ALBERT

Description: Introduction Multiple Myeloma (MM) is considered incurable and MM patients eventually relapse despite use of many promising approved drugs in standard-of-care treatment. It has been challenging to design precision medicine protocols to tailor personalized treatment for MM patients that relapse despite availability of novel drugs. In-vitro drug screening has been hampered by lack of in-vitro culture protocols that mimic tumor microenvironment and that accommodates for low cell number. Here, we report our novel MM proliferation protocol along with an in-vitro functional screening platform, that allow us to assess drug sensitivity on MM patient samples with a customized panel of 30 myeloma drugs. Using our novel drug sensitivity screening platform, we aim to identify efficient drugs for individual patients with progressive disease and select the best treatment option. Methods Previously, we have established culture settings that mimic the tumor microenvironment for MM (Wang D. et al Leukemia 2017). Here, we implemented a novel protocol that allowed primary MM cells to proliferate in a 384 well-format. Stimulated CD138+ MM cells were tested against a customized library of 30 clinically approved drugs including proteasome inhibitors (PI) and drugs that are in clinical trials. CD138+ MM cells were cultured in 384-well format in the presence of individual drugs in a concentration range over 6 logs for 72 hours (3 days). To define drugs that inhibit malignant plasma cell growth, we used the cell-based assays CellTiter-Glo® luminescent cell viability assay and CellTox™ green cytotoxicity assay as readouts by assessing drug sensitivity at day 3. We performed MM drug screening on 18 patient samples and 6 healthy B-cell (BC) control samples. We performed drug screening on myeloma cells SK-MM2 (patient derived cell line) for 527 drugs at 5 concentrations. We are currently performing drug screening on 11 MM cell lines which represents diverse cancer stage. For each patient sample, a Drug Sensitivity Score (DSS) was calculated for every drug using the IC50 value, slope and the area under the curve (AUC). Next, DSS values for the full MM patient cohort were compared to those of healthy controls to generate a selective DSS (sDSS) for each drug (sDSS = DSSpatient - average DSShealthy). Drugs which had sDSS 〉5 were considered clearly more effective for patient samples in the in vitro test. MM patient samples were assessed for sDSS score using our screening data and we ranked all the drugs by their sDSS score. We have generated sDSS score for both CTG (cell viability) and CTxG (cell toxicity) datasets. Results and conclusion To date we have performed MM drug sensitivity screening on 18 MM patient samples and 6 healthy B cells donors. We adopted a quantitative scoring approach using sDSS to rank drugs that are selective and effective in inhibiting myeloma cells. Based on our drug sensitivity analysis, proteasome inhibitors such as bortezomib and carfilzomib were more effective in inhibiting myeloma cell proliferation compared to other drugs in all 18 patient samples as well as in the 6 healthy donors. Surprising, doxorubicin showed the highest average sDSS score in 10 patients with score 12.96 followed by prednisolone with average sDSS score 6.73 (Figure 1), while proteasome inhibitor bortezomib showed average sDSS score of 4.14 and carfilzomib showed average sDSS score of 1. In addition, we observed that samples from dexamethasone-treated patients showed lower sDSS score for dexamethasone in the in vitro drug screening compared to samples from untreated patients (MM0905 and MM0706). Based on the screening data and clustering analysis, we concluded that the observed diversity in drug effectiveness between patient samples supports the hypothesis of tumor heterogeneity and creates a basis for exploring the possibility to individualize treatment choices. Figure 1: Selective Drug Sensitivity Screening (sDSS) score for 30 drugs for 13 MM patient samples. HB, Healthy donor B cells (Euclidean distance, Ward linkage method) Disclosures Schjesvold: Novartis: Honoraria; Oncopeptides: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria.

