ALBERT

Description: Introduction : Daratumumab (DARA) is a human, CD38-targeted, IgGκ monoclonal antibody. In the CASTOR study, D-Vd reduced the risk of disease progression or death by 68% and induced higher rates of deeper responses vs Vd in relapsed/refractory (RR) MM pts (Spencer, A. ASH 2017. Abs. 3145). Overall, in phase 3 studies in RRMM and newly diagnosed MM, DARA-based regimens reduced disease progression or death risk by ≥50%, doubled complete response (CR) rates, and tripled minimal residual disease (MRD)-negative rates. While progression-free survival (PFS) benefits of D-Vd vs Vd were observed regardless of the number of prior lines (PLs) of therapy, the benefit was most pronounced in pts receiving 1 PL of therapy. Here, we examine updated (2 y after interim analysis) efficacy and safety of D-Vd vs Vd in CASTOR, with a primary focus on pts with 1 PL of therapy. Method: Pts in CASTOR were randomized to receive 8 cycles (21 d/cycle) of V (1.3 mg/m2, SC) on Days 1, 4, 8, and 11 and dexamethasone (20 mg, PO or IV) on Days 1, 2, 4, 5, 8, 9, 11, and 12 with or without DARA (16 mg/kg, IV) given weekly for Cycles 1-3, Q3W for Cycles 4-8, and Q4W thereafter. Cytogenetic risk was evaluated centrally by next generation sequencing; high risk was defined as having t(4;14), t(14;16), and/or del17p abnormalities. MRD was assessed at the time of suspected CR and at 6 and 12 mo following the first treatment dose, and an additional MRD evaluation was required every 12 mo post-CR. MRD was evaluated using clonoSEQ® V2.0 (Adaptive Biotechnologies, Seattle, WA). Sustained MRD negativity was defined as maintenance of MRD negativity at 10-5 for ≥6 or ≥12 mo. Results: At the clinical cutoff date of January 11, 2018, 498 pts were included in the intent-to-treat (ITT) population (D-Vd, n = 251; Vd, n = 247). Pts received a median of 2 (1-10) PLs of therapy including 235 pts that received 1 PL (D-Vd, n = 122; Vd, n = 113). In the ITT population, 61% received prior ASCT, 66% V, 42% lenalidomide (R), and 32% were refractory to their last PL of therapy. Among 1 PL pts, 60% received prior ASCT, 51% V, 20% R, and 18% were refractory to their last PL of therapy. After a median follow-up of 31.3 mo, PFS was significantly prolonged with D-Vd compared with Vd in the ITT population (median: 16.7 vs 7.1 mo; HR, 0.32; 95% CI, 0.25-0.40, P

Description: Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study. Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019. Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline. Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa. Disclosures Weisel: Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hopkins:GSK: Employment, Equity Ownership. Fecteau:GSK: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Quigley:GSK: Employment, Equity Ownership. Jewell:GSK: Employment, Equity Ownership. Nichols:GSK: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

Description: Abstract 475FN2 Background: An IMiDs® immunomodulatory agent, Len has a dual mechanism of action: its tumoricidal effect directly leads to tumor cell death, and its immunomodulatory effect may keep the tumor in remission. A phase 3, randomized, placebo (Pbo)-controlled trial, MM-015 compares MPR-R with fixed-duration MPR and MP induction in transplant-ineligible NDMM pts. Interim results showed unprecedented reduction in disease progression risk with MPR-R (Palumbo et al, IMW 2011); this analysis focuses on pts aged 65–75 yrs in whom the greatest benefit was observed. Methods: A total of 459 pts aged ≥ 65 yrs with NDMM were enrolled. Induction consisted of nine 28-day cycles of melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), and Len 10 mg (D1-21) (MPR-R and MPR) or melphalan and prednisone with Pbo (MP). After induction, MPR-R pts received Len 10 mg (D1-21) maintenance until progression; MPR and MP pts received Pbo. Pts with progressive disease (PD) could enroll in an open-label extension phase to receive Len 25 mg (D1-21) ± dexamethasone 40 mg (D1-4, 9–12, and 17–20). This analysis includes data up to Feb 28, 2011 (median follow-up, 30 mos). Results: There were 116/152 (76%), 116/153 (76%), and 116/154 (75%) of MPR-R, MPR, and MP pts, respectively, aged 65–75 yrs. Nearly 50% had ISS stage III disease, 〉 40% had β2-microglobulin 〉 5.5 mg/L, and 40% had CrCL 〈 60 mL/min. With a median follow-up of 30 mos, MPR-R reduced progression risk by 70% and significantly prolonged median PFS (31 mos) vs MP (12 mos; hazard ratio [HR]: 0.30 [95% CI, 0.20–0.45]; P

Description: In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P 〈 .0001) and OS (P 〈 .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as ISRCTN64455289.

