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Summary Background Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab. Methods In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66–85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1–2), every 2 weeks (cycles 3–6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (Ctrough; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov , NCT03277105 . Findings Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5–9·3), overall response and Ctrough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89–1·37). The geometric means ratio for Ctrough was 107·93% (90% CI 95·74–121·67), and the maximum Ctrough was 593 μg/mL (SD 306) in the subcutaneous group and 522 μg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]). Interpretation Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies. Funding Janssen Research & Development.

In 2005 we reported the first case of transthyretin His88Arg (p. His108Arg) amyloidosis, a mutation characterised by cardiomyopathy. Six additional gene carriers of whom five have clinical symptoms of disease have now been identified in Sweden, and we have been able to identify a possible founder and to characterise the Swedish phenotype of the transthyretin (TTR) His88Arg mutation. Genealogical studies of church records were used to identify the individuals with the disease and their families. Routine clinical investigations of neurological and heart manifestation of the disease were utilised. We found that genealogically all seven individuals were related and originated from the same region in Sweden. Amyloid deposits were demonstrated in biopsies and the TTR His88Arg mutation was identified in all patients. Patients had a late onset disease (≥ 50 years of age) and all exhibited a severe amyloid cardiomyopathy. A pronounced peripheral axonal neuropathy was with certainty demonstrated in one patient only, who also was operated for a magnetic resonance confirmed spinal stenosis, however, without any effect on his neurological symptoms. Five of the patients had carpal tunnel syndrome. The first reported case is now deceased from cardiac failure. One patient has had a sequential heart and liver transplantation. One gene carrier had no symptoms or findings of disease on latest evaluation at the age of 44.the Swedish TTRHis88Arg patients all have a common Swedish founder. Cardiomyopathy with heart failure, as well as carpal tunnel syndrome and spinal stenosis were early signs of disease; but peripheral neuropathy was present in one patient before symptoms of cardiomyopathy so the phenotypical presentation of this mutation is variable.

INTRODUCTION: Daratumumab (DARA), a human IgGκ monoclonal antibody targeting CD38, is approved for intravenous (IV; 16 mg/kg) administration as a single agent or in combination with standard-of-care regimens for treatment of multiple myeloma (MM).To improve safety and reduce patient and healthcare provider burden, a subcutaneous (SC) formulation of DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.) was developed. The phase 3, randomized, open-label, non-inferiority COLUMBA study (NCT03277105) evaluated the efficacy, PK, and safety of DARA SC vs DARA IV in patients (pts) with RRMM. The results, showing the study met both co-primary endpoints (overall response rate [ORR] and Ctrough) at a median follow-up of 7.5 months, were previously presented. Here, we present updated data with longer follow-up. METHODS: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV infusion) were given in 28-day cycles: QW Cycles 1-2, Q2W Cycles 3-6, and Q4W thereafter. DARA SC (15 mL) was given by manual push over 3-5 mins at alternating left/right abdominal sites. Eligible pts (≥18 yrs) with RRMM had ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were overall response rate (ORR; analyzed by Farrington-Manning test, with non-inferiority defined as 60% retention of ORR) and maximum DARA Ctrough (pre-dose concentration on Cycle 3 Day 1; non-inferiority defined as the lower bound of 90% confidence interval [CI] for the ratio of the geometric means [GM] ≥80%). Secondary endpoints included rates of infusion-related reactions (IRRs), progression-free survival (PFS), very good partial response or better (≥VGPR), and complete response or better (≥CR). RESULTS: A total of 522 pts were randomized to receive DARA SC (n = 263) or DARA IV (n = 259). Median age was 67 yrs (20% ≥75 yrs). Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% of pts were previously treated with both PI(s) and IMiD(s). 82.2% of pts were refractory to the last line of prior therapy, and 49.4% were refractory to both PI and IMiDs. 