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Pseudo-progression and flare-up phenomena constitute a novel diagnostic challenge in the follow-up of patients treated with immune-oncology drugs. We present a case study on pulmonary flare-up after Idecabtagen Vicleucel (Ide-cel), a BCMA targeting CAR T-cell therapy, and used single-cell RNA-seq (scRNA-seq) to identify a Th17.1 driven autoimmune mechanism as the biological underpinning of this phenomenon. By integrating datasets of various lung pathological conditions, we revealed transcriptomic similarities between post CAR T pulmonary lesions and sarcoidosis. Furthermore, we explored a noninvasive PET based diagnostic approach and showed that tracers binding to CXCR4 complement FDG PET imaging in this setting, allowing discrimination between immune-mediated changes and true relapse after CAR T-cell treatment. In conclusion, our study highlights a Th17.1 driven autoimmune phenomenon after CAR T, which may be misinterpreted as disease relapse, and that imaging with multiple PET tracers and scRNA-seq could help in this diagnostic dilemma.

Not available.

Background: Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal and immune-stimulatory effects compared with immunomodulatory drugs. In preclinical myeloma models, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma. Methods: We conducted a multicohort, open-label, phase 1/2 trial (CC-220-MM-001) at 42 treatment centres in Europe, Canada, and the USA. Patients aged 18 years or older with multiple myeloma who had received at least two previous lines of therapy, including lenalidomide or pomalidomide and a proteasome inhibitor, were enrolled into the dose-escalation cohort. Patients received escalating doses of oral iberdomide (0·3–1·6 mg on days 1–21 of each 28-day cycle) plus oral dexamethasone (40 mg [20 mg if age >75 years] once per week). A dose-expansion cohort at the recommended phase 2 dose was planned for patients who had received at least three previous lines of therapy and had triple-class refractory disease (refractory to immunomodulatory drugs, proteasome inhibitors, and CD38 antibodies). Treatment continued until progressive disease or unacceptable toxicity. The primary outcomes were the recommended phase 2 dose (in the dose-escalation cohort, phase 1) and overall response rate (defined as complete response or partial response; in the dose-expansion cohort, phase 2) in the full analysis set. This trial is ongoing and is registered with ClinicalTrials.gov, NCT02773030. Findings: Between Dec 5, 2016, and Dec 16, 2020, 460 patients were assessed for eligibility across all cohorts and 197 were enrolled and treated with iberdomide plus dexamethasone (90 patients in the dose-escalation cohort and 107 in the dose-expansion cohort). In the dose-escalation cohort, 47 (52%) patients were female and 43 (48%) were male, 70 (78%) were White, and the median number of previous lines of therapy was 5 (IQR 4–8). In the dose-expansion cohort, 47 (44%) were female and 60 (56%) were male, 84 (79%) were White, and the median number of previous lines of therapy was 6 (IQR 5–8). At data cutoff (June 2, 2021), median follow-up was 5·8 months (IQR 3·0–13·7) in the dose-escalation cohort and 7·7 months (5·3–11·4) in the dose-expansion cohort. Two dose-limiting toxicities (both infections, at 1·2 mg and 1·3 mg) were observed in the dose-escalation cohort, and 1·6 mg was selected as the recommended phase 2 dose. In the dose-escalation cohort, the overall response rate was 32% (95% CI 23–43; 29 of 90 patients) across all doses, and the maximum tolerated dose was not reached. In the dose-expansion cohort, the overall response rate was 26% (95% CI 18–36; 28 of 107 patients). The most common grade 3 or worse adverse events were neutropenia (48 [45%] of 107 patients), anaemia (30 [28%]), infection (29 [27%]), and thrombocytopenia (23 [22%]). Serious adverse events occurred in 57 (53%) patients. There was one (1%) treatment-related death (sepsis) and five (5%) patients discontinued iberdomide due to adverse events. Interpretation: Iberdomide plus dexamethasone was generally safe and showed meaningful clinical activity in heavily pretreated patients with multiple myeloma, including in disease that was refractory to immunomodulatory drugs. These data suggest that further evaluation of iberdomide plus dexamethasone or other standard antimyeloma therapies is warranted. Funding: Bristol Myers Squibb.

Das multiple Myelom ist eine altersassoziierte maligne Plasmazellerkrankung, die vorrangig im Knochenmark auftritt und zur Verdrangung der normalen Hamatopoese fuhrt. Fortschritte in der molekulargenetischen Diagnostik haben das Verstandnis der biologischen Grundlage der Erkrankung entscheidend erweitert. Die schrittweise Einfuhrung von neuen Medikamenten wie Proteasominhibitoren, Immunmodulatoren und monoklonalen Antikorpern sowie der Einsatz wirksamer Kombinationstherapien haben die Prognose auch mehrfach vorbehandelter Patienten deutlich gebessert. Dennoch ist eine Heilung weiterhin nicht moglich. Neue Therapiestrategien vor allem mit immunologischen und zielgerichteten Ansatzen werden die Behandlungsmoglichkeiten in Zukunft bereichern und die Prognose fur Patienten mit multiplem Myelom weiter verbessern.

Lenalidomide is an integral, yet evolving, part of current treatment pathways for both transplant-eligible and transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). It is approved in combination with dexamethasone as first-line therapy for transplant-ineligible patients with NDMM, and as maintenance treatment following autologous stem cell transplantation (ASCT). Although strong clinical trial evidence has supported the integration of lenalidomide into current treatment paradigms for NDMM, applying those paradigms to individual patients and determining which patients are most likely to benefit from lenalidomide treatment are more complex. In this paper, we utilize the available clinical trial evidence to provide recommendations for patient selection and lenalidomide dosing in both the first-line setting in patients ineligible for ASCT and the maintenance setting in patients who have undergone ASCT. In addition, we provide guidance on management of those adverse events that are most commonly associated with lenalidomide treatment, and consider the optimal selection and sequencing of next-line agents following long-term frontline or maintenance treatment with lenalidomide.

Background: With the availability of T-cell-directed therapy and next-generation compounds of established classes of drugs, the treatment of relapsed/refractory (r/r) myeloma is getting more complex. However, treatment options in practice are limited by availability, approval, and patient comorbidity. The aim of this article is to provide a practical approach toward the choice of treatment for r/r myeloma patients. Summary: Regarding market authorization and current guidelines, at least in Germany, most patients nowadays will have received a doublet or triplet combination as first-line therapy containing a proteasome inhibitor and an immunomodulatory drug, mostly lenalidomide. We focus on the treatment options for patients that are ineligible for (another) stem cell transplantation. We will review treatment options for relapse after first- or second-line therapy and beyond third-line. Key Messages: There is promising data supporting the efficacy and safety of triplet combinations containing anti-CD38-monoclonal antibodies (anti-CD38 mAbs) at first or second relapse in combination with next-generation compounds. For the treatment beyond third-line, comparative studies are scarce but some promising compounds are available via conditional authorization, and there is more to come in the future. We will present some early phase trials featuring promising results.

OBJECTIVE A post hoc subgroup analysis of two phase III trials (NCT00416273, NCT00416208) was carried out to investigate the influence of 100/140 and 200 mg/m² melphalan as well as single/double autologous stem cell transplantation (ASCT) on progression-free survival (PFS). Additionally, the effect of bortezomib consolidation on PFS was analyzed. METHODS Following induction therapy and high-dose melphalan with subsequent ASCT, patients with newly diagnosed multiple myeloma (NDMM) were randomized 1:1 to either four 35-day cycles of bortezomib consolidation (1.6 mg/m² IV on days 1, 8, 15, 22) or observation. RESULTS Of the 340 patients included in this analysis, 13.5% received 1 × MEL100/140, 22.9% 2 × MEL100/140, 31.2% 1 × MEL200, and 32.4% 2 × MEL200. With higher cumulative melphalan dose, PFS improved (P = .0085). PFS curves of patients treated with 2 × MEL100/140 and 1 × MEL200 were very similar. The superior dose effect of MEL200 over MEL100/140 was non-existent in the bortezomib consolidation arm but pronounced in the observation arm (P = .0015). Similarly, double ASCT was only beneficial in patients without bortezomib consolidation (P = .0569). CONCLUSIONS Full dose melphalan and double transplantation seem advantageous only as long as patients are not receiving bortezomib consolidation afterwards.

This phase 3 trial compared tandem autologous stem cell transplantation (autoSCT) versus autoSCT followed by reduced-intensity conditioning allogeneic stem cell transplantation (auto/alloSCT) in patients with newly diagnosed multiple myeloma (MM) with deletion of (del) chromosome 13q (del13q). The availability/absence of a human leukocyte antigen-matched-related or matched-unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population (n = 199). Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months median follow-up, median PFS with auto/allo versus tandem autoSCT was 34.5 versus 21.8 months (P = 0.003; adjusted hazard ratio 0.55, 95% confidence interval 0.36–0.84). Median overall survival (OS) was 70.2 versus 71.8 months (P = 0.856). Two-year non-relapse mortality with auto/allo versus tandem autoSCT was 14.3% versus 4.1% (P = 0.008). In patients harboring both del13q and del17p, median PFS and OS were 37.5 and 61.5 months with auto/allo (n = 19) versus 6.1 and 23.4 months with tandem autoSCT (n = 6) (P = 0.0002 and 0.032). Our findings suggest that auto/alloSCT significantly extends PFS versus tandem autoSCT in del13q MM, and indicate some survival benefit for first-line alloSCT in high-risk MM.