Description: Background: Survival of patients (pts) with multiple myeloma (MM) decreases with increased age (Pulte, Oncologist, 2011). In addition, MM pts with advanced disease who have exhausted treatment (Tx) with novel agents have a poor prognosis (Kumar, Leukemia, 2012). Pomalidomide (POM) is a new oral agent with antimyeloma, stromal cell inhibitory, and immune modulatory effects (Quach, Leukemia, 2010; Mark, Leuk Res, 2014). In the pivotal MM-003 trial, POM in combination with low-dose dexamethasone (LoDEX) demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits vs. high-dose dexamethasone, with a tolerable safety profile in refractory or relapsed and refractory MM (RRMM; Dimopoulos, Blood, 2013). In MM-003, significant PFS and OS benefits with POM + LoDEX Tx were seen in different age groups; tolerability and dose intensity were not affected by age (Weisel, Blood, 2013). STRATUS is a multicenter, single-arm, open-label, European, phase 3b trial to further evaluate safety and efficacy of POM + LoDEX in a large pt population. This analysis examines outcomes by age (≤ 65 vs. 〉 65 yrs, and ≤ 70 vs. 〉 70 yrs). Methods: Eligible pts had refractory or relapsed and refractory disease (progressive disease [PD] during or within 60 days of last line of Tx), having previous BORT and LEN failure and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to the last prior Tx line. Pts with Eastern Cooperative Oncology Group performance status 〉 2 were excluded. Pts received 28-day cycles of POM 4 mg D1-21 + DEX 40 mg (20 mg for pts aged 〉 75 yrs) once weekly. All pts received thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent based on clinical recommendations. Tx continued until PD or unacceptable toxicity. The primary endpoint was safety; the secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, and OS. Outcomes were analyzed by pt age at baseline (≤ 65 vs. 〉 65 yrs, and ≤ 70 vs. 〉 70 yrs). Results: As of March 17th, 2014, a total of 456 pts have been enrolled, and 452 had received POM + LoDEX; 48% were aged ≤ 65 yrs, 52% were 〉 65 yrs, 71% were ≤ 70 yrs, and 29% were 〉 70 yrs. Pts were heavily pretreated (median 4-5 prior Tx depending on age subgroup). Median follow-up was 6.8 mos. Younger pts (≤ 65 yrs) were more likely to have better renal function (creatinine clearance ≥ 60 mL/min; 80%) than those aged 〉 65 (49%). Median relative dose intensity was similar independent of age (range, 0.95-0.97 mg/day). The most common grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) across age groups were neutropenia, anemia, thrombocytopenia, and pneumonia (Table). Gr 3-4 deep vein thrombosis (DVT) with prophylaxis was 1% in each subgroup. Discontinuations of POM due to TEAEs were low in pts aged ≤ 65 (0.9%), 〉 65 (3.0%), ≤ 70 (1.3%), and 〉 70 (3.8%) yrs. Outcomes by age are summarized in the Table. ORR was consistent for pts aged ≤ 65 (38%), 〉 65 (32%), ≤ 70 (35%), and 〉 70 (34%) yrs; DORs were 5.1, 6.8, and 5.8 mos and not estimable (NE) in these pt populations, respectively. Median PFS and median OS were similar across all age groups (PFS range, 4.0-4.9 mos, OS range, 10.6-11.5 mos). Conclusions: The data reported here further demonstrate the tolerability and efficacy of POM + LoDEX in pts with RRMM in the age subgroups analyzed (≤ 65 vs. 〉 65 yrs and ≤ 70 vs. 〉 70 yrs). Safety profiles were consistent, while dose intensity was similar across age groups. PFS, OS, and response rates were comparable with those previously reported in trials of POM + LoDEX in pts with RRMM and reinforce 4 mg POM as an appropriate starting dose irrespective of age. These data support POM + LoDEX as a standard Tx option for pts with refractory or RRMM regardless of age. Table 1. Age ≤ 65 yrs (n = 215) Age 〉 65 yrs (n = 237) Age ≤ 70 yrs (n = 319) Age 〉 70 yrs (n = 133) Grade 3-4 TEAEs, % Neutropenia Anemia Thrombocytopenia Pneumonia 38 30 22 13 41 24 16 10 38 29 21 11 44 23 15 11 Grade 3-4 EOI, % DVT/PE PN 1

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