Description: Background: AL amyloidosis is a rare life-threatening disease arising from a disorder of plasma cells resulting in excessive immunoglobulin free light chains (FLC) that are misfolded, aggregate, and form toxic deposits in vital organs including the heart, kidneys, and liver (Merlini G, et al. Nat Rev Dis Primers. 2018). The primary goal of therapy is to reduce or eliminate the FLC and halt the progression of organ damage and improve function. Measures that can improve hematologic responses may improve organ responses and impact survival. Treatments used in other plasma cell disorders, like multiple myeloma (MM), including autologous stem cell transplantation (ASCT), are commonly used to treat AL amyloidosis. However, there are no approved therapies for AL amyloidosis. Effective treatment, especially for patients with advanced cardiac involvement, remains a high unmet medical need (Merlini G, et al. Nat Rev Dis Primers. 2018; Milani P, et al. Expert Rev Hematol. 2018). Melflufen, a lipophilic peptide-conjugated alkylator that rapidly delivers a highly cytotoxic payload into cells through peptidase activity, is currently under investigation for the treatment of relapsed/refractory MM (RRMM). In the phase 1/2 study, O-12-M1, of patients with RRMM and ≥2 prior lines of therapy, including lenalidomide and bortezomib, melflufen plus dexamethasone showed an overall response rate of 31%, median progression-free survival of 5.7 months, and median overall survival of 20.7 months, with manageable hematologic toxicity (Richardson PG, et al. Blood. 2017; Abstract 3150). The activity of melflufen in RRMM suggests that it may have potential therapeutic applications for patients with AL amyloidosis. OP201 is a planned, phase 1/2, open-label study evaluating the safety and efficacy of melflufen and dexamethasone in patients who have AL amyloidosis and have received ≥1 prior therapy. Study Design: The planned enrollment for OP201 is approximately 46 patients. Patients must have AL amyloidosis and ≥1 prior therapy, which can include 1 prior nontransplant regimen, a prior ASCT, or 1 prior induction regimen followed by a single ASCT (without hematologic progression between induction and ASCT). Other key inclusion criteria include measurable hematologic and organ involvement (cardiac and/or renal and/or liver), Eastern Cooperative Oncology Group performance status ≤2, adequate baseline hematologic and organ function, ≤30% bone marrow plasma cells, echocardiogram with left ventricular ejection fraction ≥45% and electrocardiogram with QTcF interval of ≤470 ms. Key exclusion criteria include evidence of gastrointestinal bleeding, cardiac risk stage 3 with N-terminal pro-brain natriuretic peptide 〉5000 pg/mL, active infection, concurrent symptomatic MM, significant ventricular arrhythmias, and severe orthostatic hypotension. Phase 1 dose escalation will follow a standard 3+3 design, with 3 to 6 patients evaluable for dose-limiting toxicity at each dose level. Patients will receive melflufen intravenously at 1 of 3 dose levels (20 mg, 30 mg, or 40 mg) on day 1 and oral dexamethasone 40 mg (20 mg at investigator's discretion) on days 1 and 2 of each 28-day cycle. Treatment will continue for up to 8 cycles until stable hematologic partial response or better after cycle 4, less than hematologic partial response after cycle 2, nonhematologic or hematologic disease progression, unacceptable toxicity, or physician's determination that it is not in patient's best interest to continue treatment. The primary endpoints for the phase 1 study are safety and identifying the recommended phase 2 dose (RP2D) of melflufen. Phase 2 will include 26 patients (20 phase 2 + 6 phase 1) treated at the RP2D. The primary endpoint for phase 2 is the hematologic overall response rate after 4 cycles of treatment. Key secondary endpoints include pharmacokinetics (phase 1), best hematologic response, duration of hematologic response, organ system-specific response, duration of organ system-specific responses, time to next AL amyloidosis treatment, and overall survival. Disclosures Palladini: Sebia: Honoraria; Celgene: Other: Travel grant; Janssen-Cilag: Honoraria; Janssen-Cilag: Other: Travel grant. Schönland:Prothena: 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; Medac: Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lentzsch:Abbvie: Consultancy; Crossfires in hematologic Malignancies: Honoraria; BMS: Consultancy; Takeda: Consultancy; Clinical Care Options: Speakers Bureau; Columbia University: Patents & Royalties: 11-1F4mAb as Anti-Amyloid Strategy; Janssen: Consultancy; Multiple Myelopma Research Foundation: Honoraria; Bayer: Consultancy; Sanofi: Consultancy, Research Funding; Proclara: Consultancy; Caelum Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; International Myeloma Foundation: Honoraria. Cibeira:Amgen: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria. Hajek:PharmaMar: Honoraria, Other: Consultant or advisory relationship; Novartis: Other: Consultant or advisory relationship, Research Funding; Janssen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Amgen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Bristol-Myers Squibb: Honoraria, Other: Consultant or advisory relationship, Research Funding; AbbVie: Other: Consultant or advisory relationship; Celgene: Honoraria, Other: Consultant or advisory relationship, Research Funding; Takeda: Honoraria, Other: Consultant or advisory relationship, Research Funding. Jaccard:Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Honoraria, Research Funding; Pfizer: Honoraria. Jamroziak:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Prothena: Research Funding. Schjesvold:SkyliteDX: Honoraria; 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wechalekar:Celgene: Honoraria; GSK: Honoraria; Amgen: Research Funding; Janssen-Cilag: Honoraria; Takeda: Honoraria. Thuresson:Oncopeptides: Employment, Equity Ownership. Harmenberg:Oncopeptides: Consultancy, Equity Ownership. Byrne:Takeda: Consultancy; Oncopeptides: Consultancy. Merlini:University of Pavia: Employment.

