ALBERT

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: For pts with RRMM who have failed or progressed on treatment (Tx) with newer agents, such as lenalidomide (LEN) and bortezomib (BORT), there are few Tx options, and overall survival (OS) is short (Kumar et al, Leukemia, 2012). POM is a distinct immunomodulatory agent with tumoricidal and immunoregulatory effects, and POM + LoDEX is approved in the United States and European Union for the Tx of pts with RRMM who have had ≥ 2 prior Tx, including LEN and BORT. Tx with POM + LoDEX has shown statistically greater survival benefits than high-dose DEX (MM-003; San Miguel et al, Lancet Oncol, 2013) or POM alone (MM-002; Richardson et al, Blood, 2014). POM + LoDEX has also demonstrated high overall response rates in pts with RRMM in the STRATUS trial (MM-010), a single-arm, open-label phase 3b study being conducted in 19 countries across Europe with a primary endpoint of safety (Dimopoulos et al, EHA 2015). Italian pts constituted the largest national subset in MM-010; hence, this subanalysis examines the safety and efficacy of POM + LoDEX in pts from Italy. Patients and Methods: Pts with RRMM (progressive disease [PD] on or within 60 days of last prior Tx) who had experienced Tx failure with BORT and LEN and had received adequate prior alkylator therapy were eligible. Pts received POM 4 mg on days 1-21 of a 28-day cycle in combination with DEX 40 mg (20 mg for pts aged 〉 75 yrs) on days 1, 8, 15, and 22. Thromboprophylaxis was required for all pts, and Tx was continued until PD or unacceptable toxicity. Results: A total of 219 pts were enrolled in MM-010 in Italy. The median age of this patient population was 67.0 yrs (range, 42-84 yrs), and 54.8% of pts were male. The median time since diagnosis was 5.5 yrs, and 37.0% of pts were International Staging System stage III. Patients were heavily pretreated, with a median of 4 prior anti-myeloma regimens (range, 2-11), and most pts were refractory to LEN (95%), BORT (82.2%), or both LEN and BORT (78.1%). As of May 4, 2015, 2 pts (0.9%) were not treated, 54 pts (24.7%) were still on treatment, and 163 pts (74.4%) had discontinued. After a median follow-up of 11.3 mos, in the intention-to-treat population, the overall response rate was 37.9% (range, 31.4%-44.7%), the median duration of response was 6.8 mos (95% CI, 4.9-10.8 mos), progression-free survival (PFS) was 5.2 mos (95% CI, 4.4-6.4 mos), and OS was 12.0 mos (95% CI, 10.6-15.2 mos). The most frequent grade 3/4 treatment-emergent AEs were neutropenia (56.7%), anemia (25.8%), thrombocytopenia (23.5%), and pneumonia (12.4%). Incidence of grade 3/4 venous thromboembolism (deep vein thrombosis and pulmonary embolism) and peripheral neuropathy were infrequent (2.3% and 0%, respectively). The most common reasons for discontinuation were disease progression (49.8%), death (10.0%), and adverse events (AEs; 5.0%). AEs led to dose reductions or interruptions of POM in 23.0% and 71.0% of pts, respectively, and the median relative dose intensity for POM was 0.90. Conclusions: In line with previous studies, POM + LoDEX was active in Italian pts, a representative subset of the heavily pretreated MM-010 population. PFS and OS were consistent with those seen in previous trials. POM + LoDEX treatment was well tolerated, and discontinuations due to AEs were infrequent, consistent with the well-known toxicity profile and the appropriate drug management. This study confirms that POM + LoDEX is effective in patients with advanced RRMM, including those who have experienced failure of prior Tx with BORT and/or LEN. Disclosures Cavo: Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Petrini:Novartis: Research Funding; Celgene Corporation: Research Funding; Italfarmaco: Research Funding; Roche: Research Funding. Caravita di Toritto:Celgene Corporation: Honoraria, Research Funding. Offidani:Celgene, Janssen: Honoraria. Petrucci:Celgene Corporation: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Mundipharma: Honoraria; BMS: Honoraria. Rodeghiero:Celgene Corporation: Honoraria, Research Funding. Simcock:Celgene Corporation: Employment. Slaughter:Celgene Corporation: Employment, Equity Ownership. Herring:Celgene Corporation: Employment. Peluso:Celgene Corporation: Employment. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria.