Description: Introduction: Novel therapies for relapsed/refractory multiple myeloma (RRMM) have demonstrated durable responses that prolong survival, thus assessing health-related quality of life (HRQoL) is becoming increasingly important in patient (pt) care. Long-term RRMM treatment may lead to a higher cumulative symptom burden and negatively affect HRQoL. Indeed, the effect of treatment on HRQoL is reduced in pts with RRMM on later vs initial lines of therapy (LoTs) (Nielsen et al, Eur J Hematol 2017). Consequently, there is a need for treatments that demonstrate durable efficacy while preserving HRQoL. Pomalidomide plus dexamethasone (Pd) has been shown to be an effective treatment for RRMM that does not negatively affect HRQoL in later LoTs (Song et al, Haematologica 2015). In the randomized phase 2 ELOQUENT-3 study (NCT02654132), addition of the SLAMF7-targeted monoclonal antibody elotuzumab (elo) to Pd (EPd) showed a 46% reduction in the risk of progression/death vs Pd, and acceptable safety in pts with refractory or relapsed and refractory MM for whom therapy with lenalidomide and a proteasome inhibitor had failed (Dimopoulos et al, EHA 2018 [LB2606]). We present pt-reported outcome (PRO) data to assess the impact of EPd on HRQoL in pts from ELOQUENT-3. Methods: The M.D. Anderson Symptom Inventory MM module (MDASI-MM) and the 3-level version of the EuroQoL 5 Dimensions Questionnaire (EQ-5D-3L), which included the global health visual analog scale (VAS) measure, were administered at baseline (BL) and at the start of every 28-day treatment cycle until discontinuation and at survival follow-up. All randomized pts with BL and ≥1 post-BL assessment were included in the PRO analysis. Changes from BL scores were evaluated descriptively: high scores indicate better health for EQ-5D-3L, but more severe symptoms for MDASI-MM. Time to first deterioration was evaluated, with a deterioration event defined as the absolute value of the change from BL ≥ the responder definition threshold (MDASI-MM symptom item assessing pain, fatigue, and bone aches: 2; EQ-5D-3L VAS: 7). Results: This analysis included 117 randomized pts (EPd, n=60; Pd, n=57) who had received a median of 3 prior LoTs. PRO completion rates at BL were 79% for MDASI-MM (EPd, 85%; Pd, 72%) and 84% for EQ-5D-3L (EPd, 88%; Pd, 79%). Although completion rates between treatment groups were similar throughout the study, analysis of QoL was not feasible after Cycles 13 for EPd and 10 for Pd as the number of pts with questionnaires dropped below 20%. Mean BL QoL scores were similar for EPd vs Pd (EQ-5D-3L utility, 0.676 vs 0.682; EQ-5D-3L VAS global health status, 61.9 vs 62.9). A clinically meaningful deterioration from BL in EQ-5D-3L VAS health status (mean change -9.0) was observed with Pd at Cycle 2. In contrast, there were no clinically relevant deteriorations in EQ-5D-3L VAS health status with EPd, and a sustained improvement from BL was observed between Cycles 9 and 12 (mean change 8.2, 11.7, 9.7, and 10.4, respectively; Figure). MDASI-MM symptom scores for pain and bone aches showed no clinically relevant change from BL levels in both groups, but fatigue worsened (mean change 2.5) in the Pd group at Cycle 9. Pts who discontinued treatment early tended to have lower HRQoL in both treatment arms. There were no differences in time to first deterioration for EPd vs Pd for MDASI-MM symptoms pain, fatigue, or bone aches, or EQ-5D-3L and VAS domains. Although the risk of deterioration in the severity of MDASI-MM core symptoms (symptoms common across cancer types and treatments) was reduced by 17% (hazard ratio 0.83; 95% CI 0.49-1.42) for those receiving EPd vs Pd, this was not statistically significant (p=0.618); the median time to deterioration was 3.8 mo with EPd and 1.2 mo with Pd. Conclusions: In ELOQUENT-3, pt-reported health status was maintained in pts who remained on EPd per EQ-5D-3L VAS, with no worsening of pain, fatigue, or bone aches per MDASI-MM. There were minimal differences in QoL between pts who received EPd and Pd, suggesting that the addition of elo to Pd does not impair HRQoL, although HRQoL may have been overestimated due to the small sample and treatment discontinuation. These pt-reported findings complement strong clinical data that demonstrated clinically relevant improvements in efficacy and a favorable safety profile for EPd, further supporting the use of this regimen in RRMM. Study support: BMS. Writing support: Simon Wigfield, Caudex, funded by BMS. Figure. Figure. Disclosures