Description: Introduction A triplet combination including a proteasome inhibitor (PI) and an IMiD has shown significant efficacy in newly diagnosed multiple myeloma (NDMM) patients. A role for maintenance therapy with the PI bortezomib has been suggested in non-head to head comparisons. Therefore, we investigated the efficacy and feasibility of an oral regimen including induction therapy with ixazomib in combination with thalidomide and dexamethasone, followed by a randomization between maintenance therapy with ixazomib or placebo in elderly non-transplant eligible (nte) NDMM. We here report the final analysis of induction therapy and preliminary results of the randomization phase of the study. This trial was registered at www.trialregister.nl as NTR4910. Methods In this prospective multicenter phase II trial nte-NDMM 143 patients were treated with 9 28 day-cycles consisting of ixazomib 4 mg (day 1, 8, 15), thalidomide 100 mg (day 1-28) and dexamethasone 40 mg (day 1, 8, 15, 22) followed by randomization between either ixazomib or placebo (both day 1, 8, 15/28 days) until progression. Primary objectives were comparison of progression free survival (PFS) between maintenance therapy with ixazomib or placebo (hypothesized hazard ratio (HR) 0.39) and to determine the overall response rate (ORR) of induction therapy. Frailty was assessed by a modification of the IMWG frailty index based on age, the Charlson Comorbidity Index and the WHO performance as a proxy for (instrumental) Activities of Daily Living (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points). High risk cytogenetics was defined as del17p, t(4;14) and/or t(14;16). Results The median follow up (FU) from registration is 26.4 months (range 0.9-41.0 months). Patient characteristics are presented in table 1. Following induction treatment ORR (i.e. ≥PR) was 81% (95% confidence interval (CI) 74-87%), ≥ VGPR 47% (95% CI 38-55%) and ≥ CR 9% (95% CI 5-15%). Age ≥76 years, frailty (unfit or frail) or high cytogenetic risk did not affect the rate and quality of response. Median PFS from registration for all patients was 14.3 months (95%-CI 11.8-16.8). Frailty did not affect PFS. The median PFS for high risk and standard risk disease was comparable; 12.4 months (95%-CI 7.3-20.0) versus 14.6 months (95%-CI 11.5-17.4) respectively. The OS from registration at 18 months was 85% (95% CI 77-90). This was 90% (95% CI 72-97), 92% (95% CI 78-97) and 74% (95% CI 61-84) for fit, unfit and frail patients respectively. Seventy-eight patients (55%) were randomized. The reasons for not being randomized were toxicity (17% [24/143]), progressive disease (15% [21/143]), death (3% [5/143]) and other reasons (10% [15/143]). Median FU from randomization is 18.6 months (range 9.0-31.5 months). Baseline characteristics of randomized patients separately are presented in table 1. Upgrade of response occurred in 13% of patients receiving placebo and 10% of patients receiving ixazomib. The median PFS from randomization was 8.4 months (95%-CI 3.0-13.8) in the placebo arm and 10.1 months (95%-CI 5.6-24.1) in the ixazomib arm (p=0.47, figure 1). The OS from randomization at 18 months was 92% (95%-CI 77-97) in the placebo arm and 100% in the ixazomib arm (p=0.85). Toxicity is presented in table 2. The incidence of neuropathy was low; 8% grade 3 (mainly during thalidomide treatment; 5%) and no grade 4. There was no new onset neuropathy during ixazomib maintenance. During induction 24/143 (17%) patients discontinued therapy due to toxicity; 11 thalidomide-related neurotoxicity, 3 infection, 3 skin toxicity, 2 gastro-intestinal (GI) toxicity and 5 other. During maintenance 4/38 (11%) in the placebo (3 neurotoxicity and 1 other) versus 4/39 (10%) in the ixazomib arm (3 neurotoxicity and 1 GI) discontinued therapy due to toxicity. Discontinuation due to toxicity was comparable across age and frailty groups. Conclusion Induction treatment with 9 cycles of ITd in nte NDMM results in a high ORR of 81%, with 47% ≥ VGPR, independent of age, frailty status and cytogenetic risk. Our placebo controlled randomized phase II trial did not show an improvement in response and PFS with ixazomib maintenance therapy until progression. Ixazomib maintenance did not result in additional toxicity as compared to placebo. Disclosures Zweegman: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schjesvold:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Bayer: Consultancy; Adaptive: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy; Abbvie: Honoraria; Novartis: Honoraria. Levin:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Abildgaard:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding.