[Background]: In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status., [Patients and Methods]: Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients., [Results]: Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%)., [Conclusion]: Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status., This study was sponsored by Janssen Research & Development, LLC.

Background Rapid induction of remission is a favorable factor in pts with Hodgkin's disease and DLBCL. In MM, only few data are available on the impact of response kinetics on outcome in newly diagnosed transplant ineligible MM pts. Recently, (Abstract EP971, EHA 2021) we described a significant correlation between time to response and progression-free survival (PFS) and overall survival in this patient population. Response and time to response depend on several factors such as the biology of the underlying myeloma clone(s), the activity of the treatment regimen, and on the composition of the bone marrow immune environment. Here, we evaluated possible interconnections between the bone marrow immune environment at baseline and the time to response to therapy in a series of pts randomized to either 9 cycles KRd or KTd induction therapy followed by a second randomization to carfilzomib maintenance or observation. Patients and Methods Composition of the immune environment at baseline was analyzed in 55 pts with newly diagnosed transplant ineligible MM enrolled in a randomized phase II trial (AGMT_MM 02). Median age: 74 years (range: 58-84 years), ISS I: 21.8%, ISS II: 41.8%, and ISS III: 36.4%, cytogenetics: 30.9% high risk, 40% standard risk, 29.1% unknown, ECOG Status 0: 54.5%, 1: 45.6%. Treatment: Carfilzomib : Cycle 1 day 1+2: 20mg/m 2, days 8+9 and 15+16: 27 mg/m 2 ; Cycle 2 day 1,2,8,9,15 + 16: 27 mg/m 2 Cycle 3-9: 56mg/m 2 on days 1, 8 and 15. Lenalidomide: 25mg p.o. on days 1-21/cycle or thalidomide: 100 mg p.o. on days 1-28; in pts ≥75 years of age 50mg p.o. on days 1-28, dexamethasone: 40 mg p.o. on days 1, 8, 15, 22 (± 1 day), in pts ≥ 75 years of age 20 mg p.o. this treatment was administered for nine cycles. Thereafter, pts were randomized to carfilzomib maintenance at last tolerated dose on days 1+15 or to observation for 12 cycles. BM samples were stained with 3 different antibody combinations for the analysis of T, B and NK cells (T cells: CD45RA, CD127, CD8, TCRgd, CD25, CD197, CD4, CD3, B/NK cells: CD57, CCR7, CD314, CD85j, CD62L, CD3, CD16, CD56, CD335, HLADR, CD337). We used a semi-automated pipeline to unveil full cellular diversity based on unbiased clustering. The median and range of each cellular subgroup was calculated and compared between pts with short or longer time to response (< or ≥119 days (median)). Statistical significance of these comparisons was calculated using the Wilcoxon test. Results Median FU was 20.5 months. Twenty of the 55 pts achieved a CR (36.7%) and 16 (57.1%) of the 28 who had MRD testing were shown to be MRD negative at a sensitivity of 10 -6. Twenty-three pts achieved a VGPR (41.8%), while only 12 pts achieved a PR (21.8%). Pts were subdivided into two groups according to time to best response. Group A (n=26), median time 56 (26-112) days, group B (n=29), 265 (119-675) days. PFS was significantly longer in group B (19.1 months vs not reached, p=0.007), while for OS only a trend for better survival was noted for group B pts (median survival not reached, p=0.129). High numbers of total CD3 + cells (p=0.033) and CD4 T cells with a CD 197 loCD45RA -CD127 + phenotype (p=0.022) were associated with longer time to best response and longer PFS. An opposite result was noted for the following T cell subsets, which correlated with a shorter time to best response and shorter PFS: CD56 + T cells with (p=0.01) or without (p=0.024) HLADR and CD8 Naïve CD127 + T cells (p=0.041). Diverse results were noted when the NK cell compartment was analyzed. Higher levels of circulatory CD314 - (p Conclusion Our data show significant correlations between the composition of bone marrow immune cells at start of therapy with time to best response and PFS in newly diagnosed transplant ineligible MM pts uniformly treated with carfilzomib-based therapy. High numbers of total lymphocytes CD3 and CD4 Tcells with a CD197 loCD45RA -CD127 + phenotype correlated with significantly longer PFS and longer time to response. Furthermore, higher numbers of specific NK subsets such as those with a circulatory phenotype, correlated with better outcome. These results highlight the prognostic potential of immune monitoring and the interconnection between specific subsets of the immune environment with the course of the disease. Figure 1 Figure 1. Disclosures Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Podar: Amgen Inc.: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding; Celgene: Consultancy, Honoraria. Petzer: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Saegen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zojer: Celgene-BMS, Amgen, Takeda, Sanofi, Janssen: Consultancy, Speakers Bureau. Schreder: BMS-Celgene, Amgen: Consultancy. Melchardt: Abbvie, Celgene, Novartis: Honoraria. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Paiva: Bristol-Myers Squibb-Celgene, Janssen, and Sanofi: Consultancy; Adaptive, Amgen, Bristol-Myers Squibb-Celgene, Janssen, Kite Pharma, Sanofi and Takeda: Honoraria; Celgene, EngMab, Roche, Sanofi, Takeda: Research Funding. Ludwig: Janssen, Celgene-BMS, Sanofi, Seattle Genetics: Consultancy, Speakers Bureau; Amgen, Takeda: Consultancy, Research Funding, Speakers Bureau. OffLabel Disclosure: Carfilzomib in first-line therapy

Introduction : Despite recent advances, MM remains incurable and new therapeutic options are needed, particularly for pts with RRMM. IBER is a novel, potent oral cereblon E3 ligase modulator (CELMoD ®) compound with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory (IMiD ®) agents. Preclinically, IBER demonstrated marked synergy with DEX and with other standard myeloma treatments. CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating IBER with different treatment combinations in independent cohorts of pts with RRMM; in phase 1, the recommended phase 2 dose of IBER, when given in combination with DEX, was determined at 1.6 mg (Lonial S, et al. Blood 2019;134[suppl 1]:3119). Here we report results from the dose expansion of IBER + DEX in pts with heavily pretreated, triple-class exposed (including ≥ 1 IMiD agent, ≥ 1 proteasome inhibitor [PI], and ≥ 1 anti-CD38 monoclonal antibody [mAb]) RRMM. Methods : Eligible pts had RRMM; had received ≥ 3 prior lines of therapy, including lenalidomide (LEN), pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb; had experienced disease progression within 60 days of last myeloma therapy; and were refractory to an IMiD agent, a PI, a glucocorticoid, and an anti-CD38 mAb. Pts with central nervous system involvement were not eligible. Pts who had received prior anti-BCMA therapy were excluded, but included in a supportive cohort for safety and preliminary efficacy assessment. IBER (1.6 mg) was given orally on days (D) 1-21, in combination with DEX (40 mg; 20 mg if > 75 years of age) on D1, 8, 15, and 22 of each 28-day cycle. Thrombo-embolism prophylaxis was mandatory for all pts. Primary objective was to determine efficacy expressed as overall response rate (ORR). Secondary endpoints included additional efficacy and safety assessments. Exploratory endpoints included evaluation of health-related quality of life (HRQoL). Results : As of June 2, 2021, 107 pts had received IBER + DEX. Median age was 64 (44-83) years; median time since initial diagnosis was 6.9 (1.6-24.5) years. Extramedullary plasmacytomas were present in 25.2% of pts; 29.9% of pts had high-risk cytogenetics. Median number of prior regimens was 6 (3-23). All pts were triple-class exposed; prior therapies included autologous stem cell transplantation (78.5%), PIs (100%), IMiD agents (LEN [100%] and POM [100%]), and anti-CD38 mAbs (100%); 99.1% of pts were refractory to last myeloma regimen and 97.2% of pts were triple-class refractory. Median follow-up was 7.69 (0.5-17.5) months, with a median number of 4 (1-17) cycles received and 13 (12.1%) pts continuing treatment. Main reason for discontinuation was progressive disease (69.2%). ORR was 26.2%, with 1 (0.9%) stringent complete response, 8 (7.5%) very good partial responses, and 19 (17.8%) partial responses (Table); the clinical benefit rate (≥ minimal response) was 36.4% and disease control rate (≥ stable disease) was 79.4%. Median duration of response was 7.0 (4.5-11.3) months (Table), median progression-free survival was 3.0 (2.8-3.7) months, and median overall survival was 11.2 (9.0-not reached) months. Similar response rates were observed among a cohort of pts also exposed to BCMA therapies (N = 24, Table). Grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) were reported in 88 (82.2%) pts. Most frequent (≥ 20% pts) hematologic Gr 3-4 TEAEs were neutropenia (44.9%; and 4.7% febrile neutropenia), anemia (28.0%), thrombocytopenia (21.5%), and leukopenia (20.6%). Gr 3-4 infections were reported in 27.1% of pts; Gr 3-4 pneumonia and COVID-19 occurred in 10.3% and 4.7% of pts, respectively. Occurrence of other Gr 3-4 non-hematologic TEAEs was generally low, including gastrointestinal disorders (5.6%), fatigue (2.8%), rash (1.9%). Fifty-six (52.3%) pts and 20 (18.7%) had IBER dose interruptions and reductions due to TEAEs, respectively. Five (4.7%) pts discontinued due to TEAEs. No pt discontinued IBER due to neutropenia. Overall, HRQoL was maintained in these pts. Conclusions : IBER + DEX demonstrated promising efficacy in pts with heavily pretreated, triple-class exposed and refractory RRMM, as well as in pts who had previously received anti-BCMA therapy; this combination was generally well tolerated and TEAEs were manageable with dose reductions and interruptions. These results support the further development of IBER in MM, including phase 3 trials in combination regimens. Figure 1 Figure 1. Disclosures Lonial: Abbvie: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Popat: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Abbvie, Takeda, Janssen, and Celgene: Consultancy; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Janssen and BMS: Other: travel expenses. Hulin: Sanofi: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; abbvie: Honoraria. Jagannath: Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Takeda: Consultancy. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/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. Richardson: Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy; AbbVie: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Janssen: Consultancy; Secura Bio: Consultancy; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Minnema: Cilag: Consultancy; Janssen: Consultancy; Alnylam: Consultancy; Celgene: Other: Travel expenses; Kite/Gilead: Consultancy; BMS: Consultancy. Badros: J&J: Research Funding; Janssen: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Janssen: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Stadtmauer: Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chen: Bristol Myers Squibb: Current Employment. Nguyen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Amin: Bristol Myers Squibb: Current Employment. Kueenburg: Celgene a BMS company: Current Employment. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. van de Donk: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cellectis: Research Funding; Takeda: Consultancy; Roche: Consultancy; Novartis /bayer/servier: Consultancy.