26.3% and 17.3% of pts had a high-risk cytogenetic abnormality at baseline in the DARA SC and DARA IV groups, respectively. After a median follow-up of 13.8 months, ORR was improved from 41.1% to 43.7% for DARA SC and 37.1% to 39.4% for DARA IV (Figure). ORR were comparable across all subgroups, including body weight. Rates of deep responses (≥VGPR, ≥CR) were similar between DARA SC and DARA IV, and deeper with longer follow-up (Figure). Median duration of treatment (~5.5 months) was similar for DARA SC and DARA IV. A significantly lower rate of IRRs was observed with DARA SC vs DARA IV. At the time of data cutoff, 118 pts (evenly distributed across both arms) continued treatment on study. CONCLUSIONS: With longer follow-up, safety and efficacy data continue to support that DARA SC and DARA IV have similar safety profiles with a statistically significant reduction in IRR rates. DARA SC has a reduced treatment burden due to a considerably shorter administration duration, and DARA SC pts reported higher treatment satisfaction. Collectively, the data demonstrate a favorable benefit/risk profile for the use of an 1800 mg flat dose of DARA SC. Disclosures Usmani: Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Mateos:Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee; Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees. Vorobyev:Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy. Spicka:Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hungria:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, 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, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Moreau:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kaiser:Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Celgene, Janssen: Research Funding; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Iida:Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Research Funding; Sanofi: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Teijin Pharma: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Astellas: Research Funding. Masterson:Janssen: Employment, Equity Ownership. Lantz:Janssen: Employment, Equity Ownership. O'Rourke:Janssen: Employment, Equity Ownership. Heuck:Janssen: Employment. Qin:Janssen: Employment, Equity Ownership. Parasrampuria:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Bahlis:Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.

Introduction: DARA, a human CD38 monoclonal antibody (mAb), is approved for intravenous (IV; 16 mg/kg) administration as a single agent or in combination with standard-of-care regimens for treatment of multiple myeloma. To reduce patient and provider burden and improve safety, a subcutaneous (SC) co-formulation of DARA (flat dose of 1,800 mg, ~70% bioavailability) with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) was developed. The phase 3, randomized, open-label COLUMBA study (NCT03277105) demonstrated the non-inferiority of DARA SC vs DARA IV in terms of co-primary endpoints (ORR and Ctrough) in pts with RRMM at a median of 7.5 months follow-up. Here, we present a body weight subgroup analysis of COLUMBA, based on data from the primary analysis. Methods: DARA SC (flat dose of 1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg) were given in 28-day cycles: QW Cycles 1-2, Q2W Cycles 3-6, and Q4W thereafter. DARA SC (15 mL) was given by manual push over 3-5 mins at alternating left/right abdominal sites. Eligible pts (≥18 yrs) with RRMM had ≥3 prior lines of therapy, including a PI and an IMiD, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum DARA Ctrough (pre-dose concentration on Cycle 3 Day 1 [C3D1]). A subgroup analysis was performed by body weight (≤65 kg, >65 to 85 kg, and >85 kg). Results: In the intent-to-treat (ITT) population, 522 pts were randomized to receive DARA SC (n = 263) or DARA IV (n = 259). Median baseline body weight was 73 kg. Flat dose DARA SC achieved adequate exposure for all body weight subgroups, as maximum Ctrough (C3D1 predose) exceeded the 236 μg/mL threshold previously established in DARA IV studies as necessary for 99% target saturation (Xu XS, et al. Clin Pharmacol Ther, 2017). Across each subgroup, there was considerable overlap in maximum Ctrough for both treatment groups (Figure); however, mean DARA concentrations were 60% higher for pts ≤65 kg and 12% lower for pts >85 kg treated with DARA SC vs IV. Nevertheless, the range of Ctrough across body weights for DARA SC was within the previously observed range (36 to 1764 µg/mL for C3D1 Ctrough) for the approved DARA IV 16 mg/kg. ORR in the ITT population was 41.1% vs 37.1% for DARA SC vs DARA IV. In the body weight subgroups, ORR was 43.6% vs 38.0%, 37.3% vs 39.0%, and 43.9% vs 32.8% for DARA SC vs IV in the ≤65 kg, >65 to 85 kg, and >85 kg groups, respectively. These data suggest that the slightly lower exposure observed at higher body weights was not clinically relevant. For both treatment groups, the incidence of grade 3/4 TEAEs, grade 5 TEAEs, serious TEAEs, and IRRs was similar across body weight subgroups. An increased incidence of TEAEs of any grade with decreasing body weight for DARA SC (≤65 kg, 94.6%; >65 to 