Description: Macrophages are important tumor-promoting cells, and can constitute up to half of the tumor mass, orchestrating remodeling, inducing angiogenesis and suppressing the immune system to terminate local inflammatory responses. Colony stimulating factor (CSF-1), also known as macrophage colony-stimulating factor (M-CSF), is the most important cytokine involved in survival, proliferation and differentiation of tissue macrophages and their precursors. Previous experiments from our group has shown that amount of CSF-1 in the tumor bed correlates with successful rejection of cancer cells in a TCR-transgenic model where CD4+ T cells recognize a tumor specific antigen produced by multiple myeloma cells. We therefore tested if reduced signaling via CSF-1R, and thereby a decrease in tumor infiltrating macrophages, would results in decreased growth of multiple myeloma cells. . PLX3397, a tyrosine kinase inhibitor with specificity for CSF1R and KIT, has been demonstrated to delay tumor growth in a CD8+ T-cell-dependent manner after chemotherapeutic treatment in a murine model of mammary carcinogenesis. Here, we show that MOPC315 multiple myeloma cells implanted subcutaneously in matrigel plugs in SCID mice become infiltrated with M2 phenotype macrophages that enhances their growth. When given chow containing PLX3397, recruitment of macrophages is strikingly reduced, with significant delay in tumor growth. Importantly, this delay in tumor development is not T cell dependent, since the anti-tumor effect is seen in T cell deficient SCID-mice as well as in BALB/c mice. Importantly, treatment with PLX3397 does not abrogate efficient tumor killing, and does not affect survival, when tested in a TCR-transgenic model where CD4+ T cells via induction of M1 macrophages reject multiple myeloma. In conclusion, PLX3397 delays tumor growth by reducing amounts of tumor infiltrating M2 macrophages, while rendering effective tumor killing by M1 macrophages uninhibited. Thus, drugs that inhibit signaling of CSF-1 could be of value in treatment of multiple myeloma. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults and is currently considered incurable. Although current treatment regimens prolong life for patients, CLL eventually relapses. Efficient therapies may require a personalized approach that combines targeting cancer cells and the tumor microenvironment by restoring the patient's own anti-tumor immunity. However, a major limitation is that no efficient approach exists to identify the most effective drugs for each patient and cancer stage. With the aim to support future introduction of individualized treatment for patients, we assessed the sensitivity of CLL patient samples to several drug candidates using our in vitro functional drug sensitivity screening platform. Methods We have established novel in vitro culture settings that mimic the CLL tumor microenvironment and allow proliferation of CLL cells for 5 days. Using our unique method, we performed drug screening on 26 patient samples and 10 healthy donors against a customized, annotated library of 516 drugs including kinase inhibitors, proteasome inhibitors, B-cell pathway inhibitors and several other approved drug classes. Primary patient samples were cultured in 384 well-plates with the presence of individual drugs over a concentration range over 5 logs. Drug sensitivity was assessed using CellTiter-Glo® luminescent cell viability assay and CellTox™ green cytotoxicity assay on day 5. Drug Sensitivity Score (DSS) was then calculated for each drug using the IC50 value, slope and area under the curve (AUC). DSSs for CLL patient samples were next compared with DSS of healthy donors for the full patient sample cohort screened so far to generate a selective DSS (sDSS = DSSpatient - DSShealthy) for each patient. Drugs which have sDSS 〉5 were considered clearly more effective for patient samples in the in vitro test system. CLL samples were assessed for sDSS using our screening data and we ranked all the drugs by their score. Results In order to find drug candidates for targeted therapies in CLL patients, we performed in vitro drug sensitivity screening on 13 IgVH unmutated and 13 IgVH mutated CLL patient samples, as well as 10 healthy donors (due to the lower number of cells healthy donors were pooled into two samples of 5 donors each). Our in vitro assay showed that proteasome inhibitors, kinase inhibitors and several approved CLL drug candidates were considered sensitive in the majority of patient samples. This included venetoclax, the Bcl-2 inhibitor ABT-737, doxorubicin, acalabrutinib, other kinase inhibitors (sunitinib, volasertib, trametinib, copanlisib) and proteasome inhibitors (carfilzomib, bortezomib). Selective drug sensitivity scores of the top 5 drugs in all patient samples (73 drugs in total) are shown in the heatmap (Figure 1). Venetoclax showed a higher sDSS score in 10 of the 20 patients with an average sDSS score of 22.3 followed by ABT-737 (Bcl-2 inhibitor) with an average sDSS score of 19.7. By performing hierarchical clustering analysis (Euclidean distance, Ward linkage method), we observed unsupervised clustering of patient samples irrespective of the IgVH mutation status. We are currently expanding the analysis by classifying the patient samples by age, sex and mutation status. Conclusion Our novel CLL culture method that allows cell proliferation along with our established functional in-vitro drug sensitivity screening platform enabled us to screen a number of patient samples and evaluate the sensitivity of a library of approved drugs and investigational drug candidates for CLL. Our analysis shows that several drugs may be effective for CLL and can be tested in drug combinations in order to identify synergistic effects. As a future perspective, we want to combine machine learning strategies with the experimental drug screening strategies to identify drug combinations and validate drug candidates by xenografting and in precision medicine clinical trials. Figure 1: Selective Drug Sensitivity Screening (sDSS) score for top 3 drugs (44 drugs) for 20 CLL patient samples. Green label is IgVH mutated CLL patient samples and blue label is IgVH unmutated patient samples. Disclosures Schjesvold: Oncopeptides: Consultancy; Abbvie: Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

Description: Background The role of up-front consolidation for newly diagnosed, transplant eligible MM (NDMM) patients (pts) has not yet been prospectively addressed in the novel agents era. Methods The EMN02/HO95 trial was designed to randomly (R) compare (R1) 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT), either single or double, as intensification therapy after induction with bortezomib-cyclophosphamide-dexamethasone (VCD) (M Cavo et al, ASCO 2016, abstract #8000). A second randomization to consolidation therapy with 2 cycles of VRD vs no consolidation (R2) was performed after intensification, to be followed by lenalidomide maintenance (lenalidomide 10 mg continuously) until progression or toxicity in both arms. (VRD: bortezomib 1.3 mg/m2 intravenously days 1, 4, 8, 11; lenalidomide 25 mg orally days 1 - 21; dexamethasone 20 mg orally days 1, 2, 4, 5, 8, 9, 11, 12 of a 28 days cycle). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. A first planned interim analysis for R2 was performed in July 2016 when at least 33% (= 172) of the required events for PFS had been observed. Results From February 2011 to April 2014, 1510 pts aged ≤ 65 years with symptomatic MM were enrolled, of whom 1499 were eligible. Of these, 1211 were randomized (stratification by ISS stage) to VMP (505 pts) or HDM (1 or 2 ASCT) (706 pts). For R2 903 eligible patients were randomized to consolidation (459 pts) or no consolidation (444 pts). Median follow up from R2 was 25 months (maximum 53). Response status at time of R2 was ≥ CR (23%), ≥ VGPR (67%), ≥ PR (93%), and will be updated for status at start of maintenance. At the time of analysis, 258 events for PFS after R2 had been reported. 