Background Despite recent advances, new therapies are needed to deepen and extend remissions in early-line relapsed/refractory multiple myeloma (RRMM). Iberdomide (IBER) is a novel, potent oral cereblon E3 ligase modulator (CELMoD®) compound with enhanced tumoricidal and immune-stimulatory effects when compared with IMiD® agents. Preclinically, IBER overcomes IMiD resistance and has synergy with dexamethasone (DEX), daratumumab (DARA), and bortezomib (BORT). In a phase 1/2 trial in patients (pts) with RRMM, IberDd showed efficacy with favorable tolerability, and pharmacodynamic data demonstrated increased NK and T cell proliferation (Lonial S, et al. HemaSphere 2021; 5(S2):49). The EXCALIBER trial was initiated to compare efficacy and safety of IberDd with that of DVd, a globally approved regimen, in pts with early-line RRMM. Methods In this multicenter, open-label, phase 3 study ≈742 pts will be randomized 1:1 to receive IberDd or DVd. Pts will be stratified within each cohort by number of prior lines of therapy (1 vs 2), age (≤70 years vs >70 years), and ISS staging at study entry (I–II vs III). Key eligibility criteria include age (≥18 years), measurable disease treated with 1–2 prior lines of antimyeloma therapy where a partial response or better to ≥1 prior therapy was achieved, and disease progression during or after the last regimen. Prior treatment with anti-CD38 monoclonal antibodies and/or BORT is permitted under stringent conditions. Treatment in the IberDd arm will consist of 28-day (D) cycles (C) with 1.6 mg IBER on D1–21; 1,800 mg subcutaneous (SC) DARA on D1, 8, 15, and 22 of C1–2, D1 and 15 of C3–6, and D1 of ≥C7; and 40 mg oral DEX (20 mg if ≥75 years) on D1, 8, 15, and 22. Treatment in the DVd arm will consist of 21-D cycles for C1–8 and 28-D cycles for ≥C9; 1,800 mg SC DARA on D1, 8, and 15 for C1–3, D1 for C4–8, and D1 for ≥C9; 1.3 mg/m2 SC BORT on D1, 4, 8, and 11 for C1–8; and 20 mg oral DEX (10 mg if ≥75 years) on D1, 2, 4, 5, 8, 9, 11, and 12 for C1–8. Treatment will continue until confirmed progressive disease, unacceptable toxicity, or consent withdrawal. Primary efficacy endpoint is PFS, calculated as the time from randomization to progressive disease, or death. Assuming a decrease in the PFS risk by 25% (HR=0.75) with IberDd, under exponential distribution assumption of PFS (one-sided α=0.025) and adjusted for the 2 interim analyses, 441 PFS events will have 85% power to detect an improvement in treatment effect. Secondary efficacy endpoints include OS, duration of response, time to progression, overall response rate, measurable residual disease, and quality of life. Safety evaluations include treatment-emergent adverse events, laboratory parameters, and vital signs. Two interim analyses are planned for PFS, when ≈134 (30%) and ≈334 (75%) events have been accumulated, to examine futility and superiority, respectively. Enrollment is expected to begin in Q3, 2021. NCT number is pending.

Background CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and preliminary efficacy of IBER, an oral, novel cereblon E3 ligase modulator (CELMoD®) compound, with different treatment combinations in independent cohorts, in pts with MM. Here we report results from the IBER+DARA+DEX (IberDd), IBER+BORT+DEX (IberVd), and IBER+CFZ+DEX (IberKd) cohorts in RRMM. Methods Eligible pts received ≥2 (IberDd and IberKd cohorts) or ≥1 prior regimens (IberVd cohort), containing lenalidomide or pomalidomide, and a proteasome inhibitor. All pts had progressed ≤60 days from last therapy. Escalating oral doses of IBER were given on day (D)1–21 of each 28-D cycle in the IberDd cohort and in the IberKd cohort with weekly CFZ, and on D1–14 of each 21-D cycle in the IberVd cohort. DEX was given weekly in all 3 cohorts. Results As of April 8, 2021, 43 pts had received IberDd, 25 IberVd, and 9 IberKd. Median age was 67, 64, and 61 years, and median time since diagnosis was 7.35, 7.1, and 6.7 years in the IberDd, IberVd, and IberKd cohorts, respectively. Extramedullary plasmacytomas were present in 7 (16%), 4 (16%), and 2 (22%) pts in the IberDd, IberVd, and IberKd cohorts, respectively. Exposure to prior regimens was heterogeneous; all pts were refractory to their last prior regimen and ≥33% pts in the 3 cohorts were triple-class refractory. IBER doses ranged from 1.0 to 1.6 mg. Median follow-up was 4.17, 4.86, and 5.03 months, 22 (51%), 6 (24%), and 5 (56%) pts continue on treatment, and median cycles received were 4, 6, and 5 with IberDd, IberVd, and IberKd, respectively. Hematologic grade (G) 3–4 treatment-emergent adverse events (TEAEs) of interest included neutropenia (67%), leukopenia (23%), anemia (21%), and febrile neutropenia (5%) with IberDd; neutropenia (28%) and thrombocytopenia (24%) with IberVd; and lymphopenia (44%) and neutropenia (33%) with IberKd. Neutropenia was manageable with G-CSF. Occurrence of non-hematologic TEAEs was low, with very few G3–4 fatigue, rash, and gastrointestinal disorders. The overall response rate was 46% with IberDd, 56% with IberVd, and 50% with IberKd, including a VGPR or better of 24%, 28%, and 38%, respectively. Median time to response was 4.1 (4.0–12.0), 3.6 (3.0–13.1), and 4.1 (4.1–8.1) weeks, in the IberDd, IberVd, and IberKd cohorts, respectively. Median duration of response is 35.7 weeks in the IberVd cohort (not reached in the other cohorts). RP2D was determined at 1.6 mg in the IberDd cohort; dose evaluation continues in the other cohorts. Conclusions In pts with heavily pretreated RRMM, IberDd, IberVd, and IberKd showed a tolerable safety profile and promising efficacy. These results support further development of IBER-based regimens in MM, including the initiation of phase 3 combination studies. Previously published in Lonial S, et al. HemaSphere 2021;5(S2):49.

Lenalidomide, adriamycin, dexamethasone for induction followed by stem-cell transplant in newly diagnosed myeloma

Autologous stem cell transplantation (ASCT) is a standard treatment for eligible multiple myeloma (MM) patients, but many patients will relapse after ASCT and require subsequent therapy. The proteasome inhibitor carfilzomib is approved for relapsed or refractory MM (RRMM). In phase 3 trials, carfilzomib-based regimens (ASPIRE, carfilzomib–lenalidomide–dexamethasone; ENDEAVOR, carfilzomib–dexamethasone) demonstrated superior progression-free survival (PFS) compared with standard therapies for RRMM (ASPIRE: lenalidomide–dexamethasone; ENDEAVOR, bortezomib–dexamethasone). This subgroup analysis of ASPIRE and ENDEAVOR evaluated outcomes according to prior ASCT status. In total, 446 patients in ASPIRE and 538 in ENDEAVOR had prior ASCT. Median PFS was longer for carfilzomib-based regimens vs non-carfilzomib-based regimens for patients with prior ASCT (ASPIRE: 26.3 vs 17.8 months (hazard ratio (HR)=0.68); ENDEAVOR: not estimable vs 10.2 months (HR=0.61)), those with one prior line of therapy that included ASCT (ASPIRE: 29.7 vs 17.8 months (HR=0.70); ENDEAVOR: not estimable vs 11.2 months (HR=0.46)), and those without prior ASCT (ASPIRE: 26.4 vs 16.6 months (HR=0.76); ENDEAVOR: 17.7 vs 8.5 months (HR=0.43)). Overall response rates also favored the carfilzomib-based regimens. No new safety signals were detected. This analysis suggests that carfilzomib-based treatment may lead to improvement in PFS and response rates regardless of prior transplant status. Further evaluation is warranted.