Description: Background: The introduction of newer agents, such as lenalidomide (LEN) and bortezomib (BORT), has improved survival outcomes for pts with RRMM (Kumar et al Leukemia, 2014). However, overall survival (OS) in pts who have failed or progressed on treatment (Tx) with newer agents is short and there are few additional treatment options available (Kumar et al Leukemia, 2012). POM is a distinct immunomodulatory agent with tumoricidal and immunoregulatory effects approved in combination with DEX for the Tx of pts with RRMM in the US and EU with ≥ 2 prior Txs, including LEN and BORT. Pivotal trials with POM + LoDEX have demonstrated greater survival benefits when compared with high-dose DEX (MM-003; San Miguel et al Lancet Oncol, 2013) or POM alone (MM-002; Richardson et al Blood, 2014). The STRATUS trial (MM-010; ClinicalTrials.gov: NCT01712789; EudraCT: 2012-001888-78) is a single-arm, open-label, phase 3b study being conducted in 19 countries across Europe designed to further evaluate safety and efficacy of POM + LoDEX in RRMM. Here, we present an updated analysis of safety and efficacy. Methods: Pts with refractory or relapsed and refractory disease (progressive disease [PD] on or within 60 days of last prior Tx), Tx failure with BORT and LEN, and adequate prior alkylator therapy were eligible. Pts with the following laboratory values were excluded: absolute neutrophil count 〈 800/μL; platelets 〈 75,000 or 〈 30,000/μL for pts with 〈 50% or ≥ 50% of bone marrow nucleated cells as plasma cells, respectively; creatinine clearance 〈 45 mL/min; hemoglobin 〈 8 g/dL; and peripheral neuropathy (PN) grade (Gr) ≥ 2. POM 4 mg was administered days 1-21 of a 28-day cycle in combination with LoDEX 40 mg/day (20 mg for pts aged 〉 75 yrs) on days 1, 8, 15, and 22 until PD or unacceptable toxicity. Thromboprophylaxis was required for all pts.Follow up continued for subsequent Tx, OS, and second primary malignancy until 5 yrs post enrollment. Safety was the primary end point, and key secondary end points included overall response rate (ORR) (≥ partial response), duration of response (DOR), progression-free survival (PFS), OS, and POM exposure. Results: A total of 682 pts were enrolled. The median age was 66 yrs (range, 37-88 yrs), and the median time since diagnosis was 5.3 yrs (range, 0.5-28.1 yrs). Pts were heavily pretreated with a median of 5 prior regimens (range, 2-18). Most pts were refractory to LEN (96%), BORT (84%), or LEN and BORT (80%). As of May 4, 2015, the median follow up was 16.8 mos and the median duration of Tx was 4.9 mos. In the 676 pts receiving POM + LoDEX, the most frequent Gr 3/4 treatment-emergent adverse events (TEAEs) were hematologic events (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]. The most common Gr 3/4 nonhematologic toxicities were pneumonia (12.9%), fatigue (5.9%), and hypercalcemia (5.0%). Incidences of Gr 3/4 venous thromboembolism (deep vein thrombosis and pulmonary embolism) and PN were low (1.6% and 1.5%, respectively). Dose reductions, interruptions, and discontinuations of POM due to TEAEs were required in 22.0%, 66.3%, and 6.1% of pts; respectively. The ORR was 32.6%, with 0.6%, 7.6%, and 24.3% of pts achieving a complete response, very good partial response, and partial response, respectively. The median DOR was 7.4 mos. Median PFS and OS were 4.6 mos and 11.9 mos, respectively (Figure). Conclusions: The updated safety and efficacy results of STRATUS, the largest study of POM + LoDEX in a heavily pretreated RRMM population, were in line with results from the pivotal trials demonstrating that POM + LoDEX is effective and well tolerated. This analysis confirms that POM + LoDEX is a standard of care for pts with RRMM. Disclosures Dimopoulos: Janssen: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Onyx: Honoraria; Amgen: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Delforge:Novartis: Honoraria; Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Weisel:Amgen: Consultancy, Honoraria, Other: Travel Support; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; BMS: Consultancy, Honoraria, Other: Travel Support; Onyx: Consultancy, Honoraria; Noxxon: Consultancy. Di Raimondo:Celgene Corporation: Research Funding, Speakers Bureau. Simcock:Celgene Corporation: Employment. Miller:Celgene Corporation: Employment, Equity Ownership. Slaughter:Celgene Corporation: Employment, Equity Ownership. Peluso:Celgene Corporation: Employment. Sternas:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Moreau:Celgene: Honoraria, Other: Adboard; Amgen: Other: Adboard; Janssen: Honoraria, Other: Adboard; Takeda: Honoraria, Other: Adboard; Novartis: Honoraria, Other: Adboard.