Weisel: Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding. Paner:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Taylor:Adelphi Values: Employment; Bristol-Myers Squibb: Consultancy. Cocks:Adelphi Values: Employment; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Endomag Ltd.: Consultancy. Espensen:Adelphi Values: Employment; Bristol-Myers Squibb: Consultancy, Other: I am an employee of Adelphi Values, a consulting firm that has received payment from BMS for statistical data analysis in BMS trials. Popa-McKiver:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Cavo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: 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, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Continuous treatment with lenalidomide (len) is a new standard of care in frontline multiple myeloma (MM) (Facon. Blood. 2018;131:301-310; Pulte. Oncologist. 2018;23:734-739). The increased adoption of continuous len treatment and len maintenance highlights the need for active regimens for the treatment of MM that has relapsed or become refractory to len. Once-weekly carfilzomib (K) at 70 mg/m2 (Berenson. Blood. 2016;127:3360-3368; Moreau. Lancet Oncol. 2018;19:953-964) and twice-weekly K at 56 mg/m2 (Dimopoulos. Lancet Oncol. 2016;17:27-38) in combination with low-dose dexamethasone (d) have shown a favorable benefit-risk profile for the treatment of relapsed and/or refractory MM. This post-hoc analysis will assess the efficacy and safety of Kd in len exposed and refractory MM. Methods: Individual patient data from the phase 1/2 CHAMPION-1 (CH-1), phase 3 ENDEAVOR, and phase 3 ARROW studies were pooled to evaluate progression-free survival (PFS), overall response rate (ORR), and safety for those with previous exposure or refractoriness to len treatment. The once-weekly Kd dosing schedule in CH-1 (Berenson. Blood. 2016;127:3360-3368) and ARROW (Moreau. Lancet Oncol. 2018;19:953-964) and the twice-weekly Kd dosing schedule in ENDEAVOR (Dimopoulos. Lancet Oncol. 2016;17:27-38) have been previously described. Patients who received once-weekly Kd at 70 mg/m2 in CH-1 and ARROW, and patients who received twice-weekly Kd at 56 mg/m2 from ENDEAVOR were included in the analysis. Patients were assigned to a group according to prior lines of therapy and previous len exposure: (1) combined CH-1 and ENDEAVOR patient population (N=39) that had received 1 prior line of therapy and was previously exposed but not refractory to len (Kd, 1 prior len exposed); (2) combined CH-1 and ENDEAVOR patient population (N=32) that had received 1 prior line of therapy and was refractory to len in the last line of therapy (Kd, 1 prior len refractory); (3) combined CH-1, ENDEAVOR, and ARROW patient population (N=65) that had received 2 to 3 prior lines of therapy and was exposed but not refractory to len (Kd, 〉1 prior len exposed); (4) combined CH-1, ENDEAVOR, and ARROW patient population (N=304) that had received 2 to 3 prior lines of therapy and was refractory to len in any line of previous therapy (Kd, 〉1 prior len refractory). Results: PFS, ORR, and safety outcomes in the pooled len exposed and refractory patient populations are shown (Table 1). Len-exposed patients treated with Kd in first relapse had a median PFS of 18.3 months (95% confidence interval [CI] 14.1-21.0); PFS rate at 18 months was 54.0%. When len-refractory patients were treated with Kd in first relapse, median PFS was 15.6 months (95% CI 9.6-not estimable [NE]) and the PFS rate at 18 months was 43.1%. For len-exposed patients treated in second or third relapse, the median PFS for Kd was not reached (95% CI 10.3-NE) and PFS rate at 18 months was 57.1%. For len-refractory patients treated with Kd in second or third relapse, median PFS was 8.8 months (95% CI 7.5-11.2) and the PFS rate at 18 months was 27.8%. ORR was approximately 90% (Kd, 1 prior len exposed), 81% (Kd, 1 prior len refractory group), 77% (Kd, 〉1 prior len exposed), and 61% (Kd, 〉1 prior len refractory). Median K treatment duration (range) was 56.0 (4.0-213.0) months (Kd, 1 prior len exposed), 36.6 (1.0-201.1) months (Kd, 1 prior len refractory), 36.1 (1.1-210.7) months (Kd, 〉1 prior len exposed), and 34.0 (0.1-198.0) months (Kd, 〉1 prior len refractory). The incidence of treatment-emergent grade ≥3 adverse events (AEs) was 84.6% for patients in the Kd, 1 prior len-exposed group, 81.3% for patients in the Kd, 1 prior len-refractory group, 76.9% for patients in the Kd, 〉1 prior len-exposed group, and 74.8% for patients in the Kd, 〉1 prior len-refractory group. The rate of serious AEs in each of the pooled patient groups in this analysis is presented (Table 1). Conclusion: The Kd doublet is effective and safe in MM patients relapsing on or after treatment with len, and for patients who are refractory to len. Although data are limited by small sample size, the median PFS of 15.6 months for Kd in len-refractory patients treated in first relapse is similar in magnitude to the median PFS reported for novel triplet therapy in this population. Disclosures Mateos: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdeja:Genentech: Research Funding; Bluebird: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Teva: Research Funding; Sanofi: Research Funding; Poseida Therapeutics, Inc.: Research Funding. Dimopoulos:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Siegel:Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Ho:Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Other: travel to meeting; Celgene: Other: travel to meeting. Huang:Amgen: Employment, Equity Ownership. Sersch:Amgen: Employment. Zahlten-Kumeli:Amgen: Employment, Equity Ownership. Kimball:Amgen: Employment, Equity Ownership; WindMIL Therapeutics: Equity Ownership. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, Janssen, and Sanofi: Research Funding.

Description: Introduction In multiple myeloma, initially, there are increased numbers of osteoclasts showing increased activity, but bone formation by osteoblasts is keeping step. In later stages, parts of the bone remodeling compartments are disrupted by the interaction with myeloma cells leading to increased bone resorption which can no longer be compensated (myeloma bone disease, uncoupling of bone formation and bone resorption). Lenalidomide and bortezomib have been shown to target both, myeloma cells and the microenvironment: lenalidomide inhibits osteoclastogenesis, bortezomib is also able to stimulate osteoblast differentiation leading to increased bone formation. Aim of this study is to evaluate the impact of bortezomib-based induction treatment, high-dose therapy, and lenalidomide consolidation on alterations of bone turnover, i.e. surrogates of osteoblast- (osteocalcin, OC) and osteoclast- (collagen type I fragments, CTX-I) function, and their induction by myeloma cells (DKK1-level). Methods Serum was collected during routine sampling within the GMMG-MM5 trial (EudraCT 2010-019173-16), and levels of CTX-I, OC, and DKK1 were assessed by ELISA in triplicates using commercially available assays according to the manufacturer’s instructions (RnD Systems and Immunodiagnostic Systems). The following time points were assessed: at inclusion (n=365), after induction therapy with either PAd (n=88) or VCD (n=84), stem cell mobilization using CAD (n=69), high-dose melphalan (n=92), and 2 months lenalidomide consolidation (n=92). Up to now, serum samples of 69 patients were measured sequentially at five time points in line with the GMMG-MM5 trial. DKK1 levels were correlated with the expression in CD138-purified myeloma cells (Affymetrix microarrays, n=365). Results Prior to treatment, CTX-I levels are increased, those of OC decreased compared to healthy donors (uncoupled bone turnover). DKK1 protein levels are increased and correlate with DKK1-expression in myeloma cells. After induction therapy, osteoclast activity (CTX-I) is decreased below normal values. PAd unlike VCD further decreases osteoblast activity (OC-levels); DKK1-levels are normalized. Subsequent treatment further decreases DKK1-levels below normal values and blocks osteoclast function. After 2 months lenalidomide consolidation, no normalization of osteoblast activity is found. Conclusion The main impact on bone turnover by bortezomib-based induction treatment is a reduction of osteoclast activity alongside a decrease in DKK1-levels. During the reported period, no normalization of decreased osteoblast function was observed. Disclosures: Seckinger: Novartis Pharma: Research Funding. Goldschmidt:Novartis Pharma: Research Funding. Hose:Novartis Pharma: Research Funding.

Description: Abstract 305 Chromosomal aberrations are important prognostic parameters in multiple myeloma (MM). By using interphase fluorescent in situ hybridization (FISH) on CD138-enriched plasma cells, specific changes in interphase cells can be detected, overcoming the lack of dividing cells required for conventional cytogenetics. We evaluated the association of FISH results and outcome of a subgroup of patients (pts) within the HOVON-65/GMMG-HD4 trial, a prospective, randomized phase III trial for pts with newly diagnosed MM stage II or III according to Salmon & Durie up to 65 years. Pts were randomized to receive three cycles of VAD (arm A; vincristine, adriamycin, dexamethasone) or PAD (arm B; bortezomib, adriamycin, dexamethasone). Hematopoietic stem cells were mobilized using the CAD regimen and G-CSF. All pts received one or two cycles of high dose melphalan (200 mg/m2) with autologous stem cell transplantation followed by maintenance therapy with thalidomide 50 mg daily (arm A) or bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively, for a maximum of 2 years. Sites in Germany, the Netherlands and Belgium participated in this trial (n=833 pts). For the German pts (GMMG, n=399) FISH was performed in a single laboratory prior to start of treatment. Cytospins of CD138 purified plasma cells were subjected to FISH with two-color probe sets for the detection of numerical changes for the following chromosome regions: 1q21/8p21, 6q21/15q22, 9q34/22q11, 11q23/13q14, and 17p13/19q13, as well as for the translocations t(4;14)(p16;q32), t(11;14)(q13;q32), and t(14;16) (q32;q23). As of July 2010 data from the first consecutively enrolled 626 patients of the trial have been analyzed, including 284 GMMG pts. For this analysis, FISH results from 258 (91%) GMMG pts were available (n=131 in arm A; n=127 in arm B). Patient characteristics in the GMMG subgroup are comparable to the analyzed trial population of 626 pts. For all pts the median follow-up time from randomization was 40.3 months (mo.). The most pronounced impact on prognosis was seen for t(4;14), del17p13, and gain1q21, each significantly associated with poor prognosis with respect to progression free survival (PFS) and overall survival (OS). The strongest prognostic impact was found for del17p13. FISH analysis detected del17p13 in 9.4% of pts (A: 12.3% vs. B: 6.4%), t(4;14) in 14.8 % (16.3% vs. 13.4%), and gain 1q21 in 33.7% of pts (33.1% vs. 34.4%). When comparing pts in the two arms for PFS, we found a borderline significance for the interaction between t(4;14) and treatment arm (p=0.06), indicating that the effect of t(4;14) depends on the treatment. Pts with t(4;14) in arm A show a very poor prognosis with a median PFS time only half as long compared to patients without translocation (18 vs. 36 mo.; p=0.003). No such negative effect was observed for patients in arm B with t(4;14) (36 vs. 40 mo.; p=0.97). PAD resulted in improved 3yr-OS rates for pts with t(4;14) (A:39% vs B:76%), while 3yr-OS was 79% and 87% in pts without t(4;14). Median PFS for pts with gain 1q21 was 22 mo. (arm A) vs. 30 mo. (arm B) compared to 41 mo. in both arms for patients without gain 1q21. Pts with gain 1q21 showed a significantly better OS when treated with bortezomib (3yr-OS rates: A: 59%, B: 83%, p=0.016). Del17p13 was significantly associated with poor prognosis in both arms for OS (A: p