272/mm3) and a correlation between the increasing levels of TCPC and the parameters mentioned above was observed.The most significant correlations expressed by Cramer's V were observed between TCPC and: hemoglobin (V = 0.41), ≥60% of plasma cells in biopsy (V = 0.28), ISS (V = 0.26), β2‐microglobulin <3.5 mg/dL vs 3.5 mg/dL‐5.5 mg/dL vs >5.5 mg/dL (V = 0.26), R‐ISS (V = 0.24), Morgan risk (V = 0.24 p < 0.001), 1q gain (V = 0.24) all with a p < 0.001.Summary/Conclusion:The single platform flow cytometric method allowed us to quantify TCPC in a high number of MM patients and the values obtained were strongly related to the worst clinical and cytogenetic features. This method is fast, not expensive, feasible with a small amount of PB and can be easily performed in a high number of patients.

n the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction therapy was prospectively evaluated in transplant-ineligible patients with multiple myeloma. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. The analysis presented here (median follow-up of 71 months) is focused on maintenance treatment and on subgroup analyses defined according to the International Myeloma Working Group Frailty Score. Of the 654 evaluable patients, 217 were in the lenalidomide-dexamethasone arm, 217 in the melphalan-prednisone-lenalidomide arm and 220 in the cyclophosphamide-prednisone-lenalidomide arm. With regards to the Frailty Score, 284 (43%) patients were fit, 205 (31%) were intermediate-fit and 165 (25%) were frail. After induction, 402 patients were eligible for maintenance therapy (lenalidomide arm, n=204; lenalidomide-prednisone arm, n=198). After a median duration of maintenance of 22.0 months, progression-free survival from the start of maintenance was 22.2 months with lenalidomide-prednisone vs 18.6 months with lenalidomide (hazard ratio 0.85, P=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; P=0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-lenalidomide (hazard ratio 0.72, P=0.05) and lenalidomide-dexamethasone (hazard ratio 0.72, P=0.04). Likewise, a trend towards a better overall survival was noted for patients treated with melphalan-prednisone-lenalidomide or cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a full-dose triplet regimen, while intermediate-fit and frail patients benefit from gentler regimens. ClinicalTrials.gov registration number: NCT01093196.

Twice-weekly carfilzomib is approved at 27 and 56 mg/m2 to treat relapsed multiple myeloma patients. In the phase III study ARROW, once-weekly 70 mg/m 2 carfilzomib prolonged the median progression-free survival of relapsed multiple myeloma patients in comparison with twice-weekly 27 mg/m2 carfilzomib, without adding significant toxicity. Data were pooled from two phase I/II studies of newly diagnosed multiple myeloma patients who received nine induction cycles of carfilzomib (either 70 mg/m2 once-weekly or 36 mg/m2 twice-weekly), cyclophosphamide and dexamethasone, followed by carfilzomib maintenance. Overall, 121 transplant-ineligible patients with newly diagnosed multiple myeloma were analyzed (once-weekly, n=63; twice-weekly, n=58). We found no significant difference in median progression-free survival [35.7 months (95%CI: 23.7-not reached, NR) vs. 35.5 months (95%CI: 24.3-NR); HR: 1.39; P=0.26] and 3-year overall survival [70% [95%CI: 59%-84%) vs. 72% (95%CI: 60%-85%); HR: 1.27; P=0.5] between once-weekly and twice-weekly carfilzomib. From the start of maintenance, 3-year progression-free survival [47% (95%CI: 33%-68%) vs. 51% (95%CI: 38%-70%); HR: 1.04; P=0.92] and overall survival [72% (95%CI: 58%-89%) vs. 73% (95%CI: 59%-90%); HR: 0.82; P=0.71] were similar in the once- versus twice-weekly carfilzomib. The rate of grade 3-5 hematologic (24% vs. 30%; P=0.82) and non-hematologic (38% vs. 41%; P=0.83) adverse events was similar in the two groups. Once-weekly 70 mg/m2 carfilzomib as induction and maintenance therapy for newly diagnosed multiple myeloma patients was as safe and effective as twice-weekly 36 mg/m2 carfilzomib and provided a more convenient schedule. The trials are registered at clinicaltrials.gov identifiers: 01857115 (IST-CAR-561) and 01346787 (IST-CAR-506).