Description: Background: Patients (pts) with multiple myeloma (MM) who have relapsed on or are refractory to treatment (Tx) with novel agents lenalidomide (LEN) and bortezomib (BORT) have few effective options for Tx and short overall survival (OS; Kumar, Leukemia, 2012). Pomalidomide (POM) is a distinct oral IMiDs® immunomodulatory agent with direct antimyeloma, stromal cell inhibitory, and immune modulatory effects (Quach, Leukemia 2010; Mark, Leuk Res, 2014). POM has been approved in the United States and the European Union for the Tx of pts with ≥ 2 prior Tx, including LEN and BORT, and progressive disease (PD) on Tx (EU, in combination with low-dose dexamethasone [LoDEX]) or within 60 days of completion of the last line of Tx (US). Results from the pivotal phase 3 MM-003 trial demonstrated that POM + LoDEX significantly extended progression-free survival (PFS) and OS vs high-dose dexamethasone in this pt population (San Miguel, Lancet Oncol, 2013). STRATUS is a multicenter, single-arm, open-label phase 3b trial with 〉 85 sites across Europe designed to further evaluate safety and efficacy of POM + LoDEX in a large pt population (N = 456 at data cutoff). Methods: Eligible pts had refractory or relapsed and refractory disease (PD during or within 60 days of last line of Tx), previous BORT and LEN Tx failure, and adequate prior alkylator therapy as defined in study protocol. Pts must have been refractory to their last prior line of Tx. Key exclusion criteria included absolute neutrophil count 〈 800/μL , platelet count 〈 75,000 or 〈 30,000/μL (for pts with 〈 50% or ≥ 50% of bone marrow nucleated cells as plasma cells, respectively), creatinine clearance 〈 45 mL/min, hemoglobin 〈 8 g/dL, and peripheral neuropathy ≥ grade (Gr) 2. POM was administered at 4 mg D1-21 of a 28-day cycle in combination with LoDEX 40 mg/day (20 mg for pts aged 〉 75 yrs) on D1, 8, 15, and 22 until PD or unacceptable toxicity. All pts received thromboprophylaxis with low-dose aspirin, low-molecular-weight heparin, or equivalent. The primary endpoint was safety, and key secondary endpoints included POM exposure, overall response rate (ORR; ≥ partial response), duration of response (DOR), PFS, OS, and cytogenetic analyses. STRATUS is registered with ClinicalTrials.gov (NCT01712789) and EudraCT (2012-001888-78). Results: As of March 17, 2014, 456 pts were enrolled and 452 had received POM + LoDEX; median age was 66 yrs (range, 37-88 yrs); median time since diagnosis was 4.9 yrs (range, 0.3-22.6 yrs). Pts were heavily pretreated with a median of 5 prior Tx (range, 2-18); 78% were refractory to BORT and LEN. Median follow-up was 6.8 mos with a median of 4 cycles received. Median PFS and OS were 4.3 mos and 10.9 mos, respectively (Figure 1). The ORR was 35%, with 6% of pts achieving ≥ very good partial response (VGPR); median DOR was 6.0 mos. Similar PFS (4.2 and 3.9 mos), OS (10.9 mos for each), and ORR (34% and 33%) were achieved in pts refractory to prior LEN (n = 427) or LEN and BORT (n = 356), respectively. In addition, PFS (4.3 and 3.9 mos), OS (11.5 mos and not estimable), and ORR (27% and 37%) were consistent in pts with LEN (N = 172) or BORT (N = 189) as last prior treatment, respectively. The most frequent Gr 3-4 treatment-emergent adverse events (TEAEs) were hematologic, including neutropenia (39%), anemia (27%), and thrombocytopenia (19%); Gr 3-4 non-hematological toxicities included pneumonia (11%), fatigue (5%), and hypercalcemia (4%). Gr 3-4 deep vein thrombosis was low (1%) with prophylaxis, and peripheral neuropathy was 1%. Dose reductions of either POM or LoDEX due to TEAEs were required in 28% of pts; discontinuations due to TEAEs were infrequent (9%). Conclusions: Results from STRATUS, the largest POM + LoDEX clinical trial thus far, were consistent with those observed in the pivotal MM-003 trial, and confirm that this regimen has an acceptable safety and efficacy profile and shows substantial improvements in PFS and OS benefits. Combination therapy with POM and LoDEX represents a new standard of therapy for pts with refractory or relapsed and refractory MM in