Introduction: DARA is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the phase 3 ALCYONE study (median follow-up of 40.1 months), DARA in combination with VMP (D-VMP) reduced the risk of disease progression or death by 58% versus VMP alone (median 36.4 vs 19.3 months; HR, 0.42; 95% CI, 0.34-0.51; P Methods: Pts with TIE NDMM were randomized 1:1 to receive up to nine 6-week cycles of VMP (V 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; M 9 mg/m2 PO on Days 1-4 of Cycles 1-9; and P 60 mg/m2 PO on Days 1-4 of Cycles 1-9) ± DARA (16 mg/kg intravenously once weekly (QW) for Cycle 1 and Q3W for Cycles 2-9). Pts in the D-VMP group received DARA as maintenance therapy Q4W for Cycles 10+ until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included overall response rate (ORR), rate of ≥CR, rate of ≥very good partial response (VGPR), MRD-negativity rate (10-5), OS, and HRQoL. Outcomes were also examined at the time of best response at the beginning of DARA monotherapy (Cycle 10+) and 1 and 2 years after beginning DARA monotherapy. Results: A total of 706 (D-VMP, n=350; VMP, n=356) pts were randomized. Baseline characteristics were well balanced between groups. After a median follow-up of 40.1 months, D-VMP increased the ORR (90.9% vs 73.9%) and the rates of ≥CR (46% vs 25%), ≥VGPR (73% vs 50%), MRD-negativity (28% vs 7%; all P For patients in the D-VMP group who received DARA monotherapy in Cycle 10+, responses continued to deepen: rates of ≥CR improved from 44% at the beginning of maintenance to 64% and 68% at 1 and 2 years, respectively, after the start of DARA maintenance therapy. As in the full study population, improved PFS and OS were observed with deepening responses. Conclusions: D-VMP induced deep responses in TIE NDMM pts and improved PFS, regardless of response status. Depth of response improved PFS, OS, and time to subsequent therapy and responses continued to deepen for patients receiving DARA maintenance therapy. HRQoL was improved in both treatment groups over the course of the study as clinical response deepened. These findings suggest that the addition of DARA to VMP achieves and maintains deep responses for TIE NDMM pts, leading to better outcomes and HRQoL. Disclosures Rodriguez-Otero: Janssen, BMS: Other: Travel, accommodations, expenses; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria; BMS, Janssen, Amgen: Honoraria; Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding. Boccadoro:Mundipharma: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Martinez-Lopez:Novartis: Consultancy; Incyte: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding. Lucio:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Nagy:MorphoSys AG: Patents & Royalties. Liberati:Onconova: Research Funding; Takeda: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria, Research Funding; Morphosys: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Karyopharm: Research Funding; Verastem: Research Funding; Janssen: Honoraria, Research Funding. Takamatsu:Adaptive Biotechnologies: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; Janssen Pharmaceutical: Consultancy, Honoraria, Research Funding; SRL: Consultancy, Research Funding. Romejko-Jarosinska:Janssen: Honoraria; Celgene: Honoraria; Gilead: Honoraria, Other: travel expences ; Servier: Honoraria; Sanofi: Honoraria; Roche: Honoraria, Other: travel expences ; Macopharma: Other: travel expences ; Servier: Other: travel expences . Knop:Celgene; Bristol Myers Squibb; Sanofi; Janssen: Honoraria. Forsyth:Amgen: Consultancy; Janssen Pharmaceuticals Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Kudva:Memorial Sloan Kettering Cancer Center: Other: non-paid consultancy; Janssen: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Wroblewski:Susan Wrobleski: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.

This trial evaluated quality of life (QoL) using the EORTC QLQ-C30 and the EORTC QLQ-MY20 instruments in 90 patients with relapsed/refractory multiple myeloma during induction and maintenance therapy with eight cycles of ixazomib-thalidomide-dexamethasone, followed by 12 months of ixazomib maintenance therapy. When patient's baseline QoL was compared with data of the general population, a significant impairment in health-related QoL, physical, role, and social functioning and several other dimensions, as well as more pain and fatigue, was noted. Induction therapy resulted in significant improvement of pain and worsening of neuropathy, with no significant variation of other parameters. During maintenance treatment, scores for most dimensions including health-related QoL, physical functioning and pain, improved, while for neuropathy no improvement was observed. Time to deterioration (≥10 score points) of health-related QoL, physical functioning, pain, and neuropathy was distinctly shorter than time to progression. Health-related QoL and physical functioning at baseline correlated with overall survival.

Objective A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression-free survival (PFS) post autologous stem cell transplantation (ASCT). Methods Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18-60 or 61-75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35-day cycles of bortezomib consolidation (1.6 mg/m2 IV on days 1, 8, 15, 22) or observation only. Results Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18-60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61-75 years (n = 155), respectively. Bortezomib consolidation post-ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high-dose therapy. Conclusion Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation.

Background Bone marrow neovascularization is a hallmark of multiple myeloma and progression is associated with a substantial increase in pro-angiogenic factors that promote bone marrow angiogenesis, including vascular endothelial growth factor (VEGF-A) and hepatocyte growth factor (HGF). At present, anti-angiogenic agents are not part of treatment strategies in multiple myeloma, neither alone nor in combination with approved agents. MP0250 is a first-in-class, tri-specific multi-DARPin® drug candidate neutralizing VEGF-A and HGF as well as binding to human serum albumin to increase plasma half-life. This is a report on early safety and efficacy of MP0250 in combination with bortezomib plus dexamethasone (Vd) in RRMM patients that have previously been exposed to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs). Aims To assess the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM (MiRRoR, NCT03136653). Trial Design This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Patients will receive treatment until there is documented disease progression or unacceptable toxicity. Methods The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression-free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, and pharmacokinetics. Exploratory biomarkers for HGF and cMET in bone marrow biopsies are detected by IHC; MM specific markers, circulating HGF and VEGF levels are measured using patient plasma samples. Results As of 01 July 2019, 20 patients (7 ongoing) received a total of 137 doses (1-33 cycles) of MP0250 at the maximum tolerated dose of 8 mg/kg on Day 1 of each 21-day cycle in combination with Vd. Median age was 61 years (46-76), median time since diagnosis was 6.7 years. Median number of prior therapies was 4 (range, 2-9). All 20 patients had prior exposure to IMiDs and PIs and 9 patients received PI-based regimens as their immediate prior line of therapy before start of MP0250 + Vd. Importantly, 6 out of these 9 patients achieved responses ≥ Partial Response (PR). Treatment had been discontinued in 40% of patients due to PD, 15% due to Adverse Event (AE), 5% due to physician's decision and in 1 case at patient's request. The most frequent drug-related grade 3/4 AEs were hypertension in 7/1 patients, thrombocytopenia in 4/1 patients, grade 3 proteinuria in 4 patients and grade 3 anemia in 4 patients. There were no infusion-related reactions. No treatment-related deaths were reported. 20 patients received ≥ 1 dose of MP0250 + Vd and had at least 1 assessment of response and were included in the efficacy analysis. 1 patient (5%) achieved Complete Response, 4 patients achieved Very Good Partial Response (20%) and 3 patients achieved PR (15%) for an ORR of 40%. DOR at cutoff date is 6 months (range, 2-21). Pharmacokinetic data show sustained exposure over multiple cycles with a mean half-life of 11 days (range, 6-17). No indication of ADA-mediated drug clearance was observed. Summary Combining MP250 at 8 mg/kg with standard doses of bortezomib and dexamethasone was generally well tolerated with discontinuation due to AE in only 15% of patients. No unexpected toxicity was observed and AEs consistent with the toxicity profile of the individual agents. Analysis of the preliminary efficacy results showed an encouraging ORR of 40%. Recruitment to this Phase 2 study is ongoing. Disclosures Knop: Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; John-Hopkins University: Research Funding; MSD: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; John-Hopkins University: Research Funding; Chugai: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Molecular Partners: Research Funding; Mundipharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dürig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau. Bringhen:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gamberi:Amgen: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Castellano Acosta:Molecular Partners AG: Employment. Lang:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

Although generally not applied as first-line treatment of multiple myeloma, allogeneic hematopoietic cell transplantation (allo-SCT) can still be chosen as ultimate escalation approach in high-risk patients, preferentially within the framework of clinical trials. In this study, we investigated whether decreasing donor chimerism (DC) is predictive for relapse. In addition, we comprehensively determined the impact of several other disease- and treatment-related factors on outcome. One hundred fifty-five multiple myeloma patients whose DC status was followed serially by the short tandem repeat–based techniques at a single lab were included in this retrospective study. Outcome variables were studied in univariate and multivariable analyses. Available were 2.324 DC samples (median, 12 per patient). Loss of full DC was associated with shorter progression-free survival (PFS) (HR, 1.7; 95% CI, 1.1 to 2.6) but did not impact overall survival. Two-thirds of patients with International Myeloma Working Group–defined relapses still displayed a full DC in peripheral blood or bone marrow. Extramedullary manifestations were observed in 33% of patients, accounting for the discrepancy between DC analysis and the actual disease status. In multivariable analysis, the 2 most relevant variables for an unfavorable PFS were progressive disease before allo-SCT (HR, 3.0; 95% CI, 1.5 to 5.9) and allo-SCT at least the second relapse (HR, 2.8; 95% CI, 1.5 to 4.9), whereas for overall survival progressive disease or partial response before allo-SCT had the strongest negative effects (HR, 4.2; 95% CI, 1.9 to 9, and HR, 2.0; 95% CI, 1.0 to 3.8, respectively). Adverse cytogenetics such as del17p, t(4,14) or amp(1q21) were not associated with shorter survival after allo-SCT. Extensive DC sampling beyond robust engraftment does not appear to provide additional information helpful for disease management in most patients and is challenged by a significant incidence of extramedullary disease. In our series, allo-SCT overcame unfavorable cytogenetics.