: We conducted a pooled analysis of two phase III trials, RV-MM-EMN-441 and EMN01, to compare maintenance with lenalidomide-prednisone vs. lenalidomide in newly diagnosed transplant-eligible and -ineligible myeloma patients. Primary endpoints were progression-free survival, progression-free survival 2 and overall survival with both regimens. A secondary aim was to evaluate the impact of duration of maintenance on overall survival and on outcome after relapse. A total of 625 patients (lenalidomide-prednisone arm, n = 315; lenalidomide arm, n = 310) were analyzed. The median follow-up was 58 months. Median progression-free survival (25 vs. 19 months; p = 0.08), progression-free survival 2 (56 vs. 49 months; p = 0.9) and overall survival (73 months vs. NR; p = 0.08) were not significantly different between the two arms. Toxicity profiles of lenalidomide-prednisone and lenalidomide were similar, with the exception of neutropenia that was higher in the lenalidomide arm (grade ≥ 3: 9% vs. 19%, p < 0.001), without an increase in the rate of infections. Overall survival (median NR vs. 49 months, p < 0.001), progression-free survival from relapse (median 35 vs. 24 months, p = 0.004) and overall survival from relapse (median not reached vs. 41 months, p = 0.002) were significantly longer in patients continuing maintenance for ≥2 years. We showed that the addition of prednisone at 25 or 50 mg every other day (eod) to lenalidomide maintenance did not induce any significant advantage.

Despite recently introduced immunotherapeutic strategies the selection of an efficient, well-tolerated and affordable treatment option for advanced patients with relapsed/refractory multiple myeloma (RRMM) remains challenging. Since bendamustine (B) and the proteasome inhibitor carfilzomib (K) seem safe even in compromised patients and act synergistically a combination termed KBd including dexamethasone (d) was evaluated. This multicenter phase 1/2 trial was conducted within the European Myeloma Network as EMN09 study.

Introduction Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell proliferation with a very poor prognosis. The prevalence of poor-risk genetic lesions is higher compared with newly diagnosed multiple myeloma. pPCL requires urgent control of clinical manifestations to prevent early death because of irreversible disease complications. The aim of the EMN12/ HOVON129 study is to improve the outcome of younger and elderly patients with pPCL by incorporating carfilzomib and lenalidomide in induction, consolidation, and maintenance. This trial was registered at www.trialregister.nl as NTR5350. Methods In this ongoing non-randomized, phase 2, multicenter study, patients with previously untreated pPCL receive induction therapy with carfilzomib-lenalidomide-dexamethasone (KRd; 28-day cycles with carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16; lenalidomide 25 mg days 1-21; dexamethasone 20 mg on days 1,2,8,9,15,16,22,23). In patients ≤65 years, 4 cycles of KRd induction is followed by tandem autologous stem cell transplantation (SCT), KRd consolidation, and then maintenance with carfilzomib (27 mg/m2 on days 1,2,15,16) and lenalidomide (10 mg on days 1-21/28 days) until progression. Patients who are eligible for allogeneic SCT, may also receive autologous-allogeneic tandem transplantation. Patients ≥66 years receive 8 cycles of KRd followed by carfilzomib+lenalidomide maintenance. Supportive care consists of antibacterial-, herpes zoster-, and thrombosis-prophylaxis. Inclusion criteria are newly diagnosed pPCL (>2x109/L circulating monoclonal plasma cells or plasmacytosis >20% of the differential white cell count) and WHO-performance status 0-3. Main exclusion criteria are severe cardiac or pulmonary dysfunction; and creatinine clearance of <15 ml/min. There are no restrictions based on blood counts. Here we report the results from the first planned interim analysis for patients aged ≤65 years. The objective of this analysis was to describe overall response rate (ORR) and toxicity of induction therapy for the first 15 registered patients aged ≤65 years. Results From October 2015 till May 2019, we enrolled 33 patients with pPCL, 21 aged ≤65 