3-year. PFS from R2 was 62% in all patients, i.e., 60% without consolidation and 65% in patients with consolidation, and median PFS had not yet been reached. PFS from R2 with adjustment for R1 was prolonged in pts randomized to VRD (HR=0.78; 95% CI=0.61-1.00; P=0.045), a benefit retained across predefined subgroups with revised ISS stage III (HR=0.67; P=0.26) and in patients randomized in R1 to VMP (HR=0.76; P=0.19) and to HDM (HR=0.79; P=0.13). The benefit of consolidation was observed in patients with low-risk cytogenetics (HR=0.68; P=0.03), but not in patients with high-risk cytogenetics (del(17p) and/or t(4;14) and/or t(14;16); HR=1.03; P=0.91). At 3 years OS from R2 was 86% and 87%, respectively. Toxicity from VRD was limited with 5% CTCAE grade 4, mainly hematological. Conclusions Consolidation treatment with VRD followed by Lenalidomide maintenance until progression or toxicity shows promising results as compared to maintenance alone for younger NDMM pts, but further study follow-up is needed. This trial was registered at www.trialregister.nl as NTR 2528, EudraCT 2009-017903-28 This trial was supported by unrestricted grants from Celgene and Janssen. Disclosures Sonneveld: Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Ludwig:Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Driessen:janssen: Consultancy; celgene: Consultancy; Mundipharma-EDO: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gay:Celgene: Honoraria; Mundipharma: Other: Advisory Board; Amgen: Honoraria; BMS: Honoraria; Janssen-Cilag: Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board. Mellqvist:Mundipharma: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Palumbo:Takeda: Employment, Honoraria; Janssen Cilag: Honoraria. Cavo:Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria.

Description: Introduction Maintenance therapy has been extensively explored as a strategy for prolonging the duration of disease control and potentially survival following ASCT. To date, only lenalidomide has been approved for this indication. However, lenalidomide maintenance is associated with the development of second primary malignancies and tolerability issues. PIs are a backbone of MM treatment, and bortezomib-based maintenance has shown promising activity post-ASCT, yet the benefit of PI-based maintenance has not been demonstrated in a phase 3 trial vs placebo. Moreover, the feasibility of bortezomib maintenance in routine clinical practice is limited due to tolerability and the need for regular parenteral administration. There is a need for an oral PI maintenance therapy that can be administered for a prolonged period, improve depth of response without cumulative or late-onset toxicity, and improve convenience for patients. Methods The phase 3, double-blind, placebo-controlled, multicenter TOURMALINE-MM3 study (NCT02181413) compared weekly ixazomib vs placebo maintenance in NDMM patients who had at least a partial response (≥PR) to induction therapy with a PI and/or immunomodulatory drug (IMiD) followed by single ASCT. Patients were randomized (3:2) to receive ixazomib or matched placebo on days 1, 8, and 15 of 28-day cycles for up to 2 years or until progressive disease (PD) or unacceptable toxicity. Randomization was stratified by induction regimen (PI without IMiD vs IMiD without PI vs PI+IMiD), pre-induction ISS stage (I vs II or III), and post-ASCT response (complete response [CR] or very good partial response [VGPR] vs PR). Patients were ineligible if they had received post-ASCT consolidation or tandem ASCT. The ixazomib dose was 3.0 mg during cycles 1-4, increasing to 4 mg from cycle 5 if tolerated during cycles 1-4. The primary endpoint was PFS per independent review committee (IRC), who were blinded to treatment assignment. The key secondary endpoint was OS. Here, we report data from the final analysis for PFS (data cut-off: April 16, 2018). Results 656 patients were randomized (395 ixazomib; 261 placebo). Patient demographics were balanced between groups; overall median age was 57 years (range, 24-73), 37% vs 63% had ISS I vs II or III, 59%/11%/30% had received PI without IMiD / IMiD without PI / PI+IMiD induction therapy, 34%/45%/21% had achieved CR / VGPR / PR following induction/ASCT, and 18% had high-risk cytogenetics [del(17p), t(4;14), or t(14;16)]. After a median follow-up of 31 months with 54% of PFS events, there was a 28% reduction in the risk of progression/death, corresponding to a 39% improvement in PFS with ixazomib vs placebo (median 26.5 vs 21.3 months; hazard ratio [HR] 0.72; 95% CI: 0.582, 0.890; p=0.002; Figure). In a landmark analysis from ASCT, PFS was 30.7 vs 24.9 months (HR 0.684; 95% CI: 0.551, 0.848; p

Description: Introduction Multiple myeloma (MM) is considered an incurable disease. However, during the last years the survival has improved, partly due to the development of new drugs. The second-generation proteasome inhibitor Carfilzomib (Kyprolis®) was first approved for marketing in Norway in January 2016. Carfilzomib in combination with Dexamethasone (Kd) for patients with relapsing and/or refractory multiple myeloma (RRMM) was approved for reimbursement in August 2017, while the combination with Lenalidomide (Revlimid®) and Dexamethasone (KRd) is still not reimbursed in Norway. Both regimens now have mature and beneficial survival data (vs Vd and Rd, respectively). In the period before market approval, Carfilzomib was provided through a named patient program (NPP) for patients who had a critical disease with few treatments options. This abstract presents results from this cohort. Aim In this retrospective study all 33 Norwegian MM patients who received Carfilzomib through a named patient program (NPP) during the period of March 2014 to January 2016, were included. The aim was to describe the patients 'characteristics and their treatment responses, in addition to use the real-life experience to highlight a possible benefit of making new drugs available before marketing approval. During this study period, neither Daratumumab, Ixazomib nor Elotuzumab were available in Norway. The medical records were printed and sent from 10 different hospitals to Oslo Myeloma Center. Baseline values and treatment responses was assessed and entered into our myeloma database. Statistical analysis was done to determine response rates and time to event outcomes. Results The participants had received a median of 6 (1-11) previous lines of therapy, including bortezomib (100%), and thalidomide and/or lenalidomide (97%) before inclusion in this study Among these, 64 % or 66 % respectively was refractory to the indicated treatment. 76 % of the study participants had received at least one ASCT. Median time from diagnosis to initiating carfilzomib treatment was 5 years (0-15) for the 32 patients who received carfilzomib. Patients who received the triplet treatment KRd, had a benefit in terms of response with ORR of 19%, compared to 8 %for patients receiving Kd/K (p=0, 04). CBR for these patients was 22 % and 25 %, respectively (p=0,33). There was no difference between the two groups for PFS or OS, with a median OS of 10 months (0-24) for patients receiving KRd compared to 9 month (2-14) for Kd/K. However, patients receiving KRd showed a trend towards a better PFS compared to Kd with a median PFS of 3,5 months (1,4 - 4,6) compared to 2,5 months (0,2 - 3,8) (p=0,095). Adverse events occurred in 91 % of the patients where 41 %, 31 % and 41 % respectively experienced a Grade 3 or higher for anemia, neutropenia or thrombocytopenia (according to CTCAE vs 4.0). 19 % experienced cardiovascular complications and 3% ended treatment due to them. Of these patients, 50 % had received doxorubicin at a previous treatment line and 17% received doxorubicin in combination with Carfilzomib. Overall, 9% of the patients discontinued the treatment due to adverse events while 6 % died before the end of the treatment. Carfilzomib was not considered a direct cause of death in any of these patients. At the end of the study (January 2018), 76 % of the participants were dead. Conclusion In this real-life study, RRMM patients who received lenalidomide in addition to carfilzomib and dexametason showed a superior response in comparison with patients who received carfilzomib and dexamethasone with an ORR of 19 % versus 8 %. There was no significant overall survival benefit, but a trend towards a better PFS for KRd compared to Kd/K. As an overall conclusion, this group of highly treated MM patients had a benefit from receiving Carfilzomib in combination with lenalidomide before marketing approval. Disclosures Schjesvold: Oncopeptides: Consultancy; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria.

Description: Background: [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) positivity after first line treatment with autologous stem cell transplantation (ASCT), is strongly correlated with reduced progression free survival and overall survival (Moreau et al., JCO, 2017). However, FDG PET/CT positive patients who obtain FDG PET/CT negativity after treatment can have comparable outcomes to patients who were FDG PET/CT negative at baseline (Davies et al., Haematologica 2018). Aiming for FDG PET/CT negativity may therefore be an important goal in myeloma treatment. The use of FDG PET/CT positivity as an indication for consolidation therapy after ASCT has not been studied before. Methods: This is an ongoing, multicenter phase II study. Patients with multiple myeloma who have received standard first line treatment including ASCT and achieved very good partial response (VGPR) or better, are eligible for the study and examined by FDG PET/CT. Patients who are FDG PET/CT positive defined by the Italian Myeloma criteria for PET USe (IMPETUS) (Nanni C et al., EJNMMI 2016 and 2018) are included in the treatment phase of the study and are assessed for minimal residual disease (MRD) by Euroflow (sensitivity: 10-5) before treatment. The treatment consists of four 28-day cycles of KRd (carfilzomib 36 mg/m2 day 1,2,8,19,15 and 16 (except 20 mg/m2 day 1 and 2 first cycle), lenalidomide 25 mg day 1-21 all cycles and dexamethasone 40 mg day 1,8,15 and 22 all cycles). After four cycles, FDG PET/CT and Euroflow for MRD are repeated for response evaluation. Both patients with FDG PET/CT negativity and patients with FDG PET/CT positivity at baseline are followed for progression free survival (PFS) and overall survival (OS). Results: As of 1st of July 2019, 43 patients have been screened in the study. Sixteen patients (37%) had a positive FDG PET/CT result. Eight of 13 (62%) patients with a FDG PET/CT positive result were MRD negative. Eight patients have completed four cycles of KRD consolidation; two patients were converted into FDG PET/CT negativity; one of the two remained MRD positive, the other remained MRD negative. Three patients had reduced FDG uptake but were still considered FDG PET/CT positive; one of these converted from MRD positive to negative. One had stable disease and two had progression on FDG PET/CT whereof one converted from MRD negative to positive. Conclusion: A significant proportion (37%) of patients treated with standard first line treatment including ASCT with very good partial response or better was considered FDG PET/CT positive. Sixty-two percent of these patients were MRD negative by Euroflow, confirming the complementary features of these two methods. Treatment with four cycles of KRd improved disease status based on FDG PET/CT in 5 of 8 patients (62,5%) and converted 2 out of 8 patients to FDG PET/CT negativity. One patient was converted from MRD positivity to MRD negativity. This study is ongoing and will enroll 50 FDG PET/CT positive patients. Before the ASH 2019 meeting, we plan to screen approximately fifteen additional patients with FDG PET/CT and about five more patients will have completed KRd consolidation therapy. Table Disclosures Nørgaard: Bayer, Astrazeneca: Honoraria. Abildgaard:Janssen: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding. Revheim:South-Eastern Norway Regional Healt Authority: Research Funding. Schjesvold:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyliteDX: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: INTRODUCTION: Multiple myeloma (MM) is most frequently diagnosed among people aged 65-74, and approximately one-third of patients (pts) are aged ≥75 years. Advanced age has a negative effect on the prognosis of pts with MM. The randomized, open-label, active-controlled, multicenter phase 3 ICARIA-MM study (NCT02990338) compared treatment with the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with pomalidomide and dexamethasone (Pd) with Pd. Pts had relapsed/refractory MM (RRMM) after ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. This subgroup analysis of ICARIA-MM examined efficacy and safety in elderly pts (≥75 years) compared with younger pts. METHODS: Pts were randomized (1:1) to receive Isa-Pd or Pd. Isa (10 mg/kg IV) was given on days 1, 8, 15, and 22 (cycle 1), and days 1 and 15 in subsequent 28-day cycles. All pts received pomalidomide 4 mg on days 1-21 of each cycle and dexamethasone 40 mg (20 mg for pts ≥75 years old) on days 1, 8, 15, and 22 of each cycle. The primary endpoint was progression-free survival (PFS), assessed by an independent response committee. Subgroup analyses were conducted for pts aged