Upfront Autologous Stem Cell Transplantation Research Articles

Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Phase I/II Study of Escalating Doses of Thalidomide in Conjunction with Bortezomib and High Dose Melphalan As a Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma

Prognostic Significance of FDG-PET/CT on Determining Upfront Autologous Stem Cell Transplantation for the Treatment of Peripheral T Cell Lymphomas

Purpose: The clinical role of 18F-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET/CT) in performing upfront high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains unclear in peripheral T cell lymphomas (PTCLs). This study investigated the prognostic relevance of interim and final FDG-PET/CT in predicting the outcome of upfront ASCT for the treatment of PTCLs.Method: The study conducted newly diagnosed 96 patients with PTCLs who aged under 65 years between January 2005 and December 2016 from two independent institutions. For making a comparison of clinical outcome between transplant and non-transplant patients according to interim or final FDG- PET/CT, 37 transplanted and 59 non-transplanted patients with the same populations were evaluated as a comparative group (non-ASCT). The enrolled patients were treated with mainly anthracycline-based chemotherapy except patients with NK/T cell lymphoma who were treated with non-anthracycline-based. If achieved complete or partial remission after primary treatment, patients proceeded to upfront ASCT. FDG-PET/CT was performed at the time of diagnosis, interim, and after primary treatment. The response of interim or final FDG-PET/CT was analyzed by visual assessment using Deauville five-point scale (5-PS).Results: The characteristics of transplant patients were similar to non-transplant patients except two features (IPI score, CT response). Final FDG-PET/CT response (P<0.001, Hazard ratio (HR) 3.51), CT response (P<0.001, HR 2.11) and age (P=0.005, HR 1.07) were significant prognostic factors of progression-free survival (PFS) in transplant patients on multivariate analysis. In non-ASCT patients, final FDG-PET/CT response (P<0.001, HR 9.65), prognostic index for T-cell lymphomas (PITs) score (P=0.001, HR 5.24), and CT response (P<0.001, HR 2.34) were prognostic for PFS. After a median follow-up of 60.8 months, 5-year PFS rates of ASCT and non-ASCT patients according to interim FDG-PET/CT response were 75.5 vs 74.5% of Deauville score 1-2, 20% vs 22.2% of Deauville score 3 and 33.3% vs 42.2% of Deauville score 4, respectively (P=0.092, P=0.005; Figure 1A, 1C). 5-year PFS rates according to final FDG-PET/CT response of ASCT and non-ASCT patients were 70.2% vs 80.5% of Deauville score 1-2, 22.2% vs 25% of Deauville score 3 and 0% vs 0% of Deauville score 4, respectively (P<0.001, P<0.001; Figure 1B, 1D).Conclusion: Final FDG-PET/CT response based on Deauville 5-PS had prognostic significance on the treatment outcome of PTCLs regardless of upfront ASCT. However, patients with ≥ 3 of Deauville score assessed by interim or final FDG-PET/CT had poor prognosis even though performing upfront ASCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Hematogenous Extramedullary Relapse in Multiple Myeloma - A Multicenter Retrospective Study in 127 Patients

Background: Hematogenous extramedullary multiple myeloma (HEMM), though rare, is mainly observed in MM patients at relapse. The current study assesses the characteristics and outcomes of patients with MM who develop HEMM in the novel agent era.Methods: Consecutive patients, treated in 16 participating centers and diagnosed with HEMM, were included. Patient characteristics at diagnosis and at HEMM presentation, treatment regimens, response to therapy, response duration and survival were recorded. Factors predicting time to HEMM and survival from HEMM diagnosis were analyzed.Results: 127 patients were included. Median age at MM diagnosis was 63 years (31-94). 50% of patients had IgG MM, 26% had IgA, 23% had light chain, and 1% had other MM types. 44% had ISS 3 and 57% presented with plasmacytomas. 30% presented with high-risk cytogenetics: 19% with t(4;14),11% had 17p deletion. CD56 was expressed in 72% of cases and CD20 in 16%. 55% of the patients were treated for MM with PI, 55% with IMIDs, 62% with chemotherapy and 59% underwent autologous stem cell transplantation (ASCT) prior to HEMM.The median time to the development of HEMM was 2.8 years (95% CI 2.2-3.6). B2M levels (HR 1.04, 95% CI 1.00-1.07, p=0.03), del17p (HR 3.3, 95% CI 1.6-7.1, p=0.002) and plasmacytomas at MM diagnosis (HR 1.6, 95% CI 1.1-2.4, p=0.01) were associated with a shorter duration from diagnosis to HEMM, while upfront ASCT was associated with a longer period to the development of HEMM disease (HR 0.6, 95% CI 0.4-0.9, p=0.01).47 patients (38%) patients had no concomitant plasmacytomas at HEMM diagnosis. 33% of patients had ≥2 HEMM sites, in 53% HEMM lesion was ≥5 cm, 20% had non-secretory disease at HEMM, and 59% had an increased LDH. 61% received at least 2 lines for MM prior to HEMM. First treatment for HEMM included PIs in 50%, IMIDs in 39%, MoAbs in 10% and chemotherapy in 53%. Overall response rate (ORR) was 49% and 51% failed to respond to first treatment for HEMM. IMIDs were associated with higher odds for ORR (OR 2.2, 95% CI 1.02-4.7, p=0.04).Median survival from MM diagnosis and from HEMM diagnosis were 4.3 (CI 95% 3-5.5) and 0.5 (CI 95% 0.4-0.6) years, respectively. 5-year OS from HEMM diagnosis was 6% (1-15%)(Figure 1A).Increased LDH level at the time HEMM (HR=2.2, 95% CI 1.3-3.8, p=0.002, Figure 1B), FISH positive for t(4;14) (HR=2.3, 95% CI 1.2-4.2, p=0.01)(Figure 1C), t(14;16) (HR=5.6, 95% CI 1.3-25, p=0.02)(Figure 1D), as well as ≤3 years between MM diagnosis and HEMM (HR=1.6, 95% CI 1.04-2.4, p=0.03(Figure 1E)), were found to be associated with a significantly shorter survival from HEMM diagnosis. The achievement of CR or VGPR to treatment administered for HEMM therapy were both associated with improved OS (HR=0.2, 95% CI 0.1-0.3, p<0.001 and HR=0.5, 95% CI 0.3-0.9, p=0.02, respectively) (Figure 1F). No specific treatment was found to be associated with improved survival in patients that develop HEMM.Conclusion: In MM patients who develop HEMM, the median time from MM to HEMM diagnosis is 2.8 years. Despite the improvement in MM therapy over the last decades, patients with HEMM diagnosis have a dismal outcome. OS is significantly shorter in patients with high-risk cytogenetic abnormalities, increased LDH and time to HEMM <3 years. Further studies assessing best therapy in patients experiencing this complication are warranted. [Display omitted] DisclosuresCohen:Neopharm Israel: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Medisson Israel: Consultancy, Honoraria, Research Funding. Garderet:Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Niesvizky:Amgen Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Castillo:Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Millennium: Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding.

The Prognostic Significance of Minimal Residual Disease and Possibility of Its Correction in Multiple Myeloma

Introduction.Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients, the optimal methodology to assess MRD is not clear. The results of previous studies demonstrated the potential of multiparameter flow cytometry (MFC) and (PET-CT) in evaluation of MRD in MM. MRD monitoring should be applied in prospective clinical trials to compare and evaluate the efficacy of different treatment strategies, particularly in the consolidation and maintenance settings. The impact of MRD negativity is important, but further studies are needed to quantify the pharmacoeconomic and quality-of-life differences between early and delayed transplant strategies. Therefore, with the currently available evidence, upfront autologous stem cell transplantation (ASCT) is standard of care regardless of MRD status.Aim.We are aiming to determine the role of MRD and role of autologous stem cells transplantation in MM.Materials and methods.We've recently started a prospective one-center pilot study in subjects with MM. We analyzed 18 transplant-eligible patients with MM (the median age is 57 years, a male/female ratio is 3.5:1).The induction therapy Bortezomib-based only regimens was used in 12/18 (67%) patients, combination of Bortezomib-Immunomodulator-based regimens - in 6/18 (33%). High dose therapy (Mel200) and ASCT is carried out on 100% patients. The standard risk was established on 15 patients, 1 patient has an intermediate risk and 2 patients have high risk according to mSMART 2.0 stratification. The MFC MRD status of bone marrow was evaluated after 4-6 cycles of induction therapy and after ASCT on 5-color flow cytometry with use anti- CD38, CD138, CD45, CD19, CD20, CD27, CD56 and CD117 antibodies. We were based on two levels: MFC MRD- (<10-4) and MFC MRD- (<10-5) for assessing the significance of factors that affect MRD and for identifying the prognostic potential of MRD-negative status. The evaluation of MRD was carried out by genetic (cytogenetic and FISH) analysis of bone marrow plasma cells and PET-CT with 18-FDG before ASCT and on 100 day post ASCT.The results.The MFC MRD- (<10-4) before carrying out an ASCT reached 22.2% (4/18), the MFC MRD- (<10-5) - 0% and was not depended on the variant of pre-transplantation regimen. After the ASCT had been carried out there was a tendency to decrease the tumor burden in bone marrow from 0.65% to 0.1% and to increase the frequency of MFC MRD- (<10-4) status to 44.4% (8/18), of which MFC MRD- (<10-5) was 16.7% (3/18). MRD status was determined before ASCT and after ASCT by MFC and FISH in patients with high risk. The use of maintenance therapy with bortezomib (n = 5) or lenalidomide (n = 13) did not increase the frequency of MRD status. The PFS median in MFC MRD+ (>10-4) group was 23 months, in the MFC MRD- (<10-4) was not achieved; 2-year PFS was 43% and 100%, respectively (p=.04) We compared PFC between MFC MRD+ (>10-4) before ASCT (n = 4) and MFC MRD- (<10-4) after ASCT (n = 6) to assess the effect of ASCT in MM. The median PFS was not reached in both groups; 2-year PFS was 67% and 100%, respectively. The reliable difference between PFS in MFC MRD- (10-4-10-5) group and MFC MRD- (<10-5) was absent: the median of PFS was not achieved in both groups. PET-CT has been tested on 15 patients, PET-CT- response was achieved in 53% (8/15) patients. The PFS median in PET-CT+ group and PET-CT- group was not achieved. The 2-year PFS was higher in PET-CT+ group then PET-CT- probably due to patients with MFC MRD-. The 2-year PFS in «MFC MRD-PET-CT-» group was 100% to 55% in other patients.Conclusion.Carrying out ASCT demonstrated a tendency to increase the percentage of MFC MRD negative responses and improvement of PFS. The use of MFC in evaluation of MRD should be complemented with PET-CT and genetic methods for further analysis of the MFC MRD role status on MM patients. DisclosuresNo relevant conflicts of interest to declare.

Induction with Bortezomib Melphalan and Prednisolon (VMP) Is Associated with Unexpectedly High Discontinuation Rate in Elderly Multiple Myeloma Patients: First Analysis of the German Maintenance (GERMAIN) Trial

Induction with Bortezomib Melphalan and Prednisolon (VMP) Is Associated with Unexpectedly High Discontinuation Rate in Elderly Multiple Myeloma Patients: First Analysis of the German Maintenance (GERMAIN) Trial

Characteristics and Outcome of Multiple Myeloma Patients Presenting with Anemia Only: a Retrospective Multi-Center Study

Background:Multiple myeloma (MM) is defined as bone marrow monoclonal plasmocytosis combined with either specific laboratory or imaging findings (SLIM criteria) or one or more of the following myeloma defining events (MDE) including anemia, hypercalcemia, renal failure or lytic bone lesions (CRAB criteria). Patients who presents with anemia but without additional CRAB criteria are scarce, and their clinical course has not yet been characterized in the literature.The current study was designed to evaluate the characteristics, responsiveness to treatment, progression free and overall survival in newly diagnosed MM patients presenting with anemia only.Methods:We retrospectively analyzed the clinical features and outcomes of MM patients that presented with anemia as the only CRAB criteria (i.e. having no evidence of skeletal involvement by PETCT, MRI or total body CT, no renal involvement and no hypercalcemia), that were diagnosed and treated in 9 Israeli and Greek centers between 2010 and 2018.Baseline characteristics at diagnosis, ISS score, treatment regimens, depth and duration of response (by IMWG criteria), hemoglobin (HB) levels during treatment and overall survival (OS) were collected and analyzed.Results: 63 (28 females) patients were included in the analysis. The median age was 72.2 (range 34.4-91.9) years. The median HB level at diagnosis was 9.4 g/l (IQR 6.0-12.0) and median platelets level was 172000 (IQR 59000-454000). The median percent of plasma cells (PCs) in bone marrow at diagnosis was 60% (range 20% to 99%). 11 out of 56 (19%) patients had a high-risk FISH (t 4;14, t 14;16 or del 17p). Bortezomib -based induction was administered in 83%, and upfront autologous hematopoietic stem cell transplantation (autoHCT) was employed in 32%.ORR to 1st line was 87%. 37 (62%) achieved ≥ VGPR, 16 (25%) PR and 7 (13%) SD/PD. Significant predictors for achieving at least VGPR vs. SD or PD were higher albumin level at diagnosis (3.9±0.5 g/l vs. 3.5±0.4g/l, p<0.00), maximal HB level during treatment (13.0±1.0g/l vs. 11.5±1.2 g/l respectively, p<0.00) and maximal improvement in HB level during treatment (median 3.2 [IQR 2.2-4.5]g/l vs 2.2 [IQR 1.1-3.2]g/l, respectively, p<0.00).Median PFS in the entire cohort was 22.1±5.82 months. Predictors for PFS duration on first-line therapy were bone marrow plasmocytosis (HR 1.012 [95% CI 1.001-1.037] p=0.03) and maximal improvement in hemoglobin level (HR 0.71 [95% CI 0.55-0.91] p< 0.00). Multivariate analysis confirmed bone marrow plasmocytosis (HR 1.03 [95% CI 1.01-1.05], p<0.00), higher HB level at diagnosis (HR 0.43 [95% CI 0.27-0.67], p<0.00) and maximal improvement in HB level during therapy (HR 0.37 [95% CI 0.25-0.56] p<0.00) to be associated with longer PFS. In multivariate analysis restricted to non-transplanted patients, factors associated with longer PFS were bone marrow plasmocytosis>60% (HR 4.6 [95% CI 1.5-14.0] p<0.00), HB level at diagnosis (HR 0.32 [95% CI 0.17-0.60], p<0.00), maximal HB improvement (HR 0.23 [95% CI 0.13-0.41] p<0.00) and older age (HR 0.92 [95% CI 0.87-0.97], p<0.00).Within a median follow-up of 34 months, 19 (31%) patients have died; 12 due to PD. The median OS for the entire cohort was 65.93 months and the 3 years mortality rate was 17.5%.Predictors of mortality were high risk cytogenetics (HR 3.01 [95% CI 1.02-8.88] p= 0.04), maximal HB improvement during therapy (HR 0.73, [95% CI 0.54-0.99] p=0.04), and bone marrow plasmocytosis (HR 1.04 [95% CI 1.01 to 1.07] p= 0<.00). Furthermore, median OS for patients <60% plasmocytosis was not reached, compared to 45.3 months for patients with plasmocytosis ≥60% (p=0.048) (figure 1). Only bone marrow plasmocytosis remained as significant factor for mortality in a multivariate analysis (HR 1.04 [95% CI 1.01-1.08], p=0.01).Conclusion:MM patients presenting with anemia only, often have a remarkable bone marrow plasmocytosisResponsiveness to therapy, PFS and OS, depend on the degree of BM plasmocytosis and HB level at diagnosis, both reflecting disease burden. In line with that, response to therapy and long -term PFS can be accurately predicted by the degree of improvement in HB level.In general , patients presenting with anemia only , although they do not have renal impairment or bone disease, seem to have a relatively poor OS of approximately 5 years only , suggesting that these patients may have a relatively “rapidly growing tumor”, precluding the development of bone and renal disease. DisclosuresNo relevant conflicts of interest to declare.

Older Age As a Prognostic Factor for Overall Survival for Multiple Myeloma Patients Undergoing Upfront Autologous Hematopoietic Stem Cell Transplantation

BackgroundHigh-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is considered the standard of care for newly diagnosed, transplant-eligible multiple myeloma (MM) patients. Due to improvements in induction, stem cell mobilization, and dose adjustment of the conditioning regimen, auto-HCT is increasingly used in older MM patients, with several retrospective analyses showing similar clinical outcomes compared to younger patients.MethodsTo further confirm these results, we performed a single-center retrospective analysis of MM patients undergoing auto-HCT between January 2006 and December 2016. Patients were divided into two groups: older (> 70 years) and younger (≤ 70 years).Results1128 patients (182 older, 946 younger) were included in this analysis. Patient characteristics are summarized in the attached Table. More patients (59% vs. 45%, p = 0.01) in the older cohort had ISS stage II or III disease. Older cohort was more likely to receive reduced-dose melphalan (140 mg/m²) as conditioning regimen (32% vs 3%, p = <0.0001). There was no significant difference in high-risk cytogenetics, induction regimens, and response to induction, or post-transplant maintenance between the older and younger cohorts. The overall median follow-up among survivors was 49 months in the older and 52 months in the younger group. One-hundred-day non-relapse mortality (NRM) was 2/182 (1.1%) and 6/946 (0.6%) (p = 0.5) in the older and younger groups, respectively. However, 1-year NRM was significantly higher in the older vs. younger cohort (7 /182 (4%; unknown 3, pneumonia or respiratory failure 4) vs. 9/946 (1%; unknown 2, pneumonia or respiratory failure 4, cardiac failure 3), HR 4.1, p = 0.005). Post-transplant, 75 (41%) and 431 (45%) achieved complete remission (CR) in the older and younger groups, respectively (p = 0.29). There was no significant difference in the rate of disease progression post-transplant between older (31%) and younger (30%) groups (p = 0.3). The 5-year progression free survival (PFS) was 24% and 37% in the older and younger groups, respectively (HR 1.3, p = 0.02). Similarly, 5-year overall survival (OS) was 56% and 73% in the older and younger groups (HR 1.8, p = <0.001). In univariate analyses, age > 70 years, high-risk cytogenetics, serum creatinine level > 2 mg/dl and ISS stage III were associated with worse PFS and OS. In contrast, melphalan 200 mg/m² for conditioning and achievement of CR after induction therapy were associated with better PFS and OS. These 6 factors were studied in multivariate analyses using a classification and regression tree (CART) method. In CART analysis for PFS, ISS stage II or III, and high-risk cytogenetics were associated with shorter PFS. Similarly, in CART analysis for OS, older age (> 69 years), ISS stage II or III, and high-risk cytogenetics were associated with a shorter OS.ConclusionIn this large single-center analysis, there was no difference in 100-day NRM, CR rates and the risk of progression after auto-HCT between the older and the younger patients. However, older age was associated with a shorter PFS and OS due to increased NRM. On multivariate CART analysis, ISS stage II or III and high-risk cytogenetics were associated with a worse PFS and OS, while age > 69 years was associated with a worse OS only. The impact of comorbidities on NRM is being evaluated in ongoing analyses. [Display omitted] DisclosuresLee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Abbvie: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Thomas:Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Array Pharma: Research Funding. Orlowski:BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol Myers Squibb: Consultancy; Genentech: Consultancy; Millenium Pharmaceuticals: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding.

Melphalan-Based Autologous Transplantation in the Octogenarian Multiple Myeloma Patient Population

Abstract:Background:Upfront autologous hematopoietic stem cell transplantation (auto-HCT) combined with novel anti-myeloma drugs is considered the standard of care for transplant-eligible patients with multiple myeloma (MM). However, this treatment is generally avoided in older patients due to concerns about toxicity. MM is primarily a disease of the elderly, with >35% patients being older than 70 years of age at diagnosis. We have previously reported on the role of auto-HCT in MM patients >70 years1. In this study, we evaluate the safety and feasibility of auto-HCT in patients ≥80 years who received auto-HCT at our institution.Methods:We retrospectively reviewed the outcomes of MM patients with age ≥80 years who underwent auto-HCT between January, 2007, and June, 2018. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of auto-HCT to the last follow up or the censored date. Kaplan-Meier method was used to estimate PFS and OS.Results:Between January, 2013, and December, 2017, out of a total of 1465 MM patients referred for evaluation for auto-HCT at our institution, only 10(0.68%) were of age ≥80 years. Also, between January, 2016, and June, 2018, a total of 210 MM patients with age ≥80 years were treated at our institution, and only 3(0.14%) underwent auto-HCT. Overall among 1740 patients with MM who received an auto-HCT at our institution between the beginning of 2007 to June, 2018, 9(0.5%) patients were ≥ 80 years of age (range 80-83). Table 1 summarizes the patient characteristics of these nine patients. All patients had an ECOG performance status of either 0 or 1. The median hematopoietic stem cell transplant - comorbidity index for the cohort was 3 (range, 0-5). Eight (89%) patients were in first remission, and 1 (11%) patient had relapsed disease at auto-HCT. All patients received melphalan at a reduced dose of 140 mg/m2 as the conditioning regimen. Eight patients (89%) received maintenance therapy with lenalidomide. The median follow-up from auto-HCT was 18 months (range 0.5 - 50 months). No (0%) patient died within 100 days of auto-HCT. Out of 8 evaluable patients, 4 (50%) achieved a complete response, 2 (25%) very-good partial, and 2 (25%) achieved a partial response with an overall response rate of 100%. Eight (89%) patients were alive until the last follow-up. Median PFS was 31.5 months, while the median OS has not been reached (Fig1). 2-yr PFS and OS were 62.5% and 75% respectively. One patient died 22 months post-transplant due to non-transplant related cause.Conclusions:In selected MM patients ≥80 years old, auto-HCT was feasible, with 0% TRM, 100% response rate, and 2-year OS of 75%. Almost 90% of these patients went on to receive maintenance therapy.

A Phase 2 Study of Carfilzomib, Lenalidomide, and Dexamethasone with Lenalidomide Maintenance (KRd-r) in Newly Diagnosed Multiple Myeloma (NDMM): Sustained Long Term Deep Remissions and Prolonged Progression-Free Duration Regardless of Age or Cytogenetic Risk after 5 Years of Follow up

Background: State of the art treatment for patients with NDMM involves induction with triplet-based regimens utilizing combinations of immunomodulatory drugs and proteasome inhibitors (PI) which improve time to progression (TTP), progression-free survival, and overall survival (OS) over doublet regimens. Carfilzomib is a selective PI with FDA approval in the KRd combination regimen for the treatment of patients with relapsed or refractory MM. Carfilzomib-based combinations are associated with increased clinical benefit over bortezomib-based combinations and carfilzomib does not cause neuropathy. This phase 2 study of 45 patients demonstrated that deep responses with KRd-r is achieved in the NDMM setting (Korde et al. JAMA Onc 2015). Here, we expand on our initial results in assessing response to present the long-term durability of minimal residual disease negativity (MRDneg) complete response (CR) and time to progression. We also characterize TTP by depth of response, age, and cytogenetic risk profile.Methods:Treatment-naïve patients with MM were treated for 8 cycles (28-day cycles) with carfilzomib 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg PO days 1-21, and dexamethasone 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles and then continued KRd treatment (i.e. without default autologous stem cell transplant (ASCT)). After 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg PO maintenance on days 1-21. The primary objective of the study was to estimate the rate of ≥ Grade 3 peripheral neuropathy with secondary objectives of International Myeloma Working Group criteria for overall response rate (ORR), MRDneg CR, TTP, and response duration (DoR) assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. Assessment of MRDneg CR by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) was performed after 8 cycles of induction, 1 and 2 years of lenalidomide maintenance, and then annually.Results: Forty-five patients meeting eligibility criteria were enrolled (60% male; 42% ≥ age 65, range 40-89; race: 82% White, 13% Black, 4% Asian; isotypes: 51% IgG kappa, 16% IgG lambda, 13% IgA kappa, 9% IgA lambda, 9% free kappa, and 4% free lambda; 33% high risk cytogenetics, del(17p), t(4;14), t(14;16)or t(14;20)). The median potential follow up was 5.7 years (68.3 months). The ORR was 97.8% (95% Confidence Interval (CI): 88.2-99.9%) with a median DoR of 65.7 months (95% CI: 55.6-not reached (NR) months). Strikingly, 28 of the 45 patients, 62.2%, (95% CI: 46.5-76.2%) attained deep responses of MRDneg CR; durability of MRDneg CR was observed up to at least 70 months with a median duration of over 4 years (52.4 months; 95% CI: 35.3-61.6 months). Moreover, the median TTP was over five and a half years (67.3 months; 95% CI: 51.0-NR months) and the median OS was NR, however, at 80 months, 84.3% of patients were still alive. As expected, patients who attained MRDneg CR, by cycle 8, had a 78% reduction in the risk of progression (Hazard Ratio (HR): 0.22 (95% CI: 0.07-0.69); p=0.005) (Figure 1). Importantly, these deep responses of MRDneg CR and long progression free durations were observed regardless of age group or cytogenetic-based risk profile (Table 1). Toxicities have been previously reported and were generally manageable with no Grade ≥ 3 neuropathy or death due to toxicity.Conclusions: Upfront treatment of NDMM with the modern and highly efficacious KRd-r regimen incorporating a “by-default-delayed” ASCT strategy led to high rates of MRDneg CR (10-5 sensitivity) which even more importantly were sustained with a median duration of over 4 years. Moreover, attaining MRDneg CR, was strongly associated with a delay in progression. Clinically important, we observed that these deep responses and long progression-free durations are observed regardless of age or cytogenetic risk and stress the importance of utilizing highly efficacious triplet-based regimens for these sub-categories of NDMM. Lastly, our results with KRd-r in NDMM compare favorably to ASCT-based regimens and question the use of upfront ASCT for all patients. Our observed median TTP of 67 months is approximately 17 months longer than published data using the regimen of bortezomib, lenalidomide, and dexamethasone with ASCT (Attal et al. NEJM 2017). Updated results will be presented at the Annual Meeting. [Display omitted] DisclosuresKorde:Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Prognostic Significance of Tracking Dynamic Changes in Positron Emission Tomography (PET) Scan Pre and Post Autologous Stem Cell Transplant (ASCT)

BACKGROUND:Multiple Myeloma (MM) is a heterogenous disease with variable outcomes based on both disease biology and burden. The revised international staging system (R-ISS) can distinguish 5-year overall survival (OS) however, it does not incorporate novel imaging that provide more accurate disease burden assessment (e.g., PET-CT). Previous studies (Usmani SZ et al Blood 2013) showed that the presence of more than 3 focal lesions (FL)s detected on PET-CT scan at baseline in newly diagnosed MM patients, or the persistence of any FL post induction therapy or post- autologous stem cell transplantation (ASCT), were associated with shorter progression free survival (PFS) and overall survival (OS) in Total Therapy trials. There is limited information available on the prognostic significance of PET-CT in the context of current standard 3-drug induction followed by ASCT in clinical practice. Herein, the investigators examined the prognostic implications of post-therapy PET-CT positivity in routine clinical practice.PATIENTS AND METHODS:The LCI MM database was interrogated (3/2014-5/2018) for NDMM patients who had undergone upfront ASCT and had PET-CT data available. Continuous variables were summarized with descriptive statistics, while categorical variables were summarized with frequencies and proportions. Survival distributions were estimated with Kaplan Meier techniques and compared using a log rank test PET-CT scan results were reported as negative or positive (defined as one FL having higher 18F-FDG uptake relative to uptake in mediastinum or surrounding background, with no similar activity seen on the contralateral side, or increased activity at any location incompatible with normal physiological distribution).RESULTS:A total of 198 MM patients were identified, 62 had pre-ASCT PET-CT scans and 80 patients had post-ASCT PET-CT. Median age at transplant was 62 years (range 25 - 77), 52.0% were female. R-ISS stage I (17.2%), stage II (41.4%), stage III (1.7%). The 3 years overall survival (OS) in patients with negative PET-CT post-ASCT vs. positive PET-CT post-ASCT was 96.6% vs. 74.2% (p-value 0.002) and median progression free survival (PFS) was 35 months vs. 13 months (p-value <0.001), respectively. Patients were then divided into three groups: Cohort 1- negative PET scan pre/post ASCT (n=35), cohort 2- positive PET-CT pre-ASCT/negative PET-CT post-ASCT(n=17), and cohort 3- positive PET-CT post-ASCT(n=6). Thirty-four patients had scans pre and post ASCT; an additional n = 24 had negative PET scans pre ASCT and did not require repeat PET scan post ASCT. At one-year landmark OS for cohort-1 was 100% vs cohort-2 100% vs cohort-3 66.7 (p-value 0.002). One-year PFS for cohort-1 92.5% vs. cohort-2 100% vs. cohort-3 66.7% (p-value 0.0513).CONCLUSIONS:Negative PET-CT imaging post ASCT is associated with better OS and PFS. Also, in our population, the absence of positive FL by PET-CT scan in newly diagnosed MM patients pre and post ASCT shows a trend towards better PFS and OS. Clearance of FL by PET scan trends towards improved PFS and OS. Longer follow up is needed to declare statistical significance between those cohorts. DisclosuresAtrash:Takeda Oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Voorhees:Amgen Inc.: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Novartis: Consultancy, Other: served on an IRC; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy.

Bortezomib, lenalidomide, and dexamethasone with panobinostat for front-line treatment of patients with multiple myeloma who are eligible for transplantation: a phase 1 trial

Bortezomib with lenalidomide and dexamethasone (VRd) is a standard regimen for the front-line treatment of multiple myeloma. Panobinostat is approved in combination with bortezomib and dexamethasone in patients with myeloma who 'have been given at least two previous regimens including bortezomib and an immunomodulatory agent. We aimed to determine the maximum tolerated dose of a new regimen combining VRd with panobinostat in patients with newly diagnosed multiple myeloma. In this phase 1 study, we enrolled patients from the University of Texas MD Anderson Cancer Center (Houston, TX, USA) with newly diagnosed multiple myeloma who were aged 18 years or older and eligible for autologous stem-cell transplant (ASCT) according to International Myeloma Working Group 2014 diagnostic criteria. Participants were allocated either to the dose-escalation cohort or the dose-expansion cohort. In the dose-escalation cohort, in a 3 + 3 design, patients were treated in cycles of 21 days with bortezomib (1·3 mg/m2, subcutaneously) on days 1, 4, 8, 11; lenalidomide (25 mg, orally) on days 1-14; dexamethasone (20 mg, orally) on days 1, 2, 4, 5, 8, 9, 11, and 12; and escalating doses of panobinostat (10-20 mg, orally) on days 1, 3, 5, 8, 10, and 12. The dose level exceeded the maximum tolerated dose if at any given dose more than one of three patients, or two of six patients, had a dose-limiting toxic event. In the dose-expansion cohort, patients were given the maximum tolerated dose of the drug combination as determined from the dose-escalation cohort. Patients could proceed with upfront ASCT after two to four cycles of initial therapy or store their stem cells and proceed with a delayed ASCT approach. Patients with delayed ASCT could continue therapy for up to eight cycles, followed by maintenance with lenalidomide, dexamethasone, and panobinostat at their last tolerated dose for up to 2 years. The primary objective was to determine the maximum tolerated dose of VRd with panobinostat. Safety was assessed in all patients who completed at least one cycle of therapy. This trial is registered with ClinicalTrials.gov, number NCT01440582, and is no longer recruiting participants. Between Feb 18, 2013, and June 8, 2016, 55 patients were identified as eligible for enrolment. The dose-escalation cohort comprised 12 participants. The first three (25%) patients at dose level 1 (panobinostat 10 mg) did not encounter dose-limiting toxicity. Of six (50%) patients at dose level 2 (panobinostat 15 mg), two (33%) had dose-limiting toxic events during cycle 1; one (17%) had grade 4 thrombocytopenia with bleeding and the other had grade 3 diarrhoea, thus exceeding the maximum tolerated dose. Because the maximum tolerated dose had been exceeded, three more patients were accrued to dose level 1 and these patients did not experience dose-limiting toxic events. Dose level 1 (21 day cycles of bortezomib 1·3 mg/m2 subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg orally on days 1-14; dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12; and panobinostat 10 mg orally on days 1, 3, 5, 8, 10 and 12) was established as the maximum tolerated dose. The combination of VRd with panobinostat 10 mg is safe and effective in patients who are newly diagnosed with multiple myeloma and who are transplant eligible. Further studies in large randomised controlled settings are needed to confirm these results. Novartis and MD Anderson Cancer Center Support Grant.

Carfilzomib-based combination regimens are highly effective frontline therapies for multiple myeloma and Waldenström’s macroglobulinemia

Multiple myeloma (MM) and Waldenström’s macroglobulinemia (WM) are plasma cell disorders often treated with proteasome inhibitors. Recently, several studies evaluated carfilzomib as an initial treatment for these diseases and reported outstanding clinical outcomes. We conducted a retrospective study to report the efficacy and safety of frontline carfilzomib-based combinations in a standard of care setting. From 2014 until 2016 we identified newly diagnosed MM (n = 54) and WM (n = 6) patients treated with carfilzomib as initial therapy who met study inclusion criteria. The response rate for myeloma patients was 98% with 77% of patients undergoing upfront autologous stem cell transplant. The clinical benefit for WM was 100% with all patients having a resolution of B symptoms and anemia after treatment. Carfilzomib-based regimens are well tolerated and offer a neuropathy sparing approach with excellent responses both in newly diagnosed MM and WM making them a good choice for the frontline treatment of these diseases.

Improved outcome in patients following autologous stem cell transplantation for multiple myeloma in south eastern Norway 2001\u20132010: a retrospective, population based analysis

BackgroundWith the advent of novel drugs improved overall survival in patients with multiple myeloma, including patients who received up-front autologous stem cell transplantation (ASCT), has been reported from several centers. Here we report on overall survival in a population-based cohort of patients receiving ASCT as first line treatment and in whom novel agents were an option for second and later lines of treatment.MethodsPatients with multiple myeloma ≤ 65 years of age who were considered for ASCT from 01.01.2001–31.06.2005 (period 1) and from 01.07.2005 until 31.12.2009 (period 2) at Oslo University Hospital (OUH) were identified. Relevant data were collected from the patients’ medical records.ResultsAltogether, 293/355 patients received ASCT. In all, median OS was 82.9 months in patients ≤ 60 years of age and 59.0 months in patients 61–65 years. For patients ≤ 60 years of age median OS increased from 70.6 months to 87.7 months (p = 0. 22) and median survival after start of second line therapy increased from 34.5 months to 46.5 months (p = 0.015) between the two periods. For patients 61–65 years of age median OS increased from 57.3 months to 61.2 months (p = 0. 87) and median survival after start of second line therapy was practically unchanged (32.6 months vs. 33.1 months (p = 0.97) between the periods. In patients ≤ 60 years of age salvage ASCT was used in 34% of the patients while in patients 61–65 years of age salvage ASCT was used in 7.3% of the patients. The use of salvage ASCT and novel drugs, as well as the number of treatment lines, were higher in patients ≤ 60 years of age and increased during the study period.ConclusionIn patients ≤ 60 years of age an increased median OS of 17 months between the two periods were noted, but the difference failed to reach statistical significance. However, a statistically significant difference in median survival of 12 months after start of second line therapy was found in this age group, which may be explained by a more active second line treatment. In patients 61–65 years only a slight increase of survival, not statistically significant, was noted between the periods.

Time to plateau as a predictor of survival in newly diagnosed multiple myeloma.

Response rates in newly diagnosed multiple myeloma have improved dramatically with the introduction of highly effective novel therapies. However, survival in patients achieving optimal responses to initial treatment can vary significantly, and new prognostic indicators are required to improve risk stratification. We investigated the relationship between time to plateau (TPlat ) and survival in 1099 newly diagnosed patients treated with novel agents at our institution from 2005 to 2015. TPlat was defined as time from initiation of first-line therapy to best response to first-line therapy. The median TPlat was 4.9 months (0.7-58.6) and plateau duration was 1.8 years (0.2-11.0). Patients who required > 120 days to achieve a plateau had longer modified overall survival (mOS) and progression free survival (mPFS) calculated from a landmark of best response (P < .001 for both comparisons). Statistically significant improvement in mOS was retained in subgroup analysis based on age and whether patients received upfront autologous hematopoietic stem cell transplantation (ASCT) (P < .001 for all comparisons). Our results suggest that patients who respond more gradually to initial therapy (TPlat > 120 days) experience longer survival compared to more rapid responders. Patients with a prolonged TPlat could represent an "ongoing responder" phenotype that portends a survival advantage independent of treatment with upfront ASCT, depth of response, and biologic markers such as ISS stage and cytogenetic risk.

Management of Multiple Myeloma.

The most recent NCCN Guidelines for Multiple Myeloma include a ranking of the many treatment options for various settings as "preferred," "other," and "useful in certain circumstances." For patients eligible for autologous stem cell transplant (ASCT), the preferred regimen remains bortezomib/lenalidomide/dexamethasone (category 1) or bortezomib/cyclophosphamide/dexamethasone. Upfront ASCT also remains a preferred strategy for patients who are transplant-eligible, despite highly effective newer agents such as induction therapy. Double (tandem) ASCT may benefit patients with high-risk cytogenetics, such as 17p deletion. Lenalidomide maintenance is the standard posttransplant approach and results in improved progression-free and overall survivals. For relapsed disease, a host of new agents have been shown to improve outcomes, mostly in combination with bortezomib or lenalidomide, but their selection depends largely on response and tolerability to prior therapies.

Analysis of Clinical Factors and Outcomes Associated with Nonuse of Collected Peripheral Blood Stem Cells for Autologous Stem Cell Transplants in Transplant-Eligible Patients with Multiple Myeloma

Collection and storage of peripheral blood stem cells (PBSCs) for use in autologous stem cell transplantation (ASCT) upon first disease relapse is an accepted practice for eligible patients with multiple myeloma (MM). However, little is known about the factors and outcomes associated with nonuse of these collected and stored PBSCs by MM patients who intended to have a delayed ASCT. From January 1, 2004 to December 31, 2014 we identified 342 patients who underwent collection and storage of their PBSCs in anticipation of a delayed ASCT upon first disease relapse. Among these, 176 patients (11%) had not proceeded to a delayed ASCT at the time of this study analysis. The most common reason for not undergoing an ASCT was not experiencing a relapse on first-line therapy (53%, n = 94). However, 11% of patients (n = 37) who planned for a delayed ASCT were unable to undergo an ASCT at disease relapse. Comparison with a control group of MM patients who underwent an upfront ASCT suggested a worse overall survival from diagnosis in these patients who were ASCT ineligible at disease relapse (112 versus 80 months, P = .011). This study provides valuable data for patients and care providers to take into consideration when deciding on whether to pursue an upfront or a delayed ASCT.

Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients in response after induction: an analysis of patients from LYSA centers

BackgroundPeripheral T-cell lymphoma (PTCL) remains a therapeutic challenge. Due to the rarity and the heterogeneity of PTCL, no consensus has been achieved regarding even the type of first-line treatment. The benefit of autologous stem-cell transplantation (ASCT) is, therefore, still intensely debated. Patients and methodsIn the absence of randomized trials addressing the role of ASCT, we performed a large multicentric retrospective study and used both a multivariate proportional hazard model and a propensity score matching approach to correct for sample selection bias between patients allocated or not to ASCT in intention-to-treat (ITT). ResultsAmong 527 patients screened from 14 centers in France, Belgium and Portugal, a final cohort of 269 patients ≤65years old with PTCL-not otherwise specified (NOS) (N=78, 29%), angioimmunoblastic T-cell lymphoma (AITL) (N=123, 46%) and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-ALCL) (N=68, 25%) with partial (N=52, 19%) or complete responses (N=217, 81%) after induction was identified and information about treatment allocation was carefully collected before therapy initiation from medical records. One hundred and thirty-four patients were allocated to ASCT in ITT and 135 were not. Neither the Cox multivariate model (HR=1.02; 95% CI: 0.69–1.50 for PFS and HR=1.08; 95% CI: 0.68–1.69 for OS) nor the propensity score analysis after stringent matching for potential confounding factors (logrank P=0.90 and 0.66 for PFS and OS, respectively) found a survival advantage in favor of ASCT as a consolidation procedure for patients in response after induction. Subgroup analyses did not reveal any further difference for patients according to response status, stage disease or risk category. ConclusionsThe present data do not support the use of ASCT for up-front consolidation for all patients with PTCL-NOS, AITL, or ALK-ALCL with partial or complete response after induction.

Stem cell transplantation for T-cell lymphomas in Taiwan.

T-cell lymphomas are generally aggressive malignancies with poor prognosis. There are no standard treatment guidelines for T-cell lymphomas, and the timing of stem cell transplantation (SCT) is not well known. In this study, we investigated the outcomes of Taiwanese patients with T-cell lymphomas after SCT. We retrospectively analyzed 131 patients with T-cell lymphomas receiving SCT (autologous: 90, allogeneic: 41) from 2009 to 2014. More autologous SCT recipients were ALCL or in complete remission, and more allogeneic recipients had advanced disease. 56 patients who were sensitive to chemotherapy underwent SCT as upfront setting. The 2-year PFS and OS rates were 67.0 and 64.5%, respectively. Regarding disease status before transplantation, patients with CR1 had the best outcomes. Among different subtypes, patients with natural killer/T-cell lymphomas showed the worst outcomes, with 2-year OS rate of 23.5%. The OS rates for the other three major subtypes were as follows: 72.9% for ALCL; 75.0% for AITL; and 51.4% for PTCL-NOS. For more rare subtypes, such as ATLL and SPTCL, data from our study show that SCT can be beneficial. We concluded that upfront autologous SCT is feasible and effective for patients with low PIT, and disease status at transplant is the strong predictor of outcome.

Outcome of a Salvage Third Autologous Stem Cell Transplantation in Multiple Myeloma

To evaluate the outcomes of salvage third autologous stem cell transplantation (ASCT) in patients with relapsed multiple myeloma. We analyzed 570 patients who had undergone a third ASCT between 1997 and 2010 (European Society for Blood and Marrow Transplantation data), of whom 482 patients underwent tandem ASCT and a third ASCT at first relapse (AARA group) and 88 patients underwent an upfront ASCT with second and third transplantations after subsequent relapses (ARARA group). With a median follow-up after salvage third ASCT of 61 months in the AARA group and 48 months in the ARARA group, the day +100 nonrelapse mortality in the 2 groups was 4% and 7%, the incidence of second primary malignancy was 6% and 7%, the median progression-free survival was 13 and 8 months, and median overall survival (OS) was 33 and 15 months. In the AARA group, according to the relapse-free interval (RFI) from the second ASCT, the median OS after the third ASCT was 17 months if the RFI was <18 months, 37 months if the RFI was between 18 and 36 months, and 64 months if the RFI was ≥36 months (P < .001). In the ARARA group, the median OS after the third ASCT was 7 months if the RFI was <6 months, 13 months if the RFI was between 6 and 18 months, and 27 months if the RFI was ≥18 months (P < .001). In a multivariate analysis of the AARA group, the favorable prognostic factor was an RFI after second ASCT of ≥18 months. Progressive disease and a Karnofsky Performance Status score of <70 at third ASCT were unfavorable factors. A salvage third ASCT is of value for patients with relapsed myeloma, particularly for those with a long duration of response and chemosensitive disease at the time of transplantation.

Autologous peripheral blood stem cell transplantation for treating primary central nervous system lymphoma: a single-center retrospective study

Primary central nervous system lymphoma (PCNSL) is more difficult to treat than other lymphomas. Recently, it has been suggested that high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is effective for treating PCNSL. In the present study, we retrospectively analyzed 12 patients with PCNSL at our hospital. Five young patients with good performance status (PS) received upfront ASCT. The conditioning regimen prior to ASCT with busulfan ＋ cyclophosphamide ＋ etoposide showed good prognosis (complete remission rate of 100%). In addition, the PS improved in patients treated with high-dose chemotherapy followed by ASCT, while it worsened in those treated without ASCT. Further investigations are needed to clarify inclusion/exclusion criteria and optimize conditioning regimens for ASCT.