years and 12 aged ≥66 years. Among the first 15 patients aged ≤65 years, 47% were males; median age was 62 years (range 31-65); 67% had bone disease; and WHO performance status was 2 in 20% and 3 in 27% of patients. Patients had a high tumor burden with a median plasma cell percentage in BM biopsy of 90%. The median peripheral blood plasma cell count was 5.2x109/L (range 2.0-27.4); median platelet count was 121x109/L (range 27-289); and median GFR was 53 ml/min (range 15-81 ml/min). Patients had high-risk disease as evidenced by ISS stage 3 in 67%; elevated LDH in 53%; and high frequency of high-risk genetic lesions (del(17p) in 58%, t(4;14) in 8%, t(14;16) in 8%, del(1p) in 50%, ampl(1q) in 58%). In addition, 20% of patients had extramedullary disease. Among the first 15 registered patients, 14 received the planned 4 cycles of induction treatment, while one patient went off protocol after cycle 3 due to disease progression. After 4 induction cycles, (stringent) CR was achieved by 5 (33%), at least VGPR by 12 (80%), and ≥PR by 14 patients (93%). Table 1 shows adverse events that occurred throughout induction treatment. Adverse events mainly occurred during the first cycle of KRd, and decreased thereafter. Hematological toxicity was limited. One patient experienced a grade 3 infection. Cardiac events occurred in 2 patients: 1 grade 3 myocardial infarction, and 1 grade 2 heart failure. No patients discontinued treatment because of toxicity. Mortality during induction was 0%. In all 21 patients aged ≤65 years, 14 (67%) experienced one or more serious adverse events (SAEs), mainly hospitalizations. The majority of these SAEs occurred during the first KRd cycle (Figure 1). Conclusions KRd induced deep hematologic responses after 4 cycles of therapy (≥VGPR in 80% and ≥CR in 33%) without early death. Toxicity consisted of 20% grade 3 and 27% grade 4 events, occurred mainly during the first cycle of induction, and was manageable with appropriate interventions. In conclusion, KRd provides efficient and rapid disease control, which is essential to prevent early mortality because of irreversible disease complications and to improve survival of patients with this aggressive plasma cell proliferative disorder. Disclosures Van De Donk: Janssen Pharmaceuticals: 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; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees. Schjesvold:Novartis: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyliteDX: Honoraria; MSD: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Minnema:Jansen Cilag: Honoraria; Servier: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Celgene Corporation: Honoraria, Research Funding. Offidani:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caers:Celgene: 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; 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. Zweegman:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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. Sonneveld:Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Hajek:Amgen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Celgene: Honoraria, Other: Consultant or advisory relationship, Research Funding; AbbVie: Other: Consultant or advisory relationship; Bristol-Myers Squibb: Honoraria, Other: Consultant or advisory relationship, Research Funding; Novartis: Other: Consultant or advisory relationship, Research Funding; PharmaMar: Honoraria, Other: Consultant or advisory relationship; Takeda: Honoraria, Other: Consultant or advisory relationship, Research Funding; Janssen: Honoraria, Other: Consultant or advisory relationship, Research Funding. Gay:AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Janssen: 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; 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; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Vangsted:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Jansen: Honoraria. Musto:Celgene: Honoraria; AMGEN: Honoraria. OffLabel Disclosure: KRd is used for primary plasma cell leukemia

