Reece, Donna

Abstract Background: Initial studies with venetoclax, a BCL-2 inhibitor, alone or in combination with either dexamethasone or bortezomib and dexamethasone has shown considerable anti-tumor activity in t(11;14) MM with relapsed disease. Based on preclinical studies suggesting synergy when combined with bortezomib and phase 1 data showing efficacy for venetoclax, this combination was compared with bortezomib and dexamethasone (BortDex) in relapsed MM. While the BELLINI (NCT02755597) trial did demonstrate improved PFS with the combination, there were limited number of patients with t(11;14) treated with BortDex. The objective of this study was to assess real-world effectiveness of BortDex in patients with t(11;14) positive relapsed/refractory MM. Patients and methods: This non-interventional, retrospective observational cohort study included patients with t(11;14) MM from the International Myeloma Working Group (IMWG) retrospective study of t(11;14) MM. From the overall cohort, patients with t(11;14) MM receiving BortDex in ≥2 nd and ≤4 th line were initially selected. The cohort was further limited to patients with no evidence of allogeneic SCT within 16 weeks or autologous SCT within 12 weeks prior to BortDex initiation. Finally, patients non-refractory to prior PI regimen and not receiving BortDex regimen as part of a clinical trial were included in the study. Patient demographic and clinical characteristics along with real-world effectiveness outcomes including best response, overall survival (OS), and time to next therapy (TTNT) as a surrogate measure for progression-free survival (PFS) were assessed. All analyses were descriptive in nature and were conducted using the SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Results: Overall, 144 patients who met the inclusion criteria were analyzed. Median age was 62.5 years, 62% were male. Patients had a median of 1 prior line (range 1-3) at start of BortDex, at a median of 18.4 months (range, 1-100) from diagnosis; 29% had a prior transplant. A PR or better was observed in 53% of patients with BortDex. The median TTNT for this cohort was 8.4 months and median OS was 46.1 months. Conclusions: This retrospective study of non-trial patients with t(11;14) MM provides a benchmark for newer therapies in this patient population for comparison with both venetoclax dexamethasone as well as combinations using the -BortDex backbone. Disclosures Emechebe: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Pharmaceutical/Biotech Companies: Current holder of stock options in a privately-held company. Kumar: Tenebio: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Goldschmidt: Takeda: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant. Mateos: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Kim: Janssen, BMS: Research Funding. Dimopoulos: Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Ludwig: Janssen, Celgene-BMS, Sanofi, Seattle Genetics: Consultancy, Speakers Bureau; Amgen, Takeda: Consultancy, Research Funding, Speakers Bureau. Handa: Kyowa Kirin: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Janssen: Honoraria; BMS: Honoraria; Ono: Honoraria; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Takeda: Honoraria, Research Funding. Fernandez de Larrea: Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; GSK: Honoraria; Sanofi: Consultancy. Reece: Amgen: Consultancy, Honoraria; GSK: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Millennium: Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Karve: AbbVie: Current Employment, Current equity holder in publicly-traded company. Arriola: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.

8525 Background: RRMM patients (pts) triple-class exposed (to immunomodulatory drugs [IMiDs], proteasome inhibitors [PIs] and anti-CD38 monoclonal antibodies [mAbs]) have limited treatment (tx) options. The ongoing phase II KarMMa study (NCT03361748) is examining idecabtagene vicleucel (ide-cel; bb2121), a BCMA targeted CAR T cell therapy, in RRMM pts with ≥3 prior regimens (IMiD, PI and CD38 mAb inclusive) who are refractory to their last tx per IMWG criteria. This study aimed to 1) assess tx patterns and outcomes in real world (RW) RRMM pts similar to the KarMMa population and; 2) compare outcomes with SoC in a synthetic cohort vs ide-cel in KarMMa. Methods: In this global, noninterventional, retrospective study (KarMMa-RW), pt-level data from clinical sites, registries and databases were collated into a single data model. RW pts meeting KarMMa eligibility criteria (eligible cohort; EC) were compared with KarMMa (N = 128) using trimmed stabilized inverse probability of tx weighted propensity scores (IPTW PS) for pts in both studies with Poisson regression for ORR and ≥VGPR, and Cox models with study as a term for PFS. All models were adjusted for unbalanced covariates. Results: Of 1949 RW pts, 1171 were refractory to last regimen (median age, 68 y; median no. of prior regimens, 5; triple-class refractory, 41%). Further selection for subsequent tx, organ function and no comorbidities yielded 190 EC pts who had > 90 distinct tx regimens. With a median follow-up of 11.3 mo (KarMMa) and 10.2 mo (EC) at data cutoff (Oct 30, 2019), ORR, ≥VGPR and PFS were significantly improved in KarMMa vs EC (Table). Conclusions: Results from the KarMMa-RW study confirm that there is no clear SoC for heavily pretreated RW RRMM pts and responses are suboptimal with currently available therapies. Ide-cel showed deep, durable responses and significantly improved PFS in RRMM pts, representing a potential new tx option in RRMM. Clinical trial information: tbd . [Table: see text]

Abstract Introduction: The NCIC CTG previously reported the results of a dose-finding trial testing the combination of Melphalan (M) and Lenalidomide (L) in previously untreated patients with multiple myeloma who were ineligible for stem cell transplantation because of older age and/or comorbidity (White, Blood2007; 110: 63a). Using a 28-day schedule, M (dose indicated as mg/m2/day given on days 1–4) and L (dose indicated in mg/day given on days 1–21) was associated with excess toxicity with the regimens M9L10, M4L15 and M6L10. We concluded that phase II testing of M5L10 was warranted and now report the results of this testing. Methods: Previously untreated symptomatic and consenting patients with tissue-confirmed plasmacytosis and a measurable M-protein were eligible provided that they had acceptable hematologic and biochemical laboratory parameters and no precluding comorbidities. Planned treatment consisted of M 5 mg/m2 days 1–4 and L 10 mg days 1–21, given every 28 days for 12 cycles. As our intent was to determine dose levels that could be given independently of G-CSF, primary prophylaxis with G-CSF was not included but use of G-CSF for established neutropenia was permitted. A hematologic dose limiting toxicity (H-DLT) was defined as the need for 2 dose attenuations of L or 1 dose attenuation of M occurring within the first 3 treatment cycles. Responses to treatment were classified using 1998 EBMT criteria and assessed after 2 and 6 cycles of therapy. Results: The intended sample size was 41 patients; 35 patients (1 ineligible) were enrolled before the study was closed due to observing a frequency of DLTs that surpassed predefined boundaries. Of the 34 eligible patients, median age was 73.4 yrs and ISS was stage I = 13, stage II = 11 and stage III = 10. Prior to study closure, 27 patients were evaluable for DLT; 7 (26%) did not experience a DLT. Among the remaining 20 (74%) patients, non-hematologic (N=2) and hematologic (N=18) DLTs requiring dose attenuations were seen within the first 3 treatment cycles; the H-DLTs included severe or prolonged neutropenia (N=11), thrombocytopenia (N=2) or both (N=5). One fatal serious adverse event was observed, this was due to a stroke. The other non-hematologic DLT was a cranial nerve III palsy which subsequently resolved. Responses after 2 cycles were evaluable in 21 patients and included partial response (PR) = 11, minimal response = 6, no change = 2 and progressive disease (PD) = 2. For those patients without PD after 2 cycles, responses after 6 cycles were evaluable in 8 and included PR = 6, stable response = 1 and PD = 1. Conclusion: Although M + L is an active combination for previously untreated myeloma patients, the regimen is associated with considerable myelosuppression. Without the routine use of GCSF, the doses used in the MY.11 study were not tolerable. Inability to use planned doses may have compromised the efficacy of the combination.

Abstract Background: HLA associations for the risk of developing MM have been described in various non-Caucasian ethnic groups but have not revealed consistent results. Racial and genetic differences in cytokine polymorphisms linked to extended haplotypes; association of autoimmune disorders with HLA types; the proximity of the HLA Class I and II genes to TNF and other Class III genes responsible for complement and cytokines suggest that HLA polymorphisms may be associated with the risk of developing MM. Aim: We compared HLA-A,-B and -DRB1 2-digit allele and haplotype frequencies in patients with MM to the normal population in order to define HLA specificities associated with the risk of developing MM. Methods: A cohort of 1803 US Caucasian patients with MM were identified based on availability of HLA-A, B, DRB1 DNA-based typing or serologic typing converted to 2-digit alleles. These patients had either received a matched sibling allogeneic transplant for MM reported to the CIBMTR (N=174) or had HLA typing performed for an unrelated donor search conducted through the US National Marrow Donor Program (NMDP) (N=1629). HLA-A, B and DRB1 allele frequencies among patients were compared to A-B-DRB1 frequencies in HLA typed healthy US Caucasian controls (N= 433838) from the NMDP database. The most frequent alleles among patients and controls as well as HLA haplotype frequencies generated using the EM (expectation-maximization) algorithm were compared using Chi-Square analysis with Bonferroni correction for the number of comparisons. Results: Patients with MM had a median age of 49 (range 3–78) years and M/F ratio of 1.86 (1172/631). The controls had a median age of 44 (range 18–60) years and M/F ratio of 0.735 (183785/250053). Comparison of HLA-A, -B and –DRB1 single-locus allele frequencies between the myeloma patients and controls (those in the top 10 in either group) revealed similarity except for HLA-B*07 and B*44. B*44 was observed less frequently among the patients (a protective effect) frequency (f): 0.126 vs 0.145 (p= 0.005, Odds Ratio (OR): 0.848). On the contrary, HLA-B*07 was more common (a predisposing effect) among patients (OR: 1.135, p=0.047). Among the top 20 two locus (HLA-A-B and HLA-B-DRB1) haplotype frequencies in either group, B*44-DRB1*13 and B*07-DRB1*13 were significant: OR: 0.506 and 1.714 (p=0.003 and 0.007) respectively. A-B-DRB1 haplotype comparisons showed significance for: A*02-B*44-DRB1*04 (OR: 0.686, p=0.021), A*02-B*44-DRB1*13 (OR: 0.445, p=0.065) and A*02-B*07-DRB1*04 (OR: 1.968, p=0.029) confirming the single and B-DRB1 combination comparison results. Significantly different HLA-A, -B and -DRB1 single-locus allele or haplotype frequencies between patients and controls are shown in table 1. Conclusion: This is the largest epidemiologic study of HLA allele frequencies and the first study on HLA haplotype frequencies in MM. We observed a protective effect on the risk of developing MM with B*44 and a predisposing effect with B*07. Similar predisposing and protective haplotype associations were observed with A*02-B*07-DRB1*04 and A*02-B*44-DRB1*04 respectively. A revised analysis using a gender-matched control group is in progress. Further study including major histocompatibility region SNP mapping and candidate gene testing will help elucidate the genetic basis underlying this observation. Table 1. Allele/Haplotype Frequency Controls Frequency MM Odds Ratio (OR) P value (corrected) OR = odds of observing the allele/haplotype in patients compared to controls A*02-B*44-DRB1*13 0.00620 0.00277 0.445 0.065 B*44-DRB1*13 0.01359 0.00686 0.507 0.003 A*02-B*44-DRB1*04 0.02605 0.01813 0.686 0.021 B*44 0.14552 0.12618 0.848 0.005 B*07 0.13313 0.14836 1.134 0.047 B*07-DRB1*13 0.00814 0.01397 1.714 0.007 A*02-B*07-DRB1*04 0.00367 0.00721 1.968 0.029

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Abstract p53 deletion by fluorescence in situ hybridization (FISH) has been reported in about 10% of newly diagnosed patients (pts) with multiple myeloma (MM) and has been associated with a poor prognosis. Previous data from our centre has demonstrated that the progression-free survival (PFS) and overall survival (OS) of these pts after a single autologous stem cell transplant (ASCT) is only 16.9 and 48.2 months, respectively, compared to 24.4 and 76.6 mos, respectively, in all pts transplanted during the same time period (Mikhael et al, Blood2007; 110: abstract 953). Minimal information is available on the treatment (Tx) and course of these pts following disease progression. Therefore, we performed a retrospective review of all MM pts treated at our institution who were found to have p53 deletion. We identified 31 pts with relapsed/refractory (rel/ref) MM with this cytogenetic abnormality. At diagnosis, median age was 54 years (range, 31–70), hemoglobin 97 g/L (range, 67–149), creatinine 96 μmol/L (range, 28–1751), beta 2-microglobulin 314 nmol/L (range, 225–437), CRP 3 mg/L (range, 2–7) and LDH 205 U/L (range, 82–478); 58% were male. Immunoglobulin subtypes included: IgG (14 pts), IgA (8 pts), IgD (2 pts) and light chain only (7 pts). Concomitant cytogenetic abnormalities included 13q deletion in 68% and t(4;14) in 67% of pts evaluable. Thirty-nine percent developed plasma cell leukemia (PCL) at some point in the disease course, which was associated with a poor OS (p=0.005). All but 5 had undergone prior ASCT with a median time from diagnosis to ASCT of 8 (95% CI, 4–145) mos. Txs given for rel/ref MM consisted of the following regimens: thalidomide-based in 15, bortezomib-based in 12, lenalidomide-based in 11, alkylating agents in 9 and steroids only in 5 pts, and other regimens (D-PACE or investigational drugs) in 7 pts. The median follow-up from diagnosis in these pts is 45 (95% CI, 4–145) mos. The overall response rate (≥PR) (ORR), median PFS and median OS from the start of each regimen is shown below. Agent Median duration of Tx (mos) ORR(%) Median PFS (mos) Median OS (mos) Thalidomide 6.2 20% 5.0 11.9 Bortezomib 5.2 50% 5.6 36.1 Lenalidomide 10.6 60% 4.8 36.1 Alkylating agents 6.0 11% 5.1 30.0 Steroids 1.9 20% 1.9 33.4 Other 2.2 43% 6.3 33.4 We conclude: 1) Median PFS in pts with the p53 deletion is less than 6 months, with an OS of 2.5–3 yrs; 2) novel agents other than thalidomide produce the highest ORR in rel/ref MM with p53 deletion; 3) the short OS in the thalidomide group is likely related to the unavailability of other novel agents for subsequent relapses, as the majority of the pts were treated before 2004; 4) better strategies/drugs are required for these pts.

Abstract Background: We previously reported an 85% response rate with 54% CR/nCR using a combination of cyclophosphamide (Cy), prednisone, and bortezomib (BZ) in relapsed myeloma (MM). We now report a Phase II clinical trial using a combination of Cy, BZ, and dexamethasone (Dex) [Cybor-D] in newly-diagnosed MM. We then compare the activity of this combination with historical controls treated with our current induction standard of Lenalidomide-Dexamethasone (L-Dex). Methods: 30 patients have been enrolled on Cybor-D. Treatment consists of Cy 300mg/m2 p.o. days 1, 8, 15, and 22; BZ 1.3 mg/m2 days 1, 4, 8, and 11, and Dex 40mg p.o. days 1–4, 9–12, 17–20. Prophylactic use of acyclovir, a quinolone and antifungal prophylaxis was highly recommended for all patients on study. Growth factors were allowed. As a relevant contemporaneous control for speed and depth of response, we used 33 patients treated on a recent Mayo Clinic trial of L-Dex (Rajkumar. Blood: 2005 106;4050–3). Response was defined according to IMWG criteria although in the current trial, bone marrows for confirmation of CR are not yet available on all patients. Results: At time of current analysis, 17 patients on Cybor-D were evaluable through at least one cycle for response and toxicity. Baseline characteristics included mean age of 57, 29% female, 41/24% ISS stage II/III. There were statistically more early stage patients on L-Dex; otherwise, baseline patient characteristics were similar. The mean % decline in monoclonal (M) protein from baseline following cycles 1–4 of Cybor-D were 71%, 90%, 93%, 96%. This compares favorably with L-Dex where equivalent % decline in M proteins were 66%, 77%, 80%, and 79%. Thus, in preliminary results, Cybor-D produces a more rapid initial decline and mean % reduction in M protein than L-Dex. Overall response rate (≥ PR) after one cycle of Cybor-D was 77% with 36% obtaining ≥VGPR (L-Dex 73% and 18% respectively). The % of patients obtaining ≥VGPR after each cycle was 36%, 64%, 77%, and 100% for Cybor-D as compared to 18%, 36%, 42%, and 33% for L-Dex. The overall ≥VGPR at the end of four cycles of Cybor-D is currently100% (≥ 66%nCR using older nomeclature). Major toxicities ≥ grade 3 for Cybor-D included hematologic (37%), hyperglycemia (15%) and neuropathy (11%). Conclusions: In summary, for newly-diagnosed MM patients, four cycles of Cybor-D produces more frequent, rapid and deep responses when contrasted with historical L-Dex controls. Further confirmation of response rates and effect on TTP will be required.

Abstract One potential approach to improve the results of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) involves the use of more potent induction regimens; the achievement of deeper remission pre-ASCT should translate into longer progression-free (PFS) and overall survival (OS). To evaluate this hypothesis, we assessed the influence of the percent reduction in serum monoclonal protein (M protein) pre-ASCT in patients (pts) treated with dexamethasone-based regimens (most often VAD) on the best response, PFS and OS achieved after ASCT. Between 2000–2006, 376 pts with IgG (267) or IgA (109) non-progressive MM underwent ASCT. Median age was 59 (21–73) yrs; 60% were male. The median hemoglobin at diagnosis was 103 g/L, creatinine 98 μmol/L, β2-microglobulin 241 nmol/L and albumin 35 g/L. Maintenance therapy was given to 84 (22%) after ASCT and consisted of corticosteroids in 29, thalidomide in 10, both in 41 and other regimens in 4 pts. Patients were divided into 4 groups based on the per cent reduction in M protein after induction therapy: group A, ≥ 99%; group B, 90–98%; group C, 50–89%; group D, < 50%. Post-ASCT responses included complete remission (CR), very good partial remission (VGPR) (≥ 90% reduction in M protein), PR (≥ 50% reduction) and stable disease (SD). Median follow-up from diagnosis is 37.4 mos and from ASCT 24.1 mos. For all pts, the median OS from diagnosis is 90.8 mos (95% CI 73.9–129.1 mos) and from ASCT 63.9 mos (95% CI 50.8–69.4 mos), while the median PFS from ASCT is 21.3 mos (95% CI 19.1–23.3 mos). Maintenance therapy had no significant effect on PFS (p=0.49) or OS (p=0.59). The post-ASCT results in evaluable patients according to the percent reduction in M protein after induction therapy are summarized below. We conclude: High-grade remissions after dexamethasone-based induction therapy are uncommon, with only 2% achieving ≥ 99% and 13% achieving 90–98% reduction in serum M protein; post-ASCT CR and VGPR rates were higher in these 2 groups; there was no significant difference in PFS or OS-based on protein response prior to transplant; whether newer induction regimens, which incorporate novel agents and which produce more CRs and VGPRs before ASCT, will confer better PFS and OS post-ASCT will be of great interest. Table 1 Group N CR (%)1 VGPR (%)1 PR (%)1 SD (%)1 Median PFS (mo)2 Median OS (mo)3 1p<0.001;2p=0.77;3p=0.79 A 7 50 50 Not reached Not reached B 47 19 64 17 23.3 Not reached C 232 14 17 68 1 20.7 59.1 D 87 11 7 54 28 21.1 69.4 Figure Figure Figure Figure

Abstract Background: Single autologous stem cell transplant (ASCT) is considered the standard of care for younger multiple myeloma (MM) patients (pts). However, it is not curative and virtually all patients will ultimately relapse. As more options, such as biological therapy, are available to treat relapsed disease, the role of a second ASCT as salvage therapy is unclear. Method: Retrospective review of all MM pts who received a 2nd ASCT as salvage therapy at Princess Margaret Hospital. Results: Between February 1997 and June 2007, 61 MM pts received a second ASCT for relapsed MM at our institution. Median age was 56 yrs (range 35–71) at second transplant. 37 pts (61%) were male. Immunoglobulin subtype included IgG (36), IgA (14), light chain (6), nonsecretory (3), IgM(1) and IgD (1). Transplant conditioning regimen for first transplant was high dose melphalan (MEL) 140–200 mg/m2 in 51, MEL/etoposide(E)/TBI in 4, and MELl/TBI in 2. 2nd ASCT conditioning consisted of MEL + TBI +/− E in 2, MEL alone in 58 and Busulfan/Cyclophosphomide in 1. The median time from diagnosis to first transplant was 9.7 months (2.0–74.2). The median time to relapse after the first transplant was 32.6 months (9.7–85.6), with a median interval between transplants of 45.1 months (19.7– 115). Two transplant-related deaths occurred (3%). Response to first transplant was 4 CR (8%), 34 PR (68%), 2 MR (4%) and 10 SD (20%). Nineteen pts went on to maintenance therapy between transplants. Response to second transplant was 4 CR (8%), 41 PR (80%), 5 SD (10%) and 1 PD (2%). Median progression-free survival (PFS) was 15.8 months (0–63.8) while median overall survival (OS) was 4.2 years (0–7.0) after 2nd ASCT. The relationship between progression-free interval after 1st ASCT and the outcome of the 2nd ASCT is summarized Table 1. Patients can be stratified into two groups, those with a disease free interval of less than or greater than 24 months. The use of maintenance therapy did not differ between the two groups, 6 (40%) in patients with PFS ≤24 months and 13 (28%) in patients with PFS >24 months. Conclusions: 2nd ASCT is a feasible and safe salvage therapy in patients with relapsed MM. 2nd ASCT is effective in providing a median progression free survival of 1.25 years and median overall survival of 4.2 years after 2nd ASCT - results that compare favourably with other salvage approaches. Patients with a longer disease free interval after 1st ASCT experience a better progression free survival and overall survival after 2nd ASCT. It is reasonable, therefore, to consider a 2nd ASCT if the time to progression is greater than 2 years after first ASCT. Outcomes Based on Time to Progression Post 1st ASCT PFS post 1st ASCT # of pts median PFS post 2nd ASCT PFS post 2nd ASCT1 Median OS post 2nd ASCT OS post 2nd ASCT2 1 p< 0.005, 2 p< 0.05 ≤24 months 15 12.7 months 1 year: 46% 3.5 years 1 year: 85% 2 year: 11% 2 years: 76% 3 years 0% 3 years: 63% 4 years: 31% > 24 months 46 19.8 months 1 year: 74% 5.9 years 1 year: 91% 2 year: 45% 2 years: 82% 3 year: 31% 3 years: 65% 4 years: 55%

Background: Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving the chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in 15% of patients with myeloma, had been considered a standard risk abnormality, but recent data suggest inferior outcome. This is important as new therapeutic options such as the BCL-2 inhibitor venetoclax has been shown to be particularly effective in t(11;14) patients. Methods: This was a multicenter study to identify the outcomes of patients with t(11;14), using a retrospectively assembled cohort. Patients with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months of diagnosis, and with treatment details available and if alive, a minimum of 12 months of follow up, were enrolled. Results: The current analysis includes 1216 patients; median age of 62.56 years; 58.7% male. The median follow-up from diagnosis for the entire cohort was 51.9 months; 69.1% of the patients were alive at the last follow up. ISS stage distribution included: Stage I (35.7%), Stage II (34.0%) and Stage III (15.1%), data was missing for the rest. The distribution of concurrent FISH abnormalities included: trisomies (3.5%), del 13q (13.3%), 1q amp (8.8%), and del 17p or monosomy 17 (5.8%). Initial regimen included: 27.2% had an immunomodulatory (IMiD), 45.9% had a proteasome inhibitor (PI), 17.7% had both, and 9.0% had no novel agent. The drug classes by line of therapy are shown in Table 1. An early stem cell transplant (defined as within 12 months of start of first line treatment) was used in 49.4% of patients. The median time to next treatment (TTNT) after starting initial treatment was 26.6 (95% CI: 23.9 to 29.2) months. The median overall survival (OS) from diagnosis for the entire cohort was 95.1 (95% CI: 85.9 to 105.9) months; 4-year estimates for those diagnosed from January 2005 to December 2009, and from January 2010 to December 2014 were 77.5% and 78.6%, respectively. The median OS for those with any one high risk FISH lesion (del 17p/ 1q amp) was 67.5 (55.2, 97.1) versus 101.7 (89.7, 107.3) months. Patients with early SCT (within 12 months of diagnosis) had better OS: 108.3 (103.8, 133.0) vs. 69.8 (61.5, 80.3) months. Conclusion: Patients with t(11;14) without high risk FISH abnormalities have an excellent survival. Patients receiving a PI + IMiD combination and those receiving autologous SCT as part of initial therapy had best survival. Though numbers are limited, patients in the later lines receiving newer drugs such as venetoclax and daratumumab had high response rates and durable responses. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Bittrich:Celgene: Other: Travel Funding, Research Funding; Else Kröner Fresenius Foundation: Research Funding; Otsuka Pharmaceuticals Europe: Other: N/A; SANOFI Aventis: Membership on an entity's Board of Directors or advisory committees, N/A, Research Funding; University Hospital Wuerzburg: Employment; Bristol Myers Squibb: Research Funding; Pfizer: Other: Travel Funding; AMGEN: Other: Travel Funding; JAZZ Pharmaceuticals: Other: Travel Funding; Wilhelm Sander Foundation: Research Funding; German Research Foundation (DFG): Other: N/A; University of Würzburg: Other: N/A. Goldschmidt:Mundipharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; John-Hopkins University: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Janssen: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Molecular Partners: Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Reece:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: 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, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees. Ludwig:Celgene: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; PharmaMar: Consultancy; Janssen: Speakers Bureau; BMS: Speakers Bureau. Mangiacavalli:celgene: Consultancy; Amgen: Consultancy; Janssen cilag: Consultancy. Dimopoulos:Sanofi Oncology: Research Funding. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Yee:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; Adaptive: Consultancy. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Rosta:Cornerstone Research Group: Employment. Haltner:Cornerstone Research Group: Employment. Cameron:Cornerstone Research Group: Employment, Equity Ownership. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.