85 kg, 87.3%; >85 kg, 78.5%) was observed; incidence of any grade TEAEs was similar across body weight subgroups for DARA IV (≤65 kg, 89.1%; >65 to 85 kg, 89.5%; >85 kg, 88.5%). At the preferred term level, an decreased incidence of grade 3/4 thrombocytopenia (≤65 kg, 16.1%; >65 to 85 kg, 14.7%; >85 kg, 9.2%) and grade 3/4 neutropenia (≤65 kg, 20.4%; >65 to 85 kg, 9.8%; >85 kg, 7.7%) with increasing body weight was observed for DARA SC. An increased incidence of grade 3/4 hypertension (≤65 kg, 4.3%; >65 to 85 kg, 5.7%; >85 kg, 9.8%) with increasing body weight was observed for DARA IV. However, the incidence of maximum Grade 3 and 4 TEAEs (DARA SC, 43.0%; DARA IV, 44.6%) and the incidence of Grade 5 TEAEs (6.5% for both) were similar between treatment groups in the lowest body weight subgroup. For subjects ≤65 kg, DARA SC had a lower incidence of serious TEAEs (DARA SC, 23.7%; DARA IV, 30.4%). Conclusions: In the primary analysis, efficacy and PK co-primary endpoints were met, demonstrating non-inferiority of DARA SC to DARA IV, with similar safety profiles and significant reduction in IRR rates with DARA SC. In this subgroup analysis, ORR in all body weight subgroups was consistent with ORR in the overall population. DARA SC achieved adequate exposure and was well tolerated across all body weight subgroups. The higher concentration of DARA SC in pts ≤65 kg did not have a clinically relevant effect on safety, suggesting no dose individualization is necessary on the basis of weight. Disclosures Mateos: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Usmani:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, SkylineDX, Takeda: Other: Consultant/Advisor; Amgen, Celgene, Janssen, Sanofi, Takeda: Speakers Bureau; Amgen Array Biopharma, Bristol-Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Sanofi, Takeda: Other: Research Grant. Vorobyev:Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sanofi: Consultancy. Spicka:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Hungria:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Bladé:Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees; Irctures: Honoraria. Moreau:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kaiser:Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses. Iida:Abbvie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Gilead: Research Funding; Astellas: Research Funding; Teijin Pharma: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MSD: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Masterson:Janssen: Employment, Equity Ownership. Lantz:Janssen: Employment, Equity Ownership. O'Rourke:Janssen: Employment, Equity Ownership. Qin:Janssen: Employment, Equity Ownership. Parasrampuria:Janssen: Employment, Equity Ownership. Heuck:Janssen: Employment. Qi:Janssen: Employment. OffLabel Disclosure: This presentation/paper includes information/discussion of a subcutaneous formulation of daratumumab, which is currently under investigation in several clinical trials, but has not yet been approved. The intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of MM.

The outcome for multiple myeloma patients has improved since the introduction of bortezomib, thalidomide and lenalidomide. However, studies comparing new and conventional treatment include selected patient groups. We investigated consecutive patients (n = 1638) diagnosed in a defined period and compared survival with a gender- and age-matched cohort Swedish population (n = 9 340 682). Median overall survival for non-high-dose treated patients was 2·8 years. The use of bortezomib, thalidomide or lenalidomide in first line therapy predicted a significantly longer overall survival (median 4·9 years) compared to conventional treatment (2·3 years). Among non-high-dose treated patients receiving at least 2 lines with bortezomib, thalidomide or lenalidomide, 69% and 63% have survived at 3 and 5 years as compared to 48% and 22% with conventional drugs and 88% and 79% in the matched cohort populations, respectively. The median overall survival in high-dose treated patients was 6·9 years. Of these patients, 84% survived at 3 years and 70% at 5 years as compared to 98% and 95% in the matched cohort population. Overall survival in the best non-high-dose treated outcome group is closing the gap with the matched cohort. Upfront use of new drugs is clearly better than waiting until later lines of treatment.

Biologic and clinical observations suggest that combining imatinib with IFN-α may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-α2b (Peg–IFN-α2b) 50 μg weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg–IFN-α2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg–IFN-α2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg–IFN-α2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg–IFN-α2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg–IFN-α2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.

Abstract 2970 Evaluating real life outcomes in Multiple Myeloma (MM) pts in order to understand treatment outcome in clinical practice is very important. The introduction of novel agents (Bortezomib, Thalidomide, Lenalidomide) has been shown to increase overall survival (OS). Can MM be regarded as a chronic disease, defined as a similar OS as a matched normal population at diagnosis, after the introduction of novel agents? All pts diagnosed with MM since earliest Jan 2000 until latest Jun 2011 from 6 university clinics, 3 regional centers and 4 local hospitals in Sweden were included. Near complete response (nCR) was defined as an immeasurable M-protein in the blood and urine by standard electrophoresis. Partial response (PR) was defined as a 50% reduction in M-protein, no response (NR) as less than 50% reduction and progress was considered when the increase was ≥ 25%. The Swedish population (n = 9 340 682 in 2009) was used to select a gender and 5-yrs age strata matched cohort based on 2008–2010 observed death rates. In the total MM population n=1 843, 201 (11%) pts were excluded due to non treatment demanding disease setting the study population to n=1 642. The median follow up of pts still alive was 30 months. The median age was 70 yrs and 45% women. The most common subtype was IgG (59%) followed by IgA (22%), BJ (15%) and Other (4%). High dose treatment (HDT) was given to 517 (32%) pts. The median number of given treatment lines in both the HDT and the non-HDT population was two but the number of pts receiving more treatment lines were declining rapidly. The response distribution for the HDT population nCR/PR/NR was 47/41/12% in 1st line (induction and high-dose melphalan) and 25/42/33% in 2nd line. In the non-HDT population the response distribution was 14/42/44% in 1st line and 11/31/58% in 2nd line. Non-HDT pts receiving novel agents in 1st line had significantly higher nCR rates compared to pts receiving older drugs, 22% vs. 12% as well as pts receiving novel agents in 2nd line with nCR rates of 16% vs. 6%. In the HDT population the median time to progression/time to next treatment (TTP/TTNT) was 21.0/29.7 months in 1st line and 8.1/12.7 in 2nd line. In the non-HDT population the median TTP/TTNT was 11.0/16.8 months in 1st line and 7.3/11.4 in 2nd line. There was a significantly increased TTP/TTNT in 1st and 2nd line depending on the increased depth of the response for both the HDT and non-HDT populations. The median OS for HDT pts was 6.7 yrs 95% CI[6.1;7.6] and correlated with 1st line response (nCR 7.6, PR 6.1 and NR 6.2 yrs). When comparing HDT pts to the matched normal population the 1-year survival was 97% vs. 99%, 3-year survival 86% vs. 98% and 5-year survival 66% vs. 95%. The median OS for non-HDT pts (n=1080) was 2.7 yrs 95% CI[2.5;3.0] and increased with better response in 1st line; nCR 3.4, PR 3.0 and NR 1.9 yrs. Kaplan-Mayer analysis showed that the use of novel agents in 1st line (n=316, median age 72.1 yrs) predicted a significantly longer OS compared to conventional treatment (n=764, median age 75.4), median 4.9 vs 2.3 yrs. When comparing pts that received at least two lines of treatment, pts treated with novel agents in 1st line followed by novel agents in 2nd had not reached the median survival but had a lower CI of 6.3 yrs, novel agents in 1st line followed by old agents in 2nd line had a median OS of 4.3 yrs old agents in 1st line followed by novel agents in 2nd line had a median of OS 3.3 yrs and old agents in 1st line followed by old agents in 2nd line had a median of OS 3.0 yrs. Compared to the matched normal population non-HDT pts receiving novel agents in both 1st and 2nd line the 1-year survival was 90 % vs. 96%, 3-year survival 71% vs. 86% and 5-year survival 67% vs. 77%. The number of pts receiving 2nd and 3rd line treatment declined rapidly. Non-HDT pts treated with novel agents in 1st line had a superior response and OS compared to the group treated with standard chemotherapy. Pts treated with novel agents in 2nd line as well seem to have a further improved survival compared to other alternatives. In comparison to a normal population, matched for gender and age at diagnosis, the survival is still shorter. However, if novel agents were used in an optimal treatment sequence the survival could potentially be higher. There is still a need for further development in MM treatment before one can call it a chronic disease. Figure 1: HDT treated pts compared to a matched normal population Figure 1:. HDT treated pts compared to a matched normal population Figure 2: Non-HDT pts receiving old or novel agents in 1st line compared to a matched normal population. Figure 2:. Non-HDT pts receiving old or novel agents in 1st line compared to a matched normal population. Disclosures: Liwing: Janssen-Cilag: Employment, Equity Ownership. Mellqvist:Janssen, Celgene: Honoraria. Näsman:Janssen-Cilag: Consultancy. Aschan:Janssen-Cilag: Employment, Equity Ownership.

Abstract 3280 Poster Board III-1 Background: Imatinib mesylate (IM) 400 mg once daily (OD) is the current standard first-line therapy for CML. Several biological and clinical observations suggest that combining IM with interferon alpha (IFNa) may improve the outcome of treatment. Aim: To compare the effects of standard-dose IM to combination of IM and IFNa in newly diagnosed chronic phase CML patients with an intermediate or low Sokal risk score. The primary end point was to compare the major molecular response (MMR) rate after 12 months between the treatment arms (intention-to-treat analysis). Patients and therapies: In a Nordic CML Study Group (NMCLSG: Denmark, Finland, Norway and Sweden) and Israel multicenter study we randomized 114 newly diagnosed CML patients in complete hematological remission following 3 months of IM 400 mg OD induction therapy. The study arms were IM (Glivec, Novartis) and the combination of IM and IFNa 2b (PegIntron, Schering-Plough). IM dose was fixed at 400 mg OD. IFNa was started at 30 μg/week but could be escalated to 50 μg/week or reduced down to 15 μg/week depending on tolerability. Molecular response was evaluated by blood RQ-PCR for BCR-ABL1 and was expressed on the international scale (IS). Results: As of August 17, 2009, 79 patients were evaluable for primary endpoint and 47 of these were in MMR (59%) The rate of complete cytogenetic response (CCgR) was 68/79 (86%). Nineteen patients (17%) were considered as treatment failures (grade 4 nonhematological adverse event, refusal, loss of CCgR, progression to advanced phase, protocol violation or other reason). Conclusions: A final analysis will be performed when we have complete data on all randomized patients. The comparison by treatment arm on molecular and cytogenetic responses as well as other relevant data (treatment failures, patients off-treatment for protocol violations, refusal or toxicity) will be presented on site. Supported by European LeukemiaNet, WP 4. Disclosures: Simonsson: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. BjÖreman:BMS: Consultancy, Honoraria. Mustjoki:BMS: Honoraria. StrÖmberg:Novartis: Honoraria; BMS: Honoraria. Weiss Bjerrum:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Gruber:Novartis: Research Funding. Nagler:Novartis: Consultancy. Porkka:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding.

8005 Background: In a phase 1b trial, a SC formulation of DARA with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE drug delivery technology, Halozyme, Inc.) had adequate PK, low rates of infusion-related reactions (IRRs) and similar efficacy to DARA IV. This phase 3 study compared the efficacy, PK, and safety of DARA SC vs IV in pts with RRMM. Methods: DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL]) and DARA IV (16 mg/kg IV) were given weekly for C1-2 (28-day cycles), every 2 weeks for C3-6, and every 4 weeks thereafter. DARA SC (15 mL) was given over 3-5 mins at alternating left/right abdominal sites. Pts (≥18 years) must have received ≥3 prior lines of therapy (LOT), including a PI and an IMiD, or were double refractory. Co-primary endpoints were ORR (analyzed by Farrington-Manning test, with non-inferiority = 60% retention of ORR) and pre-dose C3D1 DARA Ctrough (non-inferiority = lower bound of 90% CI for the ratio of the geometric means [GM] ≥80%). Results: 522 pts were randomized (n=263 SC; n=259 IV). Median age was 67 yrs. Median baseline body weight was 73 kg. Pts received a median of 4 LOT and 100% had received both PI and IMiD; 17% had high cytogenetic risk at baseline. Median follow-up was 7.5 mos. ORR was 41% for DARA SC and 37% for DARA IV. DARA SC retained at least 89% of the benefit of DARA IV (97.5% confidence). The ratio of GM of Ctrough for DARA SC over DARA IV was 108% (90% CI, 96%-122%). A significantly lower rate of IRRs was observed with DARA SC vs DARA IV (12.7% vs 34.5%; P