8002 Background: High and comparable rates of MRD negativity were seen in NDMM pts after 4 28-day induction cycles with KRd followed by ASCT and 4 KRd consolidation (KRd_ASCT_KRd) and after 12 KRd cycles (KRd12), showing the superiority of both regimens over KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). Here we evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of pts. Methods: 474 NDMM pts ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10-5) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with R-ISS 1 and R-ISS 2/3. Since high-risk pts may sometimes respond rapidly, but then relapse early, we also analyzed the rate of early relapse (<18 months from randomization). We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow-up was 25 months. Rates of ≥VGPR, ≥CR, sCR, MRD negativity were comparable between KRd_ASCT_KRd and KRd12 overall, in pts with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table). A significantly lower number of pts experienced early relapse with KRd_ASCT_KRd vs KRd12 (12 pts [8%] vs 26 pts [17%]; P=0.015). This difference was mainly related to a significantly lower rate of early relapse in R-ISS Stage 2/3 pts receiving KRd_ASCT_KRd vs KRd12 (11 pts [12%] vs 22 pts [23%]; P=0.05); no difference was seen in R-ISS 1 (0 vs 2 pts). In multivariate regression analysis, KRd_ASCT_KRd vs KRd12 reduced the risk of early progression (OR 0.42; P=0.021); R-ISS Stage 2 (OR 3.6; P=0.001) and R-ISS Stage 3 (OR 4.85; P=0.003) increased the risk compared with R-ISS 1. Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk pts achieving MRD negativity. In high-risk pts ASCT reduced the risk of early relapse. Clinical trial information: NCT02203643. [Table: see text]

Background: Continuous lenalidomide‐dexamethasone (Rd) is an effective and safe treatment for elderly newly diagnosed multiple myeloma (NDMM) patients. However, the outcome of patients >75 years is still inferior to younger patients, and not only advanced age but also the occurrence of severe adverse events (AEs) may negatively affect duration of treatment and survival. Aims: In order to further optimize Rd treatment, we investigated the efficacy and feasibility of sparing continuous dexamethasone in a dose/schedule‐adjusted Rd therapy followed by lenalidomide maintenance (Rd‐R) compared with standard continuous Rd in intermediate‐fit NDMM patients. Methods: The IMWG frailty score combines age, functional status (ADL and IADL), and comorbidities (Charlson index, CCI), and it identifies fit, intermediate‐fit and frail patients, with different risk of toxicity, treatment discontinuation and mortality (Palumbo A et al. Blood 2015) . Intermediate‐fit NDMM patients (Age 76–80 years or ADL≤4 or IADL≤5 or CCI≥2), with a frailty score = 1 ( http://www.myelomafrailtyscorecalculator.net/ ) were randomized to receive Rd‐R or continuous Rd. Rd‐R treatment consisted of nine 28‐day cycles of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, followed by lenalidomide maintenance 10 mg/day (21 days), until progression. Continuous Rd consisted of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, until progression. The dose and schedule of continuous Rd was the one adopted in patients >75 years in the FIRST trial (Hulin C et al. JCO 2016) . The primary endpoint was event‐free survival (EFS), defined as progression or death for any cause or discontinuation of lenalidomide or occurrence of any hematological grade 4 or non‐hematological grade 3–4 AEs, including Secondary Primary Malignancies, whichever comes first. Results: Of 199 evaluable patients, 98 were randomized to Rd‐R and 101 to continuous Rd. Median age was 75 and 76 years (p = 0.06); 47% in Rd‐R vs 57% in continuous Rd were defined intermediate‐fit for age (≥76 years), 53% vs 43% due to an impairment in CCI, ADL or IADL (p = ns). The median follow‐up was 25 months. Best response rates were comparable between the 2 groups: ≥PR rates were 73% vs 63%, and ≥VGPR rates were 43% vs 35% in the Rd‐R vs Rd continuous group, respectively. EFS was 9.3 vs 6.6 months (HR 0.72, 95% CI 0.52–0.99, p = 0.04), in Rd‐R versus continuous Rd, respectively. No difference in progression‐free survival (PFS) and overall survival (OS) was observed. 20‐month PFS was 43% vs 42% (HR 0.93, 95% CI 0.64–1.34, p = 0.681), 20 month‐OS was 84% versus 79% (HR 0.73, 95% CI 0.40–1.33, p = 0.306; Figure 1). At least 1 non‐hematologic grade 3–4 AE rate was 31% vs 39%. The most frequent grade3–4 AEs were neutropenia (17% vs 14%), infections (9% vs 11%) and skin rash (3% vs 7%). Lenalidomide dose reduction was required in 33% of Rd‐R patients and 43% of continuous Rd patients, and lenalidomide was discontinued in 19% vs 23% of patients, respectively. Lenalidomide median relative dose intensity was 100% in Rd‐R and 90% in continuous Rd group. Summary/Conclusion: Switching to lenalidomide maintenance after 9 cycles of Rd – thus sparing steroid in this dose/schedule‐adjusted Rd‐R treatment ‐ was feasible, without a negative impact but with outcome comparable to standard continuous Rd. This is the first prospective randomized phase III trial specifically designed for intermediate‐fit NDMM patients in which a frailty‐adjusted treatment approach to balance efficacy and safety was investigated. image

Extramedullary disease is relatively frequent in multiple myeloma, but our knowledge on the subject is limited and mainly relies on small case series or single center experiences. Little is known regarding the role of new drugs in this setting. We performed a meta-analysis of eight trials focused on the description of extramedullary disease characteristics, clinical outcome, and response to new drugs. A total of 2,332 newly diagnosed myeloma patients have been included; 267 (11.4%) had extramedullary disease, defined as paraosseous in 243 (10.4%), extramedullary plasmocytoma in 12 (0.5%), and not classified in 12 (0.5%) patients. Median progression-free survival was 25.3 months and 25.2 in extramedullary disease and non-extramedullary disease patients, respectively. In multivariate analysis the presence of extramedullary disease did not impact on progression-free survival (hazard ratio 1.15, P=0.06), while other known prognostic factors retained their significance. Patients treated with immunomodulatory drugs, mainly lenalidomide, or proteasome inhibitors had similar progression-free survival and progression-free survival-2 regardless of extramedullary disease presence. Median overall survival was 63.5 months and 79.9 months (P=0.01) in extramedullary and non-extramedullary disease patients, respectively, and in multivariate analysis the presence of extramedullary disease was associated with a reduced overall survival (hazard ratio 1.41, P<0.001), in line with other prognostic factors. With the limits of the use of low sensitivity imaging techniques, that lead to an underestimation of extramedullary disease, we conclude that in patients treated with new drugs the detrimental effect of extramedullary disease at diagnosis is limited, that lenalidomide is effective as are proteasome inhibitors, and that these patients tend to acquire a more aggressive disease in later stages. (EUDRACT2005-004714-32, NCT01063179 NCT00551928, NCT01091831, NCT01093196, NCT01190787, NCT01346787, NCT01857115).

In patients with a complete response (CR), high-dose therapy with autologous stem cell transplantation (HDT-ASCT) consolidation improved progression-free survival (PFS), second PFS (PFS2), and overall survival (OS) versus R-Alk (lenalidomide, alkylator) consolidation. Also, lenalidomide maintenance therapy enhanced PFS compared with no maintenance therapy. The survival advantage with HDT-ASCT compared with R-Alk in CR patients can be attributed to the greater minimal residual disease negativity rate induced by HDT-ASCT. Background: High-dose therapy with autologous stem cell transplantation (HDT-ASCT) and maintenance treatment with novel agents are the best options for patients with newly diagnosed multiple myeloma, increasing the rate of complete response (CR) and prolonging progression-free survival (PFS) and overall survival (OS). Indeed, the achievement of a CR is a predictor of long-term survival among transplant-eligible patients. However, it is unclear whether patients reaching a CR after induction treatment could receive less intense consolidation or avoid maintenance therapy. Patients and Methods: We analyzed CR patients treated in 2 phase III trials, GIMEMA-RV-MM-PI-209 and RV-MM-EMN-441, to compare HDT-ASCT with an R-Alk (lenalidomide, alkylator) regimen as consolidation, and lenalidomide (R) maintenance with no maintenance. The primary endpoints were PFS, second PFS (PFS2), and OS from consolidation and maintenance (_m). Results: Overall, the data from 166 patients in CR were analyzed, 95 in the HDT-ASCT group and 71 in the R-Alk group. The CR patients who received HDT-ASCT had a better PFS (hazard ratio [HR], 0.55; P = .01), PFS2 (HR, 0.46; P = .02), and OS (HR, 0.42; P = .03) compared with patients randomized to R-Alk. The survival benefit with HDT-ASCT was confirmed among all the subgroups, according to age, International Staging System (ISS stage, cytogenetic profile, and receipt of maintenance therapy. CR patients who received lenalidomide maintenance had a better PFS_m (4 years: 54% vs. 19%; HR, 0.43; P = .02) compared with those who received no maintenance. However, no difference was observed in terms of PFS2_m (4 years: 72% vs. 58%; HR, 0.83; P = .67) and OS_m (4 years: 79% vs. 72%; HR, 0.82; P = .73) with maintenance therapy. Conclusion: Even in CR patients, outcomes were improved by an intensified approach with HDT-ASCT consolidation and lenalidomide-based maintenance therapy. (C) 2018 Elsevier Inc. All rights reserved.

Maintenance demonstrated to improve survival in newly diagnosed multiple myeloma (NDMM) patients and the achievement of complete response (CR) is a strong predictor of survival. Nevertheless, the role of maintenance according to response after induction/consolidation has not been investigated so far. To evaluate the impact of maintenance according to response, we pooled together and retrospectively analyzed data from 955 NDMM patients enrolled in two trials (GIMEMA-MM-03-05 and RV-MM-PI-209). Primary endpoints were progression-free survival (PFS)1, PFS2 and overall survival (OS) of CR patients randomized to maintenance and no maintenance. Secondary endpoints were PFS1, PFS2 and OS in very good partial response/partial response (VGPR/PR) patients. Overall, 213 patients obtained CR after induction/consolidation, 118 received maintenance and 95 no maintenance. In patients achieving CR, maintenance significantly improved PFS1 (HR 0.50, P < 0.001), PFS2 (HR 0.58, P 0.02) and OS (HR 0.51, P 0.02) compared with no maintenance; the advantage was maintained across all the analyzed subgroups according to age, International Staging System (ISS) stage, cytogenetic profile and treatment. Similar features were seen in VGPR/PR patients. Maintenance prolonged survival in CR and in VGPR/PR patients. The benefit in CR patients suggests the importance of continuing treatment in patients with chemo-sensitive disease. The two source studies are registered at ClinicalTrials.gov: identification numbers NCT01063179 and NCT00551928.

Background: Risk-adapted therapy is a common strategy in curable hematologic malignancies: standard-risk patients receive less intensive treatment, whereas high-risk patients require a more intensive approach. This model cannot be applied in multiple myeloma (MM), which is still incurable. Continuous treatment (CT) is a key strategy for MM treatment, since it improves duration of remission. However, the role of CT according to standard- or high-risk baseline prognosis remains an open question. Patients and methods: We performed a pooled analysis of 2 phase III trials (GIMEMA-MM-03-05 and RV-MM-PI-209) that randomized patients to CT vs fixed-duration therapy (FDT). Results: In the overall patient population (n = 550), CT improved progression-free survival1 (PFS1) (HR 0.54), PFS2 (HR 0.61) and overall survival (OS) (HR 0.71) vs FDT. CT improved PFS1 both in R-ISS I (HR 0.49) and R-ISS II/III patients (HR 0.55). Four-year PFS1 was 38% in R-ISS II/III patients receiving CT and 25% in R-ISS I patients receiving FDT, with similar trends for PFS2 and OS. High-risk patients benefited more from proteasome-inhibitor plus immunomodulatory-based CT than immunomodulatory alone. Conclusion: Good prognosis patients receiving FDT lose their prognostic advantage over high-risk patients receiving CT and high-risk patients may benefit from more intensive maintenance including proteasome inhibitors and immunomodulators.

INTRODUCTION:Early toxic death (≤60 days of diagnosis) in elderly multiple myeloma (MM) patients is attributable to active disease, age and co-morbidities. Rate of early toxic deaths is 10% with conventional chemotherapy mainly due to infection and renal failure. Novel agents have improved MM outcome at the expense of newer toxicity.METHODS:We analyzed 1146 individual patient data to assess toxic deaths during induction treatment with first-generation novel agents thalidomide, lenalidomide, bortezomib.RESULTS:During first-line therapy, 119/1146 patients (10%) died for any cause, and 47/1146 (4%) due to toxicity, including 12/1146 (1%) early deaths. The 24-month cumulative incidence was 4.1% without any difference between bortezomib (18/503 patients, 4%) and lenalidomide (29/643patients, 5%; p = 0.31). Toxic deaths occurred in 34/1039 (3%) patients <80 years and 13/107 (12%) patients ≥80 years. Causes were cardiac events (28%), infections (26%) and vascular complications (15%). In a multivariate analysis, older age and unfavorable ISS stage increased the risk of death.CONCLUSION:First-generation novel agents significantly reduced toxic deaths compared to conventional chemotherapy. One third of deaths during first-line therapy were due to cumulative drug-related toxicities, thus supportive approaches and prevention strategies should be optimized. The higher mortality rate for toxicity in octogenarians confirms the need for a careful frailty assessment.

INTRODUCTION: Twice weekly carfilzomib is approved at two different doses, 27 mg/m2 in combination with lenalidomide and dexamethasone, and 56 mg/m2 with dexamethasone, for the treatment of relapsed and/or refractory multiple myeloma (MM). To reduce the treatment burden, the phase 3 A.R.R.O.W. study compared once weekly (70 mg/m2) to twice weekly (27 mg/m2) carfilzomib in relapsed/refractory MM patients, showing that once weekly carfilzomib increased the overall response rate (ORR) and prolonged progression-free survival (PFS) as compared to the twice weekly schedule. Here we present a pooled analysis of two phase 1/2 studies to compare once vs. twice weekly carfilzomib in newly diagnosed (ND)MM patients.

Background: Proteasome inhibitor (PI)-based induction and consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2-autologous stem cell transplant (MEL200-ASCT). High response rates have been reported with the second-generation PI Carfilzomib in combination with Lenalidomide-dexamethasone (KRd) or Cyclophosphamide-dexamethasone (KCd). Aims: The primary aim was to evaluate the efficacy and safety of KRd induction-ASCT-KRd consolidation (KRd-ASCT-KRd) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd). Methods: NDMM pts ≤65 years were randomized (1:1:1; stratification ISS and age) to: KRd-ASCT-KRd: 4 28-day cycles with KRd induction (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Lenalidomide 25 mg days 1-21; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd-ASCT-KCd: 4 28-day induction cycles with KCd (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Cyclophosphamide 300 mg/m2 days 1,8,15; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized to maintenance with Lenalidomide alone or plus Carfilzomib. Centralized minimal residual disease (MRD) evaluation - 8-color second generation flow cytometry, sensitivity 10-5 - was performed in pts achieving ≥very good partial response (VGPR). Endpoints were pre-maintenance stringent complete response (sCR) and MRD negativity in intention-to-treat (ITT) analysis. Data cut-off was May 30, 2018. Results: 474 NDMM pts were randomized (KRd-ASCT-KRd, n=158; KRd12, n=157; KCd-ASCT-KCd, n=159) and analyzed. Pts characteristics were well balanced. Median follow-up was 20 months. Depth of response improved during treatment (Figure). By ITT analysis, rates of pre-maintenance sCR was similar between KRd-ASCT-KRd (41%) and KRd12 (42%), and significantly higher than with KCd-ASCT-KCd (30%; P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.047; P value KRd12 vs KCd-ASCT-KCd=0.028). Similarly, rate of ≥CR was 49% with KRd-ASCT-KRd, 52% with KRd12 and 38% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.041; P value KRd12 vs KCd-ASCT-KCd=0.014) and rate of ≥CR+unconfirmed CR (missing immunofixation confirmation) raised to 60% vs 63% vs 46% in the 3 groups, respectively; rate of ≥VGPR was 88% with KRd-ASCT-KRd, 86% with KRd12 and 74% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.002; P value KRd12 vs KCd-ASCT-KCd=0.008). In multivariate analysis, the main factor affecting probability of achieving ≥VGPR, ≥CR or sCR was treatment with KRd-ASCT-KRd or KRd12 vs KCd, with no significant impact of ISS Stage or FISH abnormalities. In ITT analysis (MRD missing [31/395 VGPR pts, 8%] and <VGPR were considered as MRD positive), MRD negativity was again similar with KRd-ASCT-KRd (58%) and KRd12 (54%) and significantly higher than with KCd-ASCT-KCd (41%; P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.004; P value KRd12 vs KCd-ASCT-KCd=0.023); 82% vs 78% vs 88% of pts in the 3 groups, respectively, could maintain extended MRD negative status with 2 MRD negative results obtained apart ≥6 months (either pre-ASCT and post consolidation or post consolidation and during maintenance). During treatment (excluding ASCT) the most frequent grade 3-4 AEs were neutropenia (KRd-ASCT-KRd 20%, KRd12 10%, KCd-ASCT-KCd 16%), thrombocytopenia (KRd-ASCT-KRd 15%, KRd12 8%, KCd-ASCT-KCd 13%) and infections (KRd-ASCT-KRd 14%, KRd12 12%, KCd-ASCT-KCd 13%). Grade 3-4 dermatologic AEs (KRd-ASCT-KRd, 5% with KRd12 12%, KCd-ASCT-KCd 1%), increase in liver enzymes (KRd-ASCT-KRd 9%, KRd12 10%, KCd-ASCT-KCd 1%) and hypertension (KRd-ASCT-KRd 3%, KRd12 8%, KCd-ASCT-KCd 3%) were more frequent with KRd12. Rates of grade 3-4 cardiac AEs (KRd-ASCT-KRd 3%, KRd12 2%, KCd-ASCT-KCd 4%) and thrombosis (KRd-ASCT-KRd 1%, KRd12 2%, KCd-ASCT-KCd 2%) were below 5% in all arms. Discontinuation for AEs was similar in the 3 arms (KRd-ASCT-KRd 6%, KRd12 8%, KCd-ASCT-KCd 7%). Conclusions: Rates of MRD negativity, sCR, ≥CR, ≥VGPR were significantly higher with KRd-ASCT-KRd and KRd12 vs KCd. At present, no differences in MRD and overall best response (sCR, ≥CR, ≥VGPR) were noticed between KRd-ASCT-KRd and KRd12; longer follow-up is needed to evaluate survival. Treatment was well tolerated. Updated data will be presented at the meeting. Figure. Figure. Gay: Roche: Other: Advisory Board; Seattle Genetics: Other: Advisory Board; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria; Takeda: Honoraria, Other: Advisory Board. Galli:Sigma-Tau: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Belotti:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board. Zamagni:BMS: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Angelucci:Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol in MDS; Celgene: Honoraria, Other: Chair DMC proptocol BELIEVE 1 and BELIVE 2 in Thalassemia; Vertex Pharmaceuticals Incorporated (MA) and CRISPR Therapeutics AG (CH): Other: Chair DMC CRISPR CAS9 in Hemoglobinopathies; Jazz Pharmaceuticals Italy: Other: Local (national) advisory board on AML; Roche Italia: Other: Local (national) advisory board on biosimilars. Annibali:Celgene; Takeda; Amgen, Janssen Cilag: Honoraria. Offidani:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Palumbo:Takeda: Employment. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria.