Kumar, Shaji

Abstract Introduction: Melphalan based chemotherapy is commonly used for treatment of light chain amyloidosis (AL). Patients with AL often receive chemotherapy before autologous stem cell transplantation (ASCT) if they have high plasma cell burden or while awaiting ASCT. Melphalan is an alkylator and can affect bone marrow stem cells. Limited data is available on the effect of melphalan on stem cell mobilization in patients with amyloidosis. This study aims to identify the impact of melphalan therapy on collection of stem cells and ASCT in amyloidosis. Methods: All patients with AL seen at our institution within 90 days of diagnosis over a 10-year period (2006 to 2015) who underwent stem cell harvest were identified from an institutional database. Data pertaining to demographics, diagnosis, treatment, stem cell harvest and ASCT was extracted from the electronic medical records. Analysis was carried out by chi-square and Fisher's exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Results: Three hundred and seventy two patients with AL who met the inclusion criteria were identified, of whom 10% (n=38) received melphalan based chemotherapy prior to harvesting, 28.5% (n=106) received non-melphalan based chemotherapy and 61.3% (n=228) received no chemotherapy prior to stem cell collection. Bortezomib based regimens were the most common (78%, n=83) non-melphalan based chemotherapy. All three groups were similar in terms of median age at diagnosis (59.1 years), median age at collection (59.4 years), gender distribution (59% males, n=221) and type of involved free light chain (FLC), with lambda being more common (72.2%, n=268). Patients who received melphalan-based chemotherapy had more cardiac (73.8% vs. 45.2% vs. 46.4%, p=0.005) and renal (84.2% vs. 50.9% vs. 68%, p=0.0002) involvement compared to other chemotherapy and no chemotherapy groups, respectively. In contrast, patients who received non-melphalan based chemotherapy had higher plasma cell burden (15% vs. 6% vs. 10%, p< 0.0001) and greater difference between involved and uninvolved FLC (44.2 mg/dL vs. 13.3 mg/dL vs. 13.2 mg/dL, p< 0.0001) compared to melphalan and no chemotherapy, respectively. Median duration of melphalan based chemotherapy was shorter at 54 days (34.5 to 79.5) or estimated 2 cycles compared to 101 days (60 to 135.5) or estimated 4 cycles (p=0.0019). Despite shorter duration of chemotherapy, total stem cell yield (million CD34/kg) was lower in patients who received melphalan based chemotherapy (5.54) compared to non-melphalan based chemotherapy (8.14) or no prior chemotherapy (7.94); p<0.0001. Similarly, day one stem cell yield (million CD34/kg) was the lowest in the melphalan group (2.71), followed by other chemotherapy group (3.63) and highest in no chemotherapy group (4.84); p<0.0001. This trend persisted for average stem cell yield per collection as illustrated in table 1. Filgrastrim (GCSF) alone was the most common mobilizing agent. However, patients with any chemotherapy prior to harvesting had higher utilization of plerixafor; 26.3% (n=10) in the melphalan group and 39.6% (n=42) in the non-melphalan group compared to 11.6% (n=27) if no prior chemotherapy (p<0.0001). However, no statistically significant difference was seen for melphalan vs. non-melphalan chemotherapy groups (p=0.44). In patients who underwent ASCT (85%, n=315), median stem cell dose (million CD34/kg) was different in the melphalan (3.66), non-melphalan (4.2) and no chemotherapy groups (4.44) (p=0.047), though the difference was not statistically significant amongst the 2 chemotherapy groups (p=0.34). There was also no difference in time to engraftment (table 1). Conclusions: Melphalan based chemotherapy, even if used for a short duration of time, significantly decreases both total stem cell yield and the yield on day one. It therefore has the potential to add to resource utilization with more collections needed. As much as possible, limited cycles of melphalan based chemotherapy or non-melphalan based treatment should be utilized in patients who are transplant eligible. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Celgene: Research Funding; pfizer: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy.

Abstract Introduction: Chemotherapeutic options for patients with systemic light chain amyloidosis (AL) who are not transplant candidates include bortezomib based therapy, melphalan with dexamethasone, and less commonly, immunomodulatory drugs (IMiDs). However, prospective clinical trial data comparing these regimens are lacking. This study aims to compare efficacy of bortezomib-based treatment to other therapies. Methods: All patients with AL seen within 90 days of diagnosis at our institution over a 10-year period (2006 to 2015) who did not undergo a stem cell transplant were identified from our institutional database. Data pertaining to demographics, diagnosis, treatment and follow-up were extracted from electronic medical records. Analyses were carried out by chi-square and Fisher's exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Progression free survival (PFS) is defined as time to death, progression requiring treatment change or relapse requiring re-institution of treatment. PFS and overall survival was analyzed via the Kaplan-Meier method. Results: Seven hundred and twenty five patients met the inclusion criteria, of which 38% (n=275) received bortezomib containing regimens and 62% (n=450) received non-bortezomib based therapies. Bortezomib was used with dexamethasone in 24% (n=67) patients; and with other drugs, most commonly cyclophosphamide, in 76% (n=208) patients. Non-bortezomib treatment regimens included melphalan-based treatment in the majority (92%, n=414) followed by IMiDs with steroids and other drugs (8%, n=36). Baseline variables similar in both groups and their distribution in the entire cohort was as follows: gender distribution (63.3% males, n=459), median age of diagnosis (66.3 years, range 32.2 to 93.6), type of involved free light chain (FLC) (lambda 73%, n=523) and median plasma cell burden (10%, range 0 to 91). Median difference between the involved and uninvolved free light chain (dFLC) was higher in the bortezomib group (29 mg/dL vs. 23 mg/dL; p=0.017). There was no difference in organ involvement. In the bortezomib group, organ involvement was as follows: cardiac (81%, n=219), renal (62%, n=168) and hepatic (18%, n=48). In the non-bortezomib group, the rates of organ involvement were similar: cardiac (78%, n=346), renal (57%, n=247) and hepatic (19%, n=85). Median duration of first line treatment was similar in the 2 groups, with 178 days in the bortezomib cohort and 187 days in the non-bortezomib cohort. Response rates are illustrated in Table 1. Rates of very good partial response (VGPR) or better response were higher in the bortezomib group (64 % vs. 54%, p=0.0002). Patients treated with bortezomib achieved VGPR faster with higher rates of VGPR or better response seen at 3 months (48% vs. 27%, p <0.0001) and 6 months (57% vs. 34%, p < 0.0001) after initiation of therapy compared to non-bortezomib treatment. Rates of organ response were similar amongst the 2 groups as shown in Table 1. However, median time taken to achieve a cardiac response was shorter in the bortezomib group (23 vs. 38 weeks, p=0.0026). In a multivariable model, bortezomib-based treatment and dFLC at diagnosis were predictors of VGPR. Relapse or progression requiring change in therapy was more common in patients treated with non-bortezomib based therapy (38%, n=143/372) compared to bortezomib-based treatment (28%, n=67/236); p =0.01). However, no difference in overall survival was observed in patients treated with bortezomib (2.2 years; 95% confidence interval (CI): 1.7 to 3.3) vs. non-bortezomib therapies (1.7 years; 95% CI: 1.3 to 2.5). Conclusion: Treatment with bortezomib-based regimens results in a deeper response including higher rates of early VGPR at 3 and 6 months from starting therapy. Moreover, these patients achieve cardiac response faster and have lower rate of relapse. However, no difference in overall survival was seen, which may be explained by subsequent use of bortezomib-based therapies in this population. Disclosures Dispenzieri: Celgene: Research Funding; Alnylam: Research Funding; pfizer: Research Funding; Jannsen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Kumar:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

Abstract Introduction Plasmacytomas comprise approximately 3% of all plasma cell malignancies. There is a paucity of large studies assessing clinical features and outcomes of this relatively uncommon disease. Our objective was to describe the patterns of clinical presentation and survival of plasmacytomas using the National Cancer Data Base (NCDB). Methods This is a retrospective study of patients with histologically confirmed diagnosis of plasmacytoma from 2000-2011 using International Classification of Diseases for Oncology version 3 (ICD-0-3) code: 9930. Patients who had bone marrow involvement were excluded from the analysis. Plasmacytomas were grouped into two broad categories: extramedullary plasmacytoma (P-EM) and bone plasmacytoma (P-bone) based on their anatomical locations. Overall survival was analyzed using Kaplan-Meier estimates. Results A total of 6,939 patients were included in the study (median age 64 years; range 18-90 years). Approximately 62% of these patients were males and 46% patients were ≥ 70 years. Racial/ethnic distribution of the disease was as follows: 76% Whites, 13% Blacks, 7% Hispanics, and 4% others. The anatomical distribution and survival of patients is depicted in the Table. P-EM comprised 30% of the patients, with remaining 70% presenting as P-bone. Among P-EM, most common sites of presentation were upper aero-digestive tract (41%) and connective/soft tissue (20%). After a median follow up of 65 months, the overall survival of P-EM was significantly better than P-bone (113 vs. 78 months; Figure). Based on outcomes, we can categorize the P-EM patients into 3 groups: good (median overall survival > 120 months: upper aero-digestive tract, lymph nodes, endocrine and digestive system), intermediate (median overall survival 90-120 months: nervous system, eye/orbit, pulmonary), and poor (median overall survival <90 months: connective/soft tissue, cardiac/mediastinum, genitourinary, and hepatobiliary system). Males had better overall survival than females in P-bone (84 vs. 67 months; p<0.0001), but had no significant survival difference in P-EM (109 vs. 116 months; p=0.7). In the P-EM group, median overall survival was worst for Blacks (98 months vs. Whites- 108 months, Hispanics- not reached, others-145 months). Conversely, for P-bone, Blacks had a better overall survival than Whites (Blacks- 99 months, Whites- 72 months, Hispanics- 156, others-84 months). Patients who were treated at an academic center had better overall survival than patients treated at other/community centers both in case of P-EM (130 vs. 108 months) and P-bone (107 vs. 69 months). Conclusions This is the largest registry-based study on plasmacytoma in the United States. Plasmacytomas have varied clinical presentation, along with significantly different survival based on sites of presentation, race, sex, and treatment facility. Our study results point toward important differences in disease biology based on location and may aid in assessing prognosis for planning treatment. Table. Anatomical distribution and median overall survival of plasmacytomas. Table Overall survival based on location (P-EM: extramedullary plasmacytoma; P-bone: bone plasmacytoma) Table. Overall survival based on location (P-EM: extramedullary plasmacytoma; P-bone: bone plasmacytoma) Figure Figure. Disclosures Kumar: Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; BMS: Consultancy; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Research Funding.

Abstract Background: BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecular inhibitor of BCL-2. When combined with bortezomib, which can inhibit MCL-1, VEN can enhance the activity of bortezomib in MM cell lines and xenograft models. Methods: In this Phase 1b, open label, dose escalation study, patients with relapsed/refractory (R/R) MM received daily VEN (50 - 1200 mg per designated dose cohort) with bortezomib and dexamethasone. The objectives of the study were to assess the safety, pharmacokinetics, maximum tolerated dose, recommended phase 2 dose (R2PD), and efficacy (objective response rate [ORR], time to progression [TTP], and duration of response [DoR]) of combination therapy in this patient population. Results: As of 01July2016, 66 patients were enrolled, with 54 in the dose escalation cohort and 12 in the safety expansion at R2PD of 800 mg. The median age was 64 years and 39 (59%) were ISS stage II/III. The median number of prior therapies was 3 (range: 1 - 13), and 21 (32%) were refractory to prior bortezomib, 37 (56%) were refractory to prior lenalidomide, and 41 (62%) had prior stem cell transplant. Forty-three (65%) patients discontinued the study for the following primary reasons: 33 related to disease progression, 5 due to AEs (1 each: respiratory failure and cardiac failure, lung adenocarcinoma, sepsis, renal impairment, and Guillain-Barre syndrome; none were considered by the investigator as related to VEN), 2 withdrew consent, and 3 for other reasons not specified. Adverse events (AEs) were reported in 65 (99%) patients, with common AEs in ≥20% of patients being diarrhea (41%), thrombocytopenia (39%), constipation (38%), nausea (36%), insomnia (32%), peripheral neuropathy (30%), peripheral edema (29%), anemia (27%), peripheral sensory neuropathy (27%), dyspnea (24%), fatigue (24%), and asthenia (24%). Grade 3/4 AEs in ≥10% of patients included thrombocytopenia (29%), anemia (15%) and neutropenia (14%). Serious AEs in ≥2 patients were febrile neutropenia, thrombocytopenia, cardiac failure, pyrexia, influenza, lower respiratory tract infection, pneumonia, sepsis, acute kidney injury, respiratory failure, embolism, and hypotension. One dose-limiting toxicity of lower abdominal pain was reported for a patient who received 1200 mg VEN. Five deaths were reported during the study, 4 due to disease progression and 1 due to respiratory syncytial virus infection (not considered by the investigator as related to VEN). After co-administration with bortezomib and dexamethasone, dose-normalized VEN exposure at steady-state appeared to be within the exposure range observed with VEN monotherapy in patients with MM. The ORR for all evaluable patients was 68% (44/65) and 26 (40%) achieved very good partial response (VGPR) or better (3 stringent complete response [sCR], 8 CR, 15 VGPR) (Figure). For all patients, median DoR was 8.8 months (95% CI: 7.2, 15.8) and TTP was 8.6 months (95% CI: 5.7, 10.2), with a median follow up of 4.9 months (range: .03 - 26.7). High ORR of 89% was seen in patients who were non-refractory to prior bortezomib (39/45) or who had 1 - 3 prior therapies (31/35). In 31 patients who were non-refractory to bortezomib and had 1 - 3 prior therapies had ORR of 94% (29/31), 68% (21/31) with VGPR or better; median DoR was 10.6 months and TTP was 11.3 months for this subgroup. Moreover, patients who were bortezomib naïve and had 1 - 3 prior lines of therapy had ORR of 100% (12/12), and median DoR was 15.8 months and TTP was 17.1 months. In patients who were non-refractory to prior bortezomib but who were refractory to lenalidomide, the ORR was 86% (19/22) as compared with 91% (20/22) in those non-refractory to lenalidomide. Clinical responses were comparable in patients with t(11;14) MM (ORR, 78% [7/9]) and without t(11;14) MM (ORR, 66% [37/56]). In the t(11;14) group, 3 patients were bortezomib-refractory, and 2 of them achieved a PR as best response. Also, 4 patients had more than 3 prior lines, with 3 of them achieving PR. Conclusions: VEN in combination with bortezomib and dexamethasone has an acceptable safety profile in patients with R/R MM. Efficacy results, including 68% ORR in all patients and 94% ORR in patients not refractory to bortezomib and who received 1 - 3 prior lines of therapy, indicates promising efficacy of this novel combination and supports the ongoing Phase 3 trial with this regimen in patients with R/R MM. Figure. Figure. Disclosures Moreau: Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Roberts:Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding. Agarwal:AbbVie: Honoraria, Research Funding; Millennium: Consultancy; Amgen: Consultancy; Janssen: Speakers Bureau; Onyx: Speakers Bureau; Celgene: Speakers Bureau. Facon:Amgen: Consultancy, Speakers Bureau; Millenium/Takeda: Consultancy; Bristol: Consultancy; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Celgene: Consultancy, Speakers Bureau; Karyopharm: Consultancy. Kumar:Glycomimetics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; BMS: Consultancy; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Touzeau:AbbVie: Research Funding. Cordero:AbbVie: Employment. Ross:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment. Jia:AbbVie: Employment. Salem:AbbVie: Employment. Leverson:AbbVie: Employment, Other: Shareholder in AbbVie. Maciag:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Harrison:Janssen Cilag: Research Funding, Speakers Bureau; AbbVie: Research Funding.

Abstract Background Ixazomib, the first oral proteasome inhibitor (PI), is approved by the US FDA, in combination with lenalidomide-dexamethasone (Rd), for the treatment of pts who have received at least 1 prior therapy. Lenalidomide is a common partner agent in regimens for RRMM; however, due to increasing use of lenalidomide treatment to progression as a standard of care in the first-line setting, novel PI-based combinations without lenalidomide are needed for RRMM. Combinations of a PI, an alkylating agent, and dexamethasone have been shown to be active, with manageable side effects, in RRMM patients (e.g. VCD - bortezomib, cyclophosphamide, dexamethasone), but require SC or IV administration of the PI. The all-oral combination of ICd may offer activity, tolerability, and more convenient administration. This open-label, multicenter phase 2 study (NCT02046070) assessed the safety and efficacy of ICd in pts with RRMM. Methods Adult pts with RRMM after 1-3 prior lines of therapy, who had ECOG performance status 0-2, were not PI-refractory, had adequate hematologic, renal, cardiac, and hepatic function, and did not have grade ≥2 peripheral neuropathy (PN) or grade 1 PN with pain, were eligible. Pts received oral ixazomib 4.0 mg and oral cyclophosphamide 300 mg/m2 on days 1, 8, and 15, plus oral dexamethasone 40 mg (20 mg for pts aged &gt;75 yrs) on days 1, 8, 15, and 22, in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR; ≥partial response [PR]); secondary endpoints included safety, pharmacokinetics (PK), complete response (CR) plus very good PR (VGPR) rate, CR rate, time to response (TTR), duration of response (DOR), and progression-free survival (PFS). Results 78 pts were enrolled; median age was 64 yrs (40% aged &gt;65 yrs), 53% were male, median time from initial diagnosis was 53.4 months (range, 12.9-142.7), and 24%/27% had ISS stage II/III disease at diagnosis. Median number of prior therapies was 2, including prior bortezomib, lenalidomide, and stem cell transplant (SCT) in 45 (58%), 38 (49%), and 50 (64%) pts, respectively; 17% were immunomodulatory-drug-naive. At data cut-off (June 20, 2016), pts had received a median of 12 treatment cycles (range, 1-22). A total of 51 (65%) pts had discontinued treatment, primarily due to disease progression (26 pts, 33%) and AEs (13 pts, 17%). Overall, 92% of pts reported AEs, including 59% with grade ≥3 AEs (51%/71% in pts aged ≤65/&gt;65 yrs), and 29% with serious AEs (30%/29%). Common AEs are listed in Table 1. AEs resulted in dose reductions of any study drug in 28 (36%) pts (28%/48% of pts aged ≤65/&gt;65 yrs) and treatment discontinuation in 11 (14%) pts (15%/13% aged ≤65/&gt;65 yrs). Ixazomib, cyclophosphamide, and dexamethasone were dose modified in 83%, 85%, and 87% of pts, respectively. Median ixazomib relative dose intensity was 96%. There were 3 on-study deaths: cardiac arrest, severe pulmonary edema, and cerebral hemorrhage secondary to thrombocytopenia, with the latter considered treatment-related. PK data showed that ixazomib exposures were comparable to those in pts treated with IRd in the TOURMALINE-MM1 study, suggesting no PK interaction with Cd. ORR was 49%, including 16% CR+VGPR (Table 2); in pts with/without prior SCT, ORR was 41%/61% (15%/18% CR+VGPR). Median TTR in responding pts was 2.14 months; median DOR was not reached, with response durations of up to 17 months. After a median follow-up of 12.5 months, median PFS was not reached; 12-month PFS rate estimate was 57.5%. Subgroup analysis showed a higher ORR (68% vs 35%), a higher CR+VGPR rate (23% vs 12%), and a significant PFS improvement in pts aged &gt;65 yrs vs pts aged ≤65 yrs (12-month PFS rate estimate 67.2% vs 50.7%; HR=0.43, p=0.028) (Figure). Although pts aged &gt;65 yrs were less likely to have had prior SCT than those aged ≤65 yrs (22% vs 78%), this did not appear to account fully for the difference in outcomes (PFS in pts without vs with prior SCT, HR=0.82, p=0.6). Conclusions All-oral triplet therapy with ICd appears to have activity in RRMM pts, with a toxicity profile consistent with that seen with ixazomib in combination with Rd (Moreau, et al; N Engl J Med 2016). Preliminary best response and PFS data suggest there may be preferential benefit in elderly pts compared to younger patients (possibly related in part to more limited use of prior high-dose alkylator [melphalan] exposure associated with SCT in elderly pts) albeit with additional toxicity. Disclosures Kumar: Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Grzasko:Celgene: Honoraria; Munipharma: Honoraria; Janssen: Honoraria. Jędrzejczak:Novartis: Consultancy, Research Funding; BMS: Research Funding; Janssen-Cilag: Consultancy; Celgene: Consultancy; Angelini: Consultancy; Roche: Consultancy, Research Funding; Amgen: Research Funding; Sandoz: Consultancy. Kyrtsonis:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gupta:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; AMAG Pharmaceuticals: Equity Ownership; Gilead Science: Equity Ownership; Array: Equity Ownership. Byrne:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Autologous stem cell transplantation is an integral part of myeloma therapy for patients who are able to undergo the treatment. While high dose melphalan has remained the typical conditioning regimen for ASCT in MM, recently there have been efforts to enhance the conditioning therapy by adding newer drugs to melphalan. Addition of bortezomib as well as carfilzomib have been attempted in phase 2 trials. Previous studies have shown that the combination of melphalan and total body irradiation (TBI) is an effective conditioning regimen. Pre-clinical studies have shown that bortezomib can sensitize MM cells to radiation, and based on this finding, we designed a clinical trial to examine the feasibility of combining low dose TBI with a combination of melphalan and bortezomib. Patients and Methods: The primary goal of the phase 1 study was to determine the maximally tolerated dose (MTD) of bortezomib that can be added to high dose melphalan and low dose TBI as part of conditioning chemotherapy in patients undergoing an ASCT for MM. The secondary goals were to examine the toxicities associated with addition of bortezomib to high dose melphalan and TBI in patients with MM and to determine the progression free rate at 1 and 2 years. Patients eligible to receive full dose melphalan conditioning regimen for ASCT were included as long as they had no more than 2 prior regimens and had not received a prior transplant. An accelerated design that was later converted to a standard 3+3 cohort design was used for dose escalation. Three patients were treated at a given dose level combination and observed for at least 36 days to assess toxicity. Melphalan 80 mg/m2 was given days -4, -3, with bortezomib at increasing doses given on day -5, -2 along with TBI of 200 cGY given on the same days of bortezomib, timed after bortezomib administration. Stem cells were infused day 0. Results: Eleven patients were enrolled; 6 were males, and the median age was 60 years. Median time from diagnosis was 5.4 months (range 3.4-7.0). Four dose levels were explored with increasing doses of bortezomib (0.7 mg/m2 to 1.6 mg/m2). No dose limiting toxicities were observed. The dose levels and the best response after ASCT are as shown in the Table. The overall response rate was 100%, including 7/11 with a CR or sCR. With a median follow-up of 12.5 months, two patients have progressed; median OS was not reached. Toxicity was mostly hematologic, with other AEs being grade 3 or less and attributable to the conditioning therapy. All patients engrafted their counts adequately. Conclusion: The combination of melphalan, bortezomib, and low dose TBI is a safe conditioning regimen in patients with MM with good efficacy. The regimen should be further examined in the phase 2 setting. Table Table. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Noxxon: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Janssen: Research Funding; Skyline: Consultancy, Honoraria.

Abstract AL amyloidosis is a systemic disease with profound effects on organ function. However, despite the broad array of disease manifestations, the effect of AL amyloidosis on thyroid function is underreported. We explored the frequency of thyroid function abnormalities in 961 untreated AL amyloidosis patients seen in our clinic between 8/2005-8/2015, with emphasis on association with other organ involvement and tumor burden. Thyroid function was assessed using the thyroid stimulating hormone assay (TSH, normal range 0.3-5 mIU/L). If TSH was abnormal, measurement of free thyroxine (FT4) and thyroid peroxidase (TPO) antibodies was routinely performed. Patients' median age was 62 [interquartile range (IQR) 56-69], 62% were male (Table). The median number of organs involved was 2 (IQR 1-3), 29% of patients had more than 2 involved organs. Seventy-seven percent of patients had cardiac involvement, 61% renal, 23% peripheral/autonomic neuropathy, 19% hepatic and 15% gastro-intestinal (GI) involvement. The median difference between involved and uninvolved light chains (dFLC) was 24.4 [interquartile range 10.6-65.2 mg/dL]. The median TSH was 3 mIU/L (range 0.1-50.1); 22% had levels above the normal range and 8% of patients had TSH greater than 7.5 mIU/L. Baseline characteristics by TSH ≤5 mIU/L and TSH >5 mIU/L subgroups can be viewed in Table. Patients with renal or hepatic involvement had higher TSH values compared to no renal or no hepatic involvement (3.2 vs 2.6 and 2.8 vs 3.8, respectively; P<0.001 for both comparisons). There was a borderline significance for higher TSH in patients with >2 organ involvement compared to 1-2 affected organs (3.3 vs 2.8; P=0.05), with a strong trend for higher TSH for dFLC ≥18 mg/dL compared to dFLC<18 mg/dL (P=0.07). In patients with renal involvement, presence of proteinuria > 2 grams/day was associated with a higher likelihood of TSH >7.5 mIU/L (13% vs 5%; P=0.003). Free thyroxine (FT4) measurements were performed in 214 (22%) of patients with a median value of 1.1 ng/dL(range 0.3-72), 6% had levels below the lower limit (0.8 ng/dL). One-hundred and sixty five patients (17%) were screened for TPO antibodies, of which 16% (n=27) had an elevated titer. L-thyroxine (median dose 100 mcg/d, range 25-350 mcg/d) was already prescribed to 157 of the patients (16%) at their first visit, but duration of treatment prior to AL amyloidosis diagnosis could not be determined. Seventeen patients (1.5%) were prescribed amiodarone (median dose 200mg/d, range 100-400 mg/d), and although numbers were low, patients with amiodarone treatment had a TSH twice as high as patients without this treatment (6 vs 2.9 mIU/L, P=0.006). In conclusion, thyroid function abnormalities are frequent at the time of AL amyloidosis diagnosis and are influenced by type of organ involvement as well as disease burden assessed by dFLC and/or number of affected organs. Amiodarone, although infrequently used in this disease, can cause a profound disturbance in thyroid function among these patients. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding. Kumar:AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Abstract Background Despite significant progress, MM remains an incurable disease. Synergistic activity of immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) has been established in preclinical and clinical studies. Data with respect to combination of newer IMiDs and PIs are scant. Recently, a small study (n=32) found the novel therapeutic regimen consisting of carfilzomib, pomalidomide and dexamethasone (KPd) to be well-tolerated and active in RRMM patients, but only 7% of patients in that study had ECOG > 1. KPd has not been extensively studied outside of clinical trials. Therefore, we evaluated real-world outcomes of KPd in RRMM patients seen in our routine dysproteinemia practice. Methods Records of MM patients consecutively seen at Mayo Clinic, Rochester from 01/ 2013 to 05/ 2016 were reviewed. Forty-five MM patients who received KPD in the R/R setting were identified and included in the analysis. The international uniform response criteria (IMWG 2006) were used to assess response rates. Additionally, minor response (MR) was assessed to determine the clinical benefit rate (CBR or ≥MR). Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 4. Duration of response was calculated for patients who have achieved a PR or greater response from time of first response to progression of disease. The time-to-event analyses were performed from the time of initiation of KPd therapy using the Kaplan-Meier method. All but one patient received K at 20/27 mg/m2 (days 1, 2, 8, 9 15, 16) dosing, P at 2 mg or 4 mg (day 1-21), and dexamethasone at 20 or 40 mg (day 1, 8, 15, 22), with 28-day cycles. Results The median age at KPd initiation was 65 years (range 29-75), 25 (56%) patients were males. 71% had an ECOG performance score of 0 to 1, and 29% had an ECOG >1. Forty percent were mSMART standard risk, while 60% were intermediate to high risk. Median time from MM diagnosis to KPd was 44 months (range 6-188), and the median number of prior treatment lines was 4 (range 1-14). Three (7%) patients were quadruple refractory to bortezomib (V), lenalidomide (R), P, and K. Ten (23%) were triple refractory to V, R, and P or K. Twenty seven (60%) were dual refractory to V and R. Table 1 shows prior treatment agents and refractoriness. The median duration of treatment with KPd was 2 months (range 0.3-16.4). KPd was used as a bridge to autologous stem cell transplant (ASCT) in 5 patients. One patient discontinued therapy due to toxicity (infection, weakness). Response was evaluable in 44 patients. The median time to first response was 1.4 months (range 0.5-6). Overall response rate (ORR) was 36%, [stringent complete response (sCR) in 1 (2%) patient, complete response (CR) in 3 (7%) patients, very good partial response (VGPR) in 2 (5%) patients, partial response (PR) in 10 (22%) patients]. Minimal response (MR) was seen in 3 (7%), leading to a CBR of 43%, while an additional 10 (23%) patients had stable disease (SD). Progressive disease (PD) was noted in 15 (34%) patients. At the time of analysis 20 (43%) patients were deceased, all from PD. The median follow up from initiation of KPd was 16.3 months (95% CI: 8.6-19.4). The median overall survival (OS) from KPd was 16.1 months (95% CI: 10.6-20.4). Median OS for dual refractory was 15.6 (95% CI: 10.6-20.5). Median OS for triple/quadruple refractory was similar to those with lesser degree of refractoriness [19.1 (95% CI: 0.92 - 27.1) months vs 13.6 (95% CI: 8.9-20.5), p= 0.82]. The median progression-free survival (PFS) was 3.3 months (95% CI: 1.9-6.4) and the median time-to-next therapy (TTNT) was 3.5 months (95% CI: 2.2-6.7). The media duration of response was 12.9 months (95% CI: 2.5-19.6). The median OS from KPd for patients who achieved at least a PR was 20.4 months (95% CI: 13.6-NR), compared to 11 months (95% CI: 8.3-NR) for others (p=0.05). Grade ≥3 hematologic toxicity was seen in 19 (42%) of evaluable patients [grade ≥3 neutropenia (29%), thrombocytopenia (31%) and anemia (22%)]. The most common non-hematologic adverse events were fatigue (38%), infections (31%), diarrhea (12%) and dyspnea (12%). Of the 4 (9%) patients who developed venous thromboembolism (VTE), two were on aspirin prophylaxis while the other two were not receiving any VTE prophylaxis. Conclusions KPd shows activity in RRMM patients although the short PFS reflects the challenges encountered with managing heavily pretreated and often less fit patients in the real world setting outside of clinical trials. Disclosures Dispenzieri: Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; pfizer: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Kumar:BMS: Consultancy; Kesios: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Glycomimetics: Consultancy; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding.

Abstract Introduction: Hematologic response criteria for light chain amyloidosis (AL) requires that difference in involved and uninvolved free light chains (dFLC) be at least 5 mg/dL (or 50 mg/L). However, many patients do not meet these criteria and are often excluded from clinical trials. These patients are challenging to follow clinically as organ response takes much longer and therefore response to treatment is difficult to evaluate in the first few cycles. This study aims to evaluate patients who had non-evaluable FLC (dFLC< 5 mg/dL) at diagnosis and compare them to those who had evaluable FLC (dFLC≥ 5 mg/dL). Methods: All patients with newly diagnosed AL seen within 90 days of diagnosis at our institution over a 10-year period (2006-2015) were identified from an institutional database. Data pertaining to demographics, diagnosis, treatment and follow-up was extracted from electronic medical records. Analysis was carried out by chi-square and Fisher's exact test for categorical variables and Kruskal-Wallis and Wilcoxon rank sum test for ordinal and continuous variables. Progression free survival (PFS) is defined as time to progression requiring treatment change or relapse requiring re-institution of treatment or death. PFS and overall survival (OS) were analyzed via the Kaplan-Meier method. Results: Of 1336 patients meeting inclusion criteria, dFLC at diagnosis was known in 1290. 85.4% (n=1101) had dFLC ≥ 5 mg/dL, while 14.6% (n=189) had non-evaluable FLC. Median age at diagnosis (65.2 vs. 63.9 years), gender distribution (males 56.1% vs.64.8%) and involved FLC (lambda: 72.2% vs. 72.9%) was similar in FLC < 5 mg/dL and FLC ≥ 5 mg/dL group. Cardiac (38.1 vs. 76.3%, p <0.0001) and liver (10.2% vs. 16.3%, p=0.03) organ involvement were less common in patients with non-evaluable FLC (table 1). NT-ProBNP was significantly lower in the group with dFLC < 5 mg/dL in patients with and without cardiac involvement, as was Mayo cardiac stage (table 1). A trend towards less gastrointestinal (GI) involvement (17.1% vs. 24%, p=0.09) was also seen with dFLC < 5 mg/dL. In contrast, a trend towards higher renal involvement was seen in patients with dFLC < 5 mg/dL (64.6% vs. 55.9%, p=0.08), though this was not statistically significant. Median 24 hour urine protein was significantly higher in all patients (with and without renal involvement) with dFLC < 5 mg/dL compared to dFLC ≥ 5 mg/dL group (table 1). Treatment details are listed in Table 1. ASCT (autologous stem cell transplant) was utilized more commonly in patients with dFLC < 5 mg/dL compared to patients with dFLC ≥ 5 mg/dL(43.2% vs. 26.1%, p <0.0001), including ASCT alone without chemotherapy (35.4% vs. 15.3%, p <0.0001).Rates of cardiac response (53.3% vs. 50.3%, p=0.88), and time to response (27.7 weeks vs. 35.6 weeks, p=0.67), were similar in both groups. Similarly, there was no difference in rates of renal and liver response and time taken to achieve a response (table 1). In patients with evaluable FLC, hematologic response was complete response (27.3%, n=245), very good partial response (21%, n=189), partial response (18%, n=160), no response (8%, n=74), progression (2%, n=15) and not known in 26.1% (n=216). In patients who had follow up data available, 30.6% (44/144) with dFLC < 5mg/dL experienced a relapse/progression with median PFS of 4.1 years (95% confidence interval (CI): 3 to 5.7), while 34.7% (304/875) with FLC ≥ 5 mg/dL experienced a relapse/progression with median PFS of 1.3 years (95% CI 1.1 to 1.5); p<0.0001. Median OS was higher in patients with dFLC < 5 mg/dL at diagnosis at 8.3 years compared to 2.4 years in patients with dFLC ≥ 5 mg/dL (p < 0.0001) as depicted in Figure 1. Conclusions: Patients with non-evaluable FLC at diagnosis have significant differences in organ involvement and survival compared to those with FLC ≥ 5 mg/dL at diagnosis. They have less cardiac and liver involvement and a trend towards less GI involvement, which may be secondary to low serum FLC burden and consequent less organ deposition. However, a trend towards higher renal involvement was seen in dFLC < 5 mg/dL group, with significantly higher urinary protein excretion. Loss of FLC in urine may result in lower serum FLC levels in this group. Survival was significantly better in patients with dFLC < 5 mg/dL, which may be explained by less cardiac involvement, lower cardiac stage and lower median FLC at diagnosis. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Jannsen: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Consultancy, Honoraria; BMS: Consultancy; AbbVie: Research Funding; Noxxon: Consultancy, Honoraria; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

Background: Nearly a third of patients with newly diagnosed myeloma (MM) have a preceding diagnosis of plasma cell proliferative disorder (PCPD), mostly monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or plasmacytoma. While high dose therapy improves survival in patients with myeloma, it is not clear if patients with preceding PCPD have a different outcome. Methods and Results: We identified 151 patients with preceding PCPD from among 804 patients undergoing high dose therapy at our institution. These included 59 patients (7.3%) who had a preexisting diagnosis of MGUS, 88 (11%) patients, in whom the diagnosis of MM was preceded by SMM, including 23 patients who also had a preceding MGUS or plasmacytoma. In addition, 27 (3.4%) patients gave a preceding history of plasmacytoma. The median duration from the first diagnosis of a PCPD to that of myeloma was 32.4 months (range, 6.1 to 31 years), and was longer for patients with an initial diagnosis of MGUS compared to those with out preceding MGUS. While response rates including complete responses were generally similar between the two groups of patients, those with any preceding PCPD had a median TTP of 24.2 months (95% CI; 20, 28.3) compared to 17.3 (95% CI; 15.7, 18.8) months for those with no previous history (De novo Myeloma); p = 0.01 (Figure 1). The median OS from transplant for patients with previous history was 63.7 months (95% CI; 50.2, 77.4) compared to 48.3 months (95% CI; 39.7, 56.9) for the de novo group, p = 0.01 (Figure 2). These differences were most striking for those with a preceding diagnosis of MGUS; who had a longer time to progression (27.6 months vs. 17.7 months; p = 0.02), and longer OS from transplant (80.2 months vs. 49.3 months, p = 0.046) compared to those without any preceding MGUS. In a multivariate analysis, transplant within 12 months of diagnosis, lower serum M-protein at transplant, PCLI <1%, absence of cytogenetic abnormalities, achievement of CR, and presence of any preexisting monoclonal disorder prior to diagnosis of myeloma were independently prognostic for risk of post transplant relapse. Conclusion: Patients with preexisting PCPD at the time of myeloma diagnosis undergoing HDT has a better outcome reflecting more indolent disease and a favorable biology than those presenting with de novo myeloma and no antecedent plasma cell dyscrasia. Figure Figure Figure Figure