whom LEN and BORT Tx failed. Disclosures Dimopoulos: Celgene: Consultancy, Honoraria. Palumbo:Array BioPharma: Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria. Weisel:BMS: Consultancy; Onyx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Noxxon: Consultancy. Ocio:Celgene Corporation: Honoraria, Research Funding. Cavo:Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Delforge:Celgene Corp: Honoraria; Janssen: Honoraria. Oriol:Celgene Corporation: Consultancy. Goldschmidt:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Doyen:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees. Simcock:Celgene Corporation: Employment. Miller:Celgene: Employment, Equity Ownership. Slaughter:Celgene: Employment. Peluso:Celgene: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene Corp: Employment, Equity Ownership. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Immunosuppressive treatment has been reported to improve cytopenia in some patients with myelodysplastic syndrome (MDS). The combined use of anti-thymocyte globulin (ATG) and cyclosporine (CSA) has been shown to be most effective in patients with immune mediated marrow failure. This trial was designed to assess the impact of immunosuppression on hematopoiesis, transfusion requirements, transformation and survival in MDS. 88 transfusion dependent patients were randomized to receive ATG+CSA (15mg/kg of horse ATG (Lymphoglobuline, Genzyme) for 5 days and oral CSA for 180 days) or best supportive care (BSC), stratified by treatment center and IPSS risk score between 2001 and 2006. The primary endpoint was best response at 6 months. Patients in the BSC arm crossed-over to ATG+CSA after 6 months or earlier in the event of progression: Eligible patients had an ECOG performance status ≤ 2 along with a transfusion dependency of 〈 2 years duration. Patients with MDS types CMMoL and RAEBt or treatment related MDS were not included in the trial. Statistical analyses consisted of comparisons of response rates and durations between treatment arms and time-to-event analyses including overall-survival (read as time from randomization to all-cause mortality) and transformation-free survival (event defined as death, transformation to higher grade MDS or leukaemia). Also evaluated was medical resource utilization and hematological and non-hematological toxicities. table 1 ATG+CSA BSC Patients: n 45 43 Age: median years (range) 62 (23–75) 65 (24–76) Sex: n male (%) 25 (56) 35 (81) IPSS score: n (low/int-1/int-2/high/na) (8/24/7/1/4) (8/25/5/0/5) MDS type: n (RA/RAS/RAEB-I/RAEB-II/hypoplastic) (21/6/9/0/9) (18/8/11/2/4) Five patients in the ATG+CSA arm did not receive treatment for various reasons whilst 13 patients in the BSC arm crossed-over on to ATG+CSA treatment. At 6 months there were 13 patients with a hematologic response (CR + PR) vs. 29 without in the ATG+CSA arm, compared to 5 with vs. 35 without in the BSC arm (p = 0.04, adjusted for the interim analysis): For various reasons no information was available for the remaining 6 patients. Transformation-free survival probability estimates at 2 years were 42% (23–60%) for patients receiving ATG+CSA and 44% (25–62%) for patients receiving BSC (p-value: 0.50). In total 29 deaths occurred; 15/45 patients randomized to receiving ATG+CSA and 14/43 patients receiving BSC. Overall survival probability estimates at 2 years were 49% (28–66%) for patients receiving ATG+CSA and 61% (40–76%) for patients receiving BSC (p-value: 0.90). The vast majority of adverse events occurred early after randomization, with particularly high WHO hematological toxicity gradings in both treatment arms. There were 24 SAEs; 17 in the ATG+CSA arm and 7 in the BSC arm. Reported SAEs were heterogeneous and included the most common types of infectious and inflammatory complications. Conclusions: In this open label randomized phase III trial of patients with transfusion dependent low and intermediate risk MDS, treatment with ATG + CSA appears to be associated with hematologic response in a subset of patients without apparent impact on transformation-free- and overall- survival.

Description: Abstract 1802 Background: Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance remains unknown. Methods: We prospectively registered 270 patients with untreated, chemotherapy resistant or relapsed follicular lymphoma. All patients received rituximab induction consisting of 4 weekly doses (375 mg/m2). Responding patients (PR and CR) were randomized to a short maintenance consisting of four doses of rituximab (375 mg/m2) every two months (arm A) or prolonged maintenance consisting of rituximab every two months for a maximum of five years or until disease progression or unacceptable toxicity (arm B). Primary endpoint is event-free survival. Here we present the safety analysis results after a median long-term maintenance period of 3.3 years. Results: From October 2004 to November 2007 165 patients were randomized, 82 in arm A and 83 in arm B. The median follow-up time is 3.2 years for arms A and B combined. While receiving maintenance therapy a total of 899 hematological and non-hematological adverse events were observed, 28 of grade 3 and 6 of grade 4. After randomization five patients experienced subsequent cancers. Seven grade 3 and 4 infections were reported. Two grade 3 infections occurred after 2 years of maintenance. Grade 3 and 4 neutropenia occurred in 6 (3.6 %) patients, decreased levels of IgG were observed in 24 (14.6 %) patients. In arm B, maintenance was stopped due to unacceptable toxicity in 2 patients after 16 and 42 months respectively and due to subsequent breast cancer in 1 patient after 20 months. One patient died 4 months after randomization because of ileus and consecutive peritonitis, considered to be unrelated to therapy. Sixty-three patients are on maintenance for two or more years of which 48 patients are on for three or more years. Two patients have completed the 5 years of maintenance. Conclusions: Rituximab maintenance beyond two years is feasible without evidence for increased toxicity. However, close follow up of patients under prolonged rituximab maintenance is still necessary. The trial has been closed for accrual but there are still patients on treatment. Disclosures: Taverna: Roche: Membership on an entity's Board of Directors or advisory committees. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Description: Abstract 4067 Background: Existing evidence has shown that continuing treatment with LEN plus dexamethasone (LEN-DEX) until disease progression in responding patients (pts) with relapsed/refractory multiple myeloma (RRMM) is associated with improved survival. In accordance with National Institute of Clinical Excellence (NICE) guidelines, LEN-DEX is reimbursed for treatment of RRMM pts after ≥2 therapies in England and Wales (current license after ≥1 prior therapy). The TCS database was designed as part of the NICE agreed pt access scheme, to track the duration of treatment for RRMM pts prescribed LEN-DEX. This scheme was not designed to record reasons for dose adjustments or treatment discontinuation. We studied LEN starting dose, dose modifications, and duration of treatment (in an anonymized dataset generated for statistical analysis). Methods: This prospective cohort analysis focused on pts enrolled in the TCS program between 1 July 2009 and 1 May 2010, to allow pts to be followed up for at least 2 years, unless they discontinued treatment earlier. The cut-off date was 30 June 2012. Associations between ordered categorical variables were measured by Spearman's rank correlation or Pearson's correlation for continuous variables. Baseline covariates (age and starting dose) were modeled using multivariable logistic regression with possible interactions considered. Statistical significance was considered at the 5% significance level. Results: A total of 1,286 pts with RRMM from 185 UK treatment centers were evaluable. The median age was 69 yrs (range, 34–91); 427 pts were aged 75 yrs (26%). Majority of pts (n = 835; 65%) initiated LEN treatment according to the recommended starting dose of 25 mg/d; 180 (14%) pts started at 15 mg, 212 (16%) at 10 mg, and 59 (5%) at 5 mg. Dose modifications were reported in 50% of pts, and the median number of changes in dose per subject was 1 (range, 0–15). The greatest percentage of dose modifications per cycle occurred in pts with the lowest starting dose (5 mg). A total of 340 (45%) pts who started on 25 mg/d and received 〉1 cycle required no dose adjustments. There was a relationship between dose adjustment and duration of treatment; pts without an adjustment received an average of 9.1 cycles while those with at least one form of adjustment received 14.3 cycles (P 〈 0.001). The median number of cycles administered was 7 (range, 1–38), similar to that seen in LEN clinical trials (median 9.2 mos in pts with ≥2 prior therapies); 456 (35%) pts remained on therapy for ≥12 cycles and 201 (16%) pts remained on therapy for ≥24 cycles. Six percent of all pts receiving ≥24 cycles had dose modifications directly after cycle 1, with the percentage of dose modifications steadily decreasing from cycle 6 onwards. There was a positive association between a higher starting dose and longer treatment duration (P 〈 0.001). Of the pts who started on 25 mg/d and ≤10 mg/d, 18% and 9% received ≥24 cycles, respectively. There was a significant negative correlation between age and the number of cycles administered (P = 0.018): of the pts aged

Description: Introduction: The introduction of newer agents, such as lenalidomide (LEN) and bortezomib (BORT), has resulted in improved survival outcomes in pts with RRMM (Kumar, Leukemia, 2012), and a greater depth of response has been associated with improved efficacy outcomes in RRMM (Harousseau, Haematologica, 2010). However, once pts become refractory to these newer agents, they experience poorer outcomes, with short overall survival (OS; Kumar, Leukemia, 2012). POM + LoDEX is approved for the treatment of pts with RRMM with ≥ 2 prior treatments, including LEN and BORT. A previous subanalysis of pts treated with POM + LoDEX in the MM-003 trial demonstrated that pts with a deeper response, as measured by a reduction in serum M protein, experienced longer OS and progression-free survival (PFS; San Miguel, ASH 2013). POM + LoDEX was shown to be safe and effective in the phase 3b STRATUS trial (MM-010; Dimopoulos, EHA 2015); here, we present the outcomes in this pt population by prior treatment and depth of response. Patients and Methods: Pts with RRMM (progressive disease [PD] on or within 60 days of last prior treatment) with prior adequate alkylator therapy in whom LEN and BORT treatment failed were eligible. POM 4 mg was administered on days 1 to 21 of a 28-day cycle in combination with LoDEX (40 or 20 mg for pts aged ≤ 75 or 〉 75 yrs, respectively) on days 1, 8, 15, and 22. Treatment was continued until PD or unacceptable toxicity, and thromboprophylaxis was required for all pts. For this efficacy analysis, pts were grouped according to prior treatment history or reduction in serum M protein level. Results: As of May 4, 2015, 682 pts were enrolled and 676 have received POM + LoDEX. In the intent-to-treat population, the median age was 66 yrs, 56% of pts were male, the median time since diagnosis was 5.3 yrs, and pts had received a median of 5 prior regimens. Approximately half of all pts (54.5%) had received prior thalidomide (THAL), and 186 vs 496 pts had received ≤ 3 vs 〉 3 prior regimens of therapy, respectively. Most pts were refractory to LEN (96%), BORT (84%), or both LEN and BORT (80%). The overall response rates (ORRs) were generally similar regardless of prior THAL, number of prior regimens, and LEN/BORT refractoriness. Pts who received prior THAL had an ORR of 30.4% compared with 35.2% for pts who did not receive prior THAL (Table). Similarly, for pts with a history of ≤ 3 vs 〉 3 prior antimyeloma regimens, ORR was 28.5% vs 34.1%. ORR did not appear to be impacted by refractory status to LEN and/or BORT (ORR, 32.1%-32.9%). PFS was comparable and independent of prior THAL exposure, number of prior regimens, and LEN/BORT refractoriness (PFS, 3.9-4.6 mos). Median OS was also similar for pts with or without prior THAL exposure (11.4 mos vs 12.0 mos, respectively), as was OS for pts with ≤ 3 vs 〉 3 prior regimens (12.8 mos vs 11.9 mos, respectively). Pts with LEN and/or BORT refractoriness had the same median OS of 11.9 mos. Analysis of PFS by serum M protein levels showed that a greater reduction in these levels was associated with a longer median PFS: for pts with a serum M protein reduction of 〈 25%, ≥ 25% to 〈 50%, and ≥ 50%, median PFS was 3.0, 4.8, and 7.6 mos, respectively. Conclusions: The efficacy of POM + LoDEX in this heavily pretreated population was independent of treatment history. ORR, OS, and PFS were not significantly impacted by treatment history with THAL, having ≥ 3 prior regimens, or refractoriness to LEN and/or BORT. As shown previously with POM + LoDEX, there was a clear trend toward prolonged PFS in pts with a greater reduction in serum M protein levels. This analysis supports POM + LoDEX as a standard of care for pts with RRMM. Figure 1. Figure 1. Disclosures Moreau: Celgene: Honoraria, Other: Adboard; Takeda: Other: Adboard; Janssen: Other: Adboard; Amgen: Other: Adboard; Novartis: Other: Adboard. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Delforge:Novartis: Honoraria; Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Weisel:Amgen: Consultancy, Honoraria, Other: Travel Support; Noxxon: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Travel Support. Knop:Celgene Corporation: Consultancy. de Arriba:MundiPharma: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Simcock:Celgene Corporation: Employment. Miller:Celgene Corporation: Employment, Equity Ownership. Slaughter:Celgene Corporation: Employment, Equity Ownership. Watkins:Celgene Corporation: Employment. Herring:Celgene Corporation: Employment. Biyukov:Celgene: Employment, Equity Ownership. Peluso:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Dimopoulos:Amgen: Honoraria; Novartis: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Onyx: Honoraria.

Description: Mantle cell lymphoma (MCL) has a very poor prognosis. Remissions are often incomplete and short with a median survival of less than 3 years and a 5 year survival of 〈 30%. Young patients are usually treated with intensive chemotherapy regimens or a stem cell transplant. In elderly, unfit patients aggressive treatments are not a realistic approach. This trial set out to assess Gemcitabine in the treatment of patients with newly diagnosed, relapsed or chemotherapy resistant MCL not fit enough for intensive chemotherapy regimens. The primary endpoint was the objective response. Eligibility criteria were a WHO performance status 〈 2, age ≥ 18 years, a histologically confirmed diagnosis of MCL along with at least one measurable lesion of diameter ≥ 11 mm, ≤ 2 previous lines of chemotherapy. Gemcitabine was given in doses of 1000mg/m2 as a 30 minute infusion on days 1 and 8 of each 3 week cycle for a total of 9 cycles. To prevent flu-like symptoms, one dose of steroids per Gemcitabine infusion was administered. Response duration was read as the time from trial registration to a relapse for patients reaching a remission on the trial therapy. Progression-free survival was defined as the time from trial registration to death or disease progression, treatment failure as early termination of the trial treatment. Patient enrollment began in Aug 2004. Stage I analysis concluded the trial treatment was not promising for further investigation, due to only 1 (10%) patient reaching a remission, and patient accrual stopped after the inclusion of 18 patients in March 2006. Median age at enrollment was 70 years. 66% of the patients were male. MCL was newly diagnosed in 50% of the patients and relapsed in the remainder. Ann Arbor stage IV rating was present in 15 patients, stage II in 1 patient and stage I in 2 patients. Bone marrow involvement was reported in 10 patients. Gastrointestinal tract involvement was reported in 4 patients. Involvement of 〉 1 extranodal organ was seen in 3 patients. One CR, 4 PRs, 8 SDs and 4 PDs were recorded as a best response. The patient achieving a CR was one of the patients presenting with a stage IV disease. Most myelotoxicities occurred during the first chemotherapy cycle. Neutropenia CTC grade 1 in 24 (19.8%), grade 2 in 35 (28.9%) and grade 3/4 was seen in 24 (19.8%) of the cycles. Thrombocytopenia CTC grade 1 was recorded in 55 (45.5%) cycles and grade 2/3 in 9 (7.7%) cycles. Three patients developed non-hematological serious adverse events, defined as an inpatient or prolonged hospitalisation or a life threatening illness related to the trial medication; dyspnea, glomerular microangiopathy with hemolytic uremic syndrome, and hyperglycemia. The median time-to-progression and response duration was 8.0 (95% confidence interval: 5.5 – 9.3) and 10.6 (95% confidence interval: 5.5 – 10.9) months respectively. The median time-to-treatment failure was not reached. We conclude that Gemcitabine is well tolerated and that it can stabilise MCL in elderly patients. However, Gemcitabine as a monotherapy has only limited activity in MCL patients in terms of treatment response. Further trials should therefore assess gemcitabine in frail patients with MCL.

Description: Key Points STRATUS (MM-010), the largest POM + LoDEX trial, confirms the regimen offers clinically meaningful benefit and is generally well tolerated. STRATUS supports POM + LoDEX as a standard of care for patients with RRMM who have poor prognosis and high need for effective treatments.