Based on ELOQUENT-2, combination therapy with the monoclonal antibody elotuzumab was approved for relapsed/refractory multiple myeloma in the US and Europe. However, outside clinical trials, the optimal integration of elotuzumab into the sequence of treatment lines remains to be determined. Therefore, we analyzed safety and efficacy of elotuzumab/immunomodulatory drug combinations in a real-life cohort of 33 patients from our institution. The most frequent grade 3/4 adverse event was lymphopenia which did not increase the incidence of viral reactivations. After a median of four prior treatment lines, an overall response rate of 60% and a median progression-free survival (PFS) of 8 months were observed. The presence of cytogenetic high-risk status had no impact on PFS while low disease burden and high numbers of natural killer (NK)-cells at treatment initiation were associated with longer PFS. We observed an extramedullary relapse in three patients, associated with reduced expression of the elotuzumab target antigen SLAMF7 on extramedullary myeloma cells in one patient. Thus, biomarkers like disease burden, NK-cell count and SLAMF7 expression on myeloma cells may help to define myeloma patients with high likelihood to respond to elotuzumab treatment. Prospective trials investigating these biomarkers in larger patient cohorts are highly warranted.

Background Carfilzomib, the second-generation proteasome inhibitor, is still awaiting approval for the treatment of multiple myeloma in Europe. Results from clinical trials have demonstrated favorable efficacy in advanced disease but have opened an ongoing debate on cardiac complications related to carfilzomib treatment. ‘Real-life’ data are scarce. Methods/Patients At our institution, 22 patients were registered within the European Carfilzomib Access Program for treatment with carfilzomib, dexamethasone, and a third combination partner depending on patient characteristics and prior treatment. Patients had received a median of six previous lines of therapy, and most were refractory to bortezomib (77%) and immunomodulatory drugs (95%). Results Overall response rate was 65% with a median progression-free survival of 6.0 months and a median duration of response of 6.8 months. Median overall survival was 14.9 months. Grade 3/4 adverse events (AEs) occurred in 50% of patients with 23% experiencing left ventricular failure. The risk of cardiac AEs was markedly increased after previous radiotherapy of the thoracic spine and concomitant administration of doxorubicin. Conclusion Carfilzomib-based treatment is efficient in advanced multiple myeloma. In our ‘real-life’ patients, we found considerable cardiotoxic effects in some cases, indicating a need for careful patient selection and close monitoring of the at-risk population.

Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in ≥3 % of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time.

The primary objective of this phase 1 study was to evaluate the safety and tolerability of the anti-glucose regulated protein 78 monoclonal immunoglobulin M antibody PAT-SM6 in subjects with relapsed or refractory multiple myeloma. Twelve heavily pretreated patients received four intravenous infusions of PAT-SM6 at doses of 0.3, 1, 3, and 6 mg/kg within 2 weeks. Efficacy, pharmacokinetics and immunogenicity were followed up until the end of the trial (day 36). In addition, immune cell patterns in peripheral blood were assessed by flow cytometry and glucose regulated protein 78 expression status was evaluated in bone marrow specimens by immunohistochemistry and flow cytometry at screening. All doses administered were found to be safe and well tolerated; the maximum tolerated dose was not reached. The most common treatment emergent adverse event was leukopenia (grades 1 and 2) in eight out of the 12 multiple myeloma patients. Pharmacokinetic analysis demonstrated dose-proportional increases in drug serum concentration. The terminal half-life ranged from 5.86 to 8.41 h, the apparent volume of distribution ranged from 101 to 150 mL/kg, and clearance ranged from 8.11 to 16.1 mL/h/kg. All patients showed glucose regulated protein 78 surface expression on multiple myeloma cells. Four out of the 12 patients (33.3 %) had stable disease, according to the International Myeloma Working Group criteria, after PAT-SM6 treatment across the doses 1, 3 and 6 mg/kg. In summary, single-agent PAT-SM6 was well tolerated with modest clinical activity in relapsed or refractory multiple myeloma. Further trials exploring the combination of PAT-SM6 with existing myeloma therapies are planned. Trial registration: clinicaltrials.gov identifier: NCT01727778

Summary We assessed the safety and efficacy of bortezomib, cyclophosphamide and dexamethasone (VCD) induction therapy in previously untreated multiple myeloma patients. A total of 414 patients received three 21-day cycles of VCD prior to autologous stem-cell transplantation (ASCT). Most common grade ≥3 adverse events were leucopenia (31·4%) and thrombocytopenia (6·8%). The overall response rate (ORR) by investigator-based assessment was 85·4%. Most patients (74%) underwent successful central laboratory-based molecular cytogenetic analysis. No clinically relevant differences in ORR post-induction were seen between patients with or without high-risk cytogenetic abnormalities (86·2% vs. 84·3%). Further follow-up data are available for 113 patients receiving ASCT who were included in a prospective consolidation trial (median follow-up, 55·5 months); median progression-free survival (PFS) was 35·3 months and median overall survival (OS) was not reached. In patients with high-risk versus standard-risk cytogenetics, median PFS was 19·9 vs. 43·6 months (P

Response-adapted consolidation with bortezomib after ASCT improves progression-free survival in newly diagnosed multiple myeloma

We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM.

Background We describe a patient with a high-titer warm immunoglobulin (Ig)A autoantibody resulting in death due to hemagglutination rather than to hemolysis. Case Report A 47-year-old male patient presented with an intriguing pronounced vascular erythema of the skin. A livedo reticularis associated with cold agglutinin of high thermal amplitude was suspected. The patient's condition unexpectedly and abruptly deteriorated resulting in death 3 days after admission. Study Design and Methods Conventional serologic procedures and immunochemical methods were used. Results Serologic and immunochemical examinations revealed a warm IgA autoantibody of high titer with anti-Band 3 specificity. Although the patient presented with severe anemia, only mild signs of hemolysis were observed, with no evidence of complement activation. The autopsy revealed an enormous accumulation of agglutinated red blood cells in liver and spleen and a B-cell lymphoma and cerebral edema. Thus, the patient's death was largely caused by hypoxia related to hemagglutination rather than to hemolysis and/or anemia per se. Conclusion Strongly hemagglutinating antibodies may not only cause immune hemolysis but also hypoxia due to intravascular hemagglutination.

Die Therapieergebnisse fur Patienten mit multiplem Myelom konnten in den letzten 20 Jahren schrittweise verbessert werden. Darstellung des aktuellen Entwicklungsstands der Therapiekonzepte fur jungere Patienten mit multiplem Myelom. Auswahl, Nennung, Bewertung und Diskussion der praxisrelevanten grosen klinischen Studien in der Primartherapie des multiplen Myeloms. Vergleichende Betrachtung der verschiedenen Transplantationsformen. Bei jungeren Patienten mit multiplem Myelom wird eine Hochdosistherapie mit autologer Blutstammzelltransplantation breit national und international eingesetzt. Eine Tandemtransplantation kann den Effekt einer ersten Hochdosistherapie verbessern und konsoldieren – mit vorteilhaftem progressionsfreiem Uberleben und Gesamtuberleben. Durch den Einsatz neuer Substanzen wie Bortezomib und Lenalidomid in der Induktionstherapie (vor Hochdosistherapie) sowie Konsolidierungs- und Erhaltungstherapie (nach Hochdosistherapie) konnen die Remissionsraten, das progressionsfreie Uberleben und teilweise auch das Gesamtuberleben der Patienten verbessert werden. Die allogene Transplantation stellt eine Option fur Patienten in gutem Allgemeinzustand und zytogenetischen oder klinischen Hochrisikomerkmalen dar und sollte moglichst im Rahmen von klinischen Studien erfolgen. Zytogenetische Veranderungen wie Translokation t(4;14) oder 17p-Deletion sind mit einer schlechteren Prognose assoziiert, konnen allerdings in ihrer negative Bedeutung durch die neuen Therapieansatze teilweise uberwunden werden. Die Hochdosistherapie mit autologer Blutstammzelltransplantation bewahrt sich weiterhin als Standardtherapie jungerer Patienten mit multiplem Myelom. Die Gesamtergebnisse der Therapie konnen durch den zusatzlichen und kombinierten Einsatz neuer Substanzen nachweislich verbessert werden. Die Auswirkungen auf das Gesamtuberleben konnen allerdings noch nicht abschliesend beurteilt werden. Die zunehmende Verfugbarkeit von weiteren neuartigen Medikamenten lasst auf weitere Therapieverbesserungen und moglicherweise Heilungschancen hoffen.

Extramedullary disease (EMD) in multiple myeloma (MM) is characterised by an aggressive biology and an adverse prognosis especially when occurring at relapse. Due to the high proliferation found in EMD lesions, we analysed outcome data of patients treated with a lymphoma-type therapy not based on novel compounds, the Dexa-BEAM protocol. Retrospective analysis of MM patients having received Dexa-BEAM (including dexamethasone, carmustine, cytarabine, etoposide and melphalan) at our institution from January 2007 to November 2012. In all, 18 patients were identified, 11 of whom had EMD. Objective response (≥PR) to Dexa-BEAM was achieved in more than half of the patients with EMD (6/11); consecutive high-dose consolidation strategy with autologous or allogeneic stem cell transplantation improved upon the depth of remission in two thirds of EMD patients (4/6) with ongoing remissions in three patients. In contrast, all patients without consolidation relapsed. Progression-free survival after Dexa-BEAM was short in both patient groups with intramedullary or extramedullary myeloma with a median of 3 and 4 months, respectively. Toxicity was relevant with one treatment-related death and grades 3 and 4 toxicities in all 18 patients. Dexa-BEAM is an effective induction regimen in medically fit patients with extramedullary manifestations to regain disease control prior to an intended autologous or allogeneic transplantation.

Introduction The kidney is an important target organ in plasma cell dyscrasias, subjected to various mechanisms of injury such as tubular obstruction, hypercalcemia, and pre-existing disease. Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) is of concern as treatment-related toxicity (for instance infections and mucositis) is known to increase with renal impairment (RI). However, even severe MM-induced RI may recover with anti-myeloma treatment. We set out to compare three induction regimens in patients (pts) with transplant-eligible NDMM in terms of renal recovery and toxicity, MM response and associated adverse events (AEs). Pts from two prospective trials (NCT00833560, NCT01685814) were analyzed, provided post-induction (PInd) restaging data was available. They received three 3-week induction cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD); btz, lenalidomide (len), and dex (VRD); or three 4-week cycles with len, adriamycin, and dex (RAD). All pts had to have measurable disease, an estimated glomerular filtration rate (eGFR) of >30 ml/min and to be up to 60 (VCD) and 65 years (yrs) of age, respectively. VCD consisted of intravenous (IV) btz 1.3 mg/m² on day (D) 1, 4, 8, 11; IV cyclophosphamide 900 mg/m2D1; dex 20 mg D 1+2, 4+5, 8+9, 11+12. VRD of subcutaneous (SQ) btz 1.3 mg/m² D 1, 4, 8, 11; len 25 mg, D1-14; dex 20 mg D 1+2, 4+5, 8+9, 11+12; and RAD of len 25 mg D1-21; IV adriamycin 9 mg/m² D1-4; dex 40 mg D 1-4 + 17-20. MethodsThis is a secondary analysis of a phase 2 and a phase 3 study. We hypothesized MM disease response (and in turn, renal recovery) would be best with VRD. GFR was estimated by the MDRD IV or CKD-Epi formulas. The increase (and decrease, respectively) of renal function expressed by "GFRpost induction- GFRscreening" was tested for significance (p 50 ml/min and ≤ 70 ml/min (group II) were observed in 11.6 % of VCD pts, 29.9% of VRD and 25.2 % of RAD pts, respectively. 78.2% of VCD pts, 56.1% of VRD and 63.9% of RAD pts had a baseline eGFR of > 70 ml/min (group III; pPR (p=.0387). In the whole cohort, proportion of patients in eGFR group I had decreased from 10.0 to 3.0% (p +2 ml/min(/1.73m²)/month, respectively. 25.7% of VCD, 29.4% of VRD and 23.3% of RAD pts fell into the +2 ml/min was achieved by 55.2% of VCD vs 42.1% of VRD treated pts, respectively (Figure 1; p +2 ml/min(/1.73m²)/month. It is tempting to speculate that either the difference between SQ and IV btz, differential effects of len and cyclophosphamide on kidney function or non-MM related factors account for these unexpected and discordant renal and MM responses. Kidney-specific AEs, urine protein studies and comorbidities will be presented. Disclosures Mügge: Celgene: Research Funding; Celgene, Janssen: Honoraria. Schreder:Janssen, Celgene: Consultancy, Honoraria. Schaefer-Eckart:Pfizer, Janssen, Celgene: Honoraria. Metzler:Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Hertenstein:RS Media: Research Funding. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Salwender:Janssen Cilag: Consultancy, Honoraria, Other: Travel grants; Celgene: Honoraria, Other: Travel grants; AMGEN: Honoraria, Other: Travel grants; Sanofi: Honoraria, Other: Travel grants; Bristol-Myers Squibb: Honoraria, Other: Travel grants; Takeda: Honoraria, Other: Travel grants; Oncopeptides: Honoraria, Other: Travel Grants. von Lilienfeld-Toal:Celgene, Oncopeptides: Consultancy, Honoraria. Straka:Celgene, Janssen, AMGEN: Consultancy, Research Funding, Speakers Bureau. Knop:Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. OffLabel Disclosure: Lenalidomide, adriamycin, dexamethsone in newly diagnosed multiple myeloma

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. The addition of DARA to standard-of-care regimens in phase 3 studies reduced the risk of disease progression or death by ≥44%, nearly doubled the rate of complete response or better, and induced a ≥3-fold increase in minimal residual disease (MRD)-negativity rates versus standard of care alone in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma. In the primary analysis of the phase 3 ALCYONE study (median follow-up: 16.5 months), a significant progression-free survival (PFS) benefit (median not reached vs 18.1 months; hazard ratio [HR], 0.50; P 36 months of follow-up from ALCYONE, including analysis of overall survival (OS) from a prespecified interim analysis. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age (≥65 years) or comorbidities were randomized 1:1 to receive up to nine 6-week cycles of VMP (bortezomib 1.3 mg/m2 subcutaneously on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; melphalan 9 mg/m2 orally and prednisone 60 mg/m2 orally on Days 1-4 of Cycles 1-9) with or without DARA (16 mg/kg intravenously once weekly for Cycle 1, once every 3 weeks for Cycles 2-9, and once every 4 weeks for Cycles 10+ until disease progression). The primary endpoint was PFS. Secondary endpoints included overall response rate, rate of complete response or better, rate of very good partial response or better, MRD-negativity rate (10-5 threshold), PFS on subsequent line of therapy (PFS2), OS, and safety. Results: A total of 706 patients were enrolled in this study (D-VMP: n = 350; VMP: n = 356). Patient baseline characteristics were well balanced between treatment arms. The median (range) age was 71 (40-93) years, and 29.9% of patients were ≥75 years of age. 518 (84.1%) and 98 (15.9%) of 616 patients evaluated had standard and high (del17p, t[14;16], and/or t[4;14] positive) cytogenetic risk, respectively, as assessed via local fluorescence in-situ hybridization/karyotyping. Median PFS was 36.4 months with D-VMP versus 19.3 months with VMP after a median follow-up of 40.08 months (HR, 0.42; 95% confidence interval [CI], 0.34-0.51; P Conclusions: For the first time, we demonstrate that the addition of DARA to VMP prolongs OS in patients with transplant-ineligible NDMM, with a 40% reduction in the risk of death versus VMP alone after a median follow-up of 40 months. D-VMP continued to demonstrate a significant PFS benefit, which was also maintained during the subsequent line of therapy. These findings, together with the phase 3 MAIA study (DARA plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone), continue to support the addition of DARA to frontline treatment regimens in patients with transplant-ineligible NDMM. Disclosures Mateos: Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria. Cavo:Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria; Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene: Speakers Bureau. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Sanofi Oncology: Research Funding. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: 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; Juno: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Knop:Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Lucio:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Nagy:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cook:Celgene, Jannsen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squibb, GlycoMimetics, Seattle Genetics and Sanofi: Honoraria. Liberati:Janssen: Honoraria; Bristol & Mayer: Honoraria; Celgene: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Campbell:Janssen: Honoraria, Research Funding, Speakers Bureau. Garg:Novartis, Janssen: Research Funding; Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria. Krevvata:Janssen: Employment. Wang:Janssen: Employment. Kudva:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Wroblewski:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.

Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 - < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 - < 60 mL/min (P

Autologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of preceeding induction chemotherapy cycles has been unclear. A total of 434 patients 60 to 70 years of age were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction cycles. For all patients, double autologous transplantation after melphalan 140 mg/m2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without it. On the intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval [CI] 0.84 to 1.28; P=0.36). Per protocol the progression-free survival was 23.7 months versus 23.0 months (p=0.28). For patients with age ≥ 65 years (55%) the outcome was not inferior. Patients with low-risk cytogenetics (absence of del17p13, t(4;14) and 1q21 gains) showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on the hazard ratio, the short treatment trunk consisting of mobilization chemotherapy and tandem MEL140 with autologous transplantation achieved 96% of the progression-free survival, demonstrating value as an independent component of myeloma therapy in older patients with multiple myeloma regarded fit for autologous transplantation (NCT 02288741).

Presented at the 50th Annual American Society of Clinical Oncology Meeting (2014), the 56th American Society of Hematology Annual Meeting (2014), the 20th Congress of the European Hematology Association (2015), the 15th International Myeloma Workshop (2015), and the 57th American Society of Hematology Annual Meeting (2015)., Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated., This study was funded by Celgene Corporation.

Extramedullary (e) relapse in multiple myeloma (MM) has an adverse prognosis, but knowledge concerning biological features and preferred treatment is scarce. We screened the myeloma registry of our institution for eMM relapses and identified 24 cases among 357 patients (pts). Only 8% of eMM relapses occurred after initial therapy, but 54% occurred after third-line or subsequent therapy. Baseline molecular cytogenetics revealed high-risk features in 10 of 19 evaluable patients. Most frequently, eMM presented as soft tissue (67%) and organ involvement (25%) or malignant effusion (12.5%). Incidence of leptomeningeal/CNS involvement was 21%. At eMM relapse, bone marrow infiltration was absent in 46% and low in 21%. Ten eMM biopsies were available showing increased proliferation, i.e., Ki-67 of 67% (range, 30–90%) of all cancer cells. Pts received radiation therapy, dose-intense chemotherapy, novel agents, and allogeneic SCT resulting in an overall response rate of 54%. Median progression-free survival was 2 (95% CI 0.08–3.92) and median overall survival 7 months (95% CI 3.56–10.43), respectively, with only three patients being alive at 12 months from diagnosis. EMM relapse may present at any anatomical site with frequent CNS involvement. Biological features include increased proliferation and low rate of marrow involvement. Prognosis remains poor despite intensive treatment.

Background MP0250 is a first-in-class selective tri-specific multi-DARPin® drug candidate neutralizing VEGF-Α and HGF as well as binding to human serum albumin to increase its plasma half-life. Preclinical studies have shown that MP0250 enhances sensitivity of Multiple Myeloma (MM) cells to bortezomib, inhibits tumor growth and reduces bone destruction. In this clinical phase 2 trial (NCT03136653), we are investigating the safety, tolerability and efficacy of the combination of MP0250 plus bortezomib and dexamethasone (dex) in patients (pts) with relapsed/refractory (RR) MM previously exposed to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Aims To study the efficacy and safety of MP0250 in combination with bortezomib and dexamethasone in patients with RRMM. Trial Design This trial is recruiting adults ≥18 years of age with RRMM who have progressed after at least two prior treatment regimens including bortezomib and an IMiD. A dose-escalation phase (part 1) consisting of two cohorts will define a safe dose of the combination of MP0250 plus bortezomib + dex followed by a dose-expansion phase (part 2). Patients were enrolled to receive iv MP0250 on day 1 + subcutaneous bortezomib 1.3 mg/m² on days 1, 4, 8, 11, oral dexamethasone (dex) 20 mg on days 1-2, 4-5, 8-9, 11-12 of each 21-day cycle. Up to 40 patients will be enrolled. Patients will receive treatment until there is documented disease progression or unacceptable toxicity. Methods The primary endpoint is efficacy in terms of overall response rate (ORR) per International Myeloma Working Group criteria. Secondary endpoints include safety, immunogenicity, progression free survival (PFS) and duration of response (DOR). Exploratory endpoints include overall survival, pharmacokinetics and potential biomarkers that include MM specific markers and cytokines monitoring bone homeostasis. The safety analysis set (SAF) is defined as patients who have received at least 1 dose of the combination of MP0250 plus bortezomib + dex. Results Data cut off was 21 July 2018. 8 pts have been treated in cohort 1 and 3 pts in cohort 2. Median time from initial diagnosis to first dose was 4.8 years (range, 1-10). Median number of prior therapies was 3 (range, 2-5). All 11 pts had prior exposure to IMiDs and PIs and 4 pts were considered PI refractory. Four patients received PI immediately prior to receive MP250 in combination. The most frequent drug-related grade ≥ 3 AEs: hypertension in 3 pts, thrombocytopenia in 6 pts, proteinuria in 2 pts and transient liver enzyme elevation in 1 patient. One dose-limiting toxicity has been reported in cohort 1 (grade 3 hypertension) and two in cohort 2 (grade 3 epistaxis, grade 3 proteinuria). There were no infusion-related reactions. Best response achieved in the 8 efficacy evaluable pts in cohort 1 was VGPR in 1 and PR in 4 for an overall response rate (ORR, ≥PR) of 62.5%. In cohort 2, 1 patient achieved Minimal Response (MR), 1 patient stable disease and 1 progressive disease. Three of four patients who were coming immediately from a PI based regimen achieved a response. Pharmacokinetics data in cohort 1 show sustained exposure over multiple cycles with a mean half-life of 11 days, and no indication of ADA mediated drug clearance was observed. Data from cohort 1 patients show accumulation of MP0250-HGF complexes over multiple cycles confirming the stable binding of MP0250 to HGF suggesting that all circulating HGF is neutralized. Summary Data from cohort 1 (8 mg/Kg q3w) suggest that MP0250 can be safely combined with bortezomib and dex in patients with relapsed and refractory MM. Durable responses were seen in patients who came from PI based pretreatment suggesting that MP0250 might be capable to reverse PI resistance. Disclosures Knop: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Goldschmidt:Sanofi: Consultancy, Research Funding; ArtTempi: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding. Raab:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dürig:Janssen: Consultancy, Honoraria; Celgene: Honoraria; Roche: Honoraria, Speakers Bureau. Castellano Acosta:Molecular Partners AG: Employment. Lemaillet:Molecular Partners AG: Employment. Cortijo:Molecular Partners AG: Employment. Sudhir:Molecular Partners AG: Employment.

Introduction Based on improvement of overall survival (OS), lenalidomide (R) maintenance after up-front autologous stem cell transplantation has recently been approved for multiple myeloma (MM) patients (pts). Conversely, in transplant non-eligible (TNE) pts R maintenance after R-based induction improved progression free survival (PFS) but had no impact on OS. First-line treatment with VMP is considered a standard of care for newly diagnosed (ND) TNE pts, but whether maintenance therapy with R after VMP induction can further improve PFS and OS is currently unknown. Aims The prospective phase IIb GERMAIN trial (EudraCT-No: 2012-003023-38) aimed to evaluate the role of R maintenance after VMP induction in ND TNE MM pts. The trial, which planned to include 286 ND TNE MM pts, closed early in December 2017 due to insufficient accrual and high discontinuation rate. The present analysis focuses on the reasons for the high drop out rate. Methods After induction with 6 courses of VMP (Mateos et al., Lancet Oncology 2010), pts achieving at least a partial response (PR) were randomized 1:1 to R 10 mg or placebo (PCB) daily until progression (PD) or unacceptable toxicity. Pts with Results From May 2014 to December 2017 85 pts were enrolled. Median age was 75 years (range 63-87). A significant proportion of pts presented with at least one concomitant illness: 75% were hypertensive, 29% had a cardiac disorder, 37% a metabolic disorder and 19% a chronic kidney disease. Induction was completed by 53 pts and 40 pts entered maintenance randomization (Figure 1). Of patients completing induction therapy 77% achieved at least a PR, including 11% of sCR/CR and 26% of VGPR. Overall 70% of pts discontinued the study; main reasons for trial discontinuation were PD (24%), unacceptable toxicity (17%), investigator decision (16%) and withdrawal of informed consent (12%). Of pts discontinuing treatment, 27 pts (47%) stopped during induction, and in 71% of these cases discontinuation was due to unacceptable toxicities (26%) or investigator (26%) and patients (19%) decision. Only one pt discontinued due to insufficient response during induction. In total 745 adverse events (AE) and 71 serious AEs (SAE) were reported; of these 814 had complete data and were analyzed. During induction 571 AE occurred, of which 110 (19%) were of grade ≥3. Seventy-one pts (86%) reported at least one AE, and 49 (59%) at least one grade ≥3 AE. The most common grade ≥3 AE were: leukopenia (25%), thrombocytopenia (20%), cardiac toxicity (10%), infections (8%), peripheral neuropathy (6%), anemia and gastrointestinal toxicity (5% each). The cumulative probability of development of a grade ≥3 AE at 6 months was 59% (95% CI: 47 to 69%). SAEs during VMP were 54; 39% of pts experienced at least one SAE during induction. The cumulative probability for an SAE at 6 months was 41% (95% CI: 30 to 51%). During induction 4 deaths were recorded, all within the first month of treatment. Of the pts randomized to maintenance treatment 37 received at least one dose of R/PCB and were considered evaluable. Twenty-one pts (36%) discontinued the study during maintenance. Main reason for discontinuation was PD (11 pts, 4 in R and 9 in PCB arm); only 2 pts (both in R arm) discontinued due to AE 2 and 21 months after start of maintenance, respectively. Of the AE recorded during maintenance (n=157, 92 in the R and 65 in the PCB group) 17% were grade ≥3 and 12 were considered SAE. At least one AE and at least one SAE were reported in 29 (78%) and 8 pts (22%), respectively. Four secondary malignancies (1 basal cell carcinoma, 1 AML, 1 bladder cancer and 1 lung cancer) were reported, 1 during VMP induction and 3 during maintenance. Conclusions In comparison to other studies focusing on ND TNE MM pts, our study investigated a remarkably elderly and frail population. In the cohort investigated, treatment with VMP resulted in increased toxicity and higher rate of discontinuation. Nevertheless, in those pts able to complete induction a promising ORR was observed. In elderly and frail MM pts, regimens other than VMP should be considered for induction. Disclosures Brioli: Celgene: Honoraria, Other: Travel support, Research Funding; Janssen: Honoraria. Hänel:Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Pfirrmann:Novartis: Research Funding. von Lilienfeld-Toal:Janssen: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Fabisch:Novartis: Research Funding. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria.

Introduction High-dose chemotherapy and stem cell transplant (SCT) remains a standard of care in medically fit patients (pts) with newly diagnosed (ND) MM. Induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks among the most effective regimens and VRD/SCT was superior to VRD alone in an RCT. In a phase 2 study, we demonstrated RAD induction (lenalidomide 25 mg d1-21; Adriamycin 9 mg/m2 iv d1-4; dexamethasone 40 mg d 1-4 and 17-20 every 4 weeks) followed by SCT to be safe and effective (Knop et al., Leukemia 2017). Therefore, we decided to compare RAD versus (vs) VRD (lenalidomide 25 mg, d1-14; subcutaneous bortezomib 1.3 mg/m2 d 1, 4, 8, 11; dexamethasone 20 mg d 1+2, 4+5, 8+9, 11+12 every 3 weeks) induction (3 cycles each) in an RCT. MethodsThe current study was set up according to a double 2x2-factorial design to enrol transplant-eligible pts up to 65 years. The post-induction (PI) complete response (CR) rate as per IMWG criteria was the efficacy co-primary endpoint. We hypothesized the CR rate following RAD to be non-inferior to VRD which was estimated to be 20%. The study was powered to confirm non-inferiority of RAD at a margin of 10% with a one-sided alpha level of .05. Cytogenetic characterization was performed by fluorescence in situ hybridization (FISH) from CD138-enriched plasma cells. Minimal residual disease (MRD) was assessed by second-generation eight-color flow cytometry (FC; EuroFlow protocol). Bone marrow (BM) samples from baseline and defined restaging time points were analyzed for an acquisition of ⩾107cells/sample. In a subgroup of 103 pts, we evaluated the applicability of comprehensive immunoglobulin (Ig) amplicon next generation sequencing (NGS) to detect molecular MRD markers and to compare the results with FC. NGS-based marker screening was performed in baseline BM. Sequencing libraries were prepared using 2-step PCR employing multiplex primer sets for IGH V-D-J (FR1, FR2 and FR3), IGH D-J and IGK loci (V-J and KDe). For MRD detection, we used 1-step library preparation with the same primer sets. Results476 pts with a median age of 55 (range, 32-65) years were randomized between 05/2012 and 06/2016 and 469 received at least one dose of study drug. High-risk (HR) FISH abnormalities comprised del17p (11.3% of pts); t(4;14) (11.7%); and t(14;16) (4.5%). 232 pts were randomized to receive RAD, and 237 to VRD, respectively. 90.5% of RAD vs 93.7% of VRD pts completed all 3 cycles. PI CR rate was 13.5% (95% CI, 9.4%-18.7%) with RAD vs 13.4% (95% CI, 9.3-18.5) with VRD, (P=.971). Rates of ≥VGPR were 40.6% (50% CI, 34.2%-47.3%) with RAD vs 48.9% (95% CI, 42.3-55.6%) with VRD (P=.076). In pts with HR cytogenetics, rates of ≥VGPR were 43.3% (RAD) vs. 59.3% (VRD; P=.096). From 317 pts with paired samples, 33/151 (21.9%) of RAD vs 45/166 (27.1%) of VRD pts were FC MRD negative (P=.169) following induction at a median sensitivity level of 6.73x10-6. 197/239 positive pts (82.4%%) had MRD levels above 0.01%, and 42 (17.6%), between 0.0001 and 0.01%. Flow MRD negativity as per IMWG MRD criteria (Kumar et al, Lancet Oncol 2016) was seen in 8/151 (5.2%) pts with RAD vs 6/166 (3.6%) with VRD (P=.27). The remainder of pts did not (yet) fulfil IMWG CR for various reasons. NGS marker screening identified at least 1 Ig marker in 98/103 evaluable patients. To date, 47/98 pts were analyzed for NGS MRD following induction. Four out of 47 (8.5%) subjects were sequencing negative (3/4 post-VRD) with all of them also being IMWG FC MRD negative. One VRD patient died during induction for a mortality rate of 0.2 %. 62.1% of RAD vs 55.3% of VRD pts experienced at least one serious adverse event (SAE; p=.16). SAEs with relationship to study drugs of at least °3 severity occurred in 26.3% (RAD) vs 23.6% (VRD) pts (p=.523). ConclusionsTo the best of our knowledge, this is the first RCT to compare two R-based triplets in SCT-eligible pts. The co-primary efficacy endpoint was met with identical PI CR rates of around 13% for RAD and VRD, respectively. However, a trend emerges to favor VRD over RAD in terms of at least VGPR including HR FISH subjects. Analysis of MRD by multicolor FC showed 5% of pts to be already IMWG flow MRD-negative. Results for all 98 pts evaluable for NGS MRD will be presented. As of yet, too few progression events have occurred to estimate the second co-primary endpoint, 3-year progression-free survival. Longitudinal response and MRD analysis are ongoing. Disclosures Langer: Celgene: Consultancy. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. Blau:Amgen: Other: Advisory board; BMS: Other: Advisory board; Novartis: Other: Advisory boards; Takeda: Other: Advisory board; Janssen: Other: Advisory board, Research Funding; Celgene: Other: Advisory board, Research Funding. Rollig:Janssen: Research Funding; Bayer: Research Funding. Dechow:AMGEN: Consultancy; Celgene: Honoraria. Gramatzki:Affimed: Research Funding. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Schmidt:Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Introduction Ixazomib is an effective PI that combines the advantage of oral administration with a favorable toxicity profile. Recent results showed significant activity, both in newly diagnosed, and in pretreated patients (pts). Ixazomib in combination with lenalidomide-dexamethasone (IRd) was significantly superior over Rd in pts with relapsed/refractory multiple myeloma (RRMM), and was able to overcome the negative impact of poor risk cytogenetics. Ixazomib-thalidomide-dexamethasone (IxaThalDex) has been shown to be effective in pts with newly diagnosed MM and is used in this trial in pts with RRMM. Here, we evaluate the impact of cytogenetic risk factors on outcome in pts with RRMM treated with IxaThalDex. Patients and Methods Ninety pts with RRMM and one or more prior lines of therapy (TX) were enrolled. Treatment regimen: Ixazomib (4mg, d 1, 8 and 15), thalidomide (100mg/d), and dexamethasone (40mg once/week). Pts aged ≥75 years received lower doses of thalidomide (50mg/d) and of dexamethasone (20mg). Pts were scheduled for 8 cycles followed by ixazomib maintenance therapy (4mg, days 1, 8, 15 of a 28 cycle and 3mg in pts aged ≥75 years) for one year. Preplanned FISH analysis was performed on CD138 selected bone marrow plasma cells. The cut-off level for positivity was 10% for t(4;14), and 20% for del(17p) and 1q21 gain, respectively. The previously defined primary endpoint was progression-free survival (PFS), and secondary objectives were overall response rate, overall survival (OS), and impact of cytogenetic risk and of renal impairment, safety and myeloma frailty status. PFS and OS was estimated according to Kaplan-Meier and differences evaluated by log-rank test. Response rates were compared using Fisher's Exact Test. Findings Seventy-six of the 90 pts of the intent to treat group (ITT) received at least two cycles and comprise the per protocol population (PP). Complete FISH data are available in 61 pts. Pt characteristics of the ITT group: Age, median 67 (44 -84) years, ISS stage I: 37, II 30, III: 22, not known: 1, median number of prior TX lines: 1 (range: 1-8). Forty-three pts have completed all 8 cycles of induction therapy (median number of cycles: 6). Forty-one pts started Ixazomib maintenance therapy and 6 completed the planned 12 cycles as yet. Median follow-up is 15.3 months. PR or better was achieved in 46 pts (60.5%), CR in 8 (10.5%), VGPR in 13 (17.1%), PR in 25 (32.9%), and MR in 6 (7.9%) pts, yielding a clinical benefit rate of 68.4%. Thirteen (21.3%) pts of the 61 pts with FISH data available presented with t(4;14), 5 (8.1%) with del(17p), and 32 (52.5%) with 1q21 gain. Response rates (≥PR) did not differ significantly (p values not shown) between pts with high-risk (HR) [t(4;14) and/or del(17p)], and standard-risk (SR) cytogenetic risk profile: 64.7% vs. 53.2%, nor in those with and without 1q21 gain: 46.9% vs. 69.2%, or those with HR cytogenetics and/or 1q21 gain 48.7% vs. 68.2, and were comparable to those of the entire PP patient group (60.5%). Median PFS at the time of reporting is 8.8 mos. in the ITT and 10.2 mos. in the PP group. PFS did not differ in pts with HR and SR cytogenetics (10.3 vs. 9.3 months, p=0.703). In contrast, a tendency for shorter PFS was noted in pts with 1q21 gain (6.9 vs. 11.6 months, p=0.067). Similar findings were observed in pts with HR and/or 1q21 gain vs. those without these features (7.0 vs. 10.8 months; p=0.117). Median OS has not been reached, neither in the ITT nor in the PP group. OS did not differ between pts with HR and SR cytogenetics (p=0.961), similarly, Pts with 1q21 gain had significantly shorter OS (median: 19.6 vs. not reached, p=0.001); a similar reduction in OS was noted when pts with HR cytogenetics and/or 1q21 gain were compared to those without these features (median: 19.6 months vs. not reached, p=0.003) Discussion and Conclusion The all oral IxaThalDex regimen overcame the negative impact of HR cytogenetics [t(4;14) and del(17p)] both in terms of PFS and OS. Similarly, there was no difference in the depth of response between the groups. However, in those with 1q21 gain alone, or with a HR feature and/or 1q21 gain, a tendency of shorter PFS was noted. OS was significantly shorter in the latter groups. These findings suggest that 1q21 gain should be included in the HR category in pts exposed to ixazomib plus thalidomide-dexamethasone. Figure 1: PFS and OS in pts with and without HR cytogenetics (1A and 1B) and in those with and without HR cytogenetics and/or 1q21 gain (1C and 1D). Disclosures Ludwig: BMS: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Cilag-Janssen: Speakers Bureau. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Gunsilius:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Petzer:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria. Greil:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Merck: Honoraria, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees.