ALBERT

Description: Introduction: Lenalidomide (L) is an immunomodulatory compound, or IMiD®, which has impressive activity against both relapsed/refractory (RRMM) and newly diagnosed MM (NDMM). Although approximately 15% of NDMM patients (pts) treated with thalidomide (another IMiD®) plus dexamethasone (D)(TD) will develop thromboembolic events (TEEs), less is known about the thrombotic risk associated with LD. In 2 large Phase III studies comparing LD to D + placebo (P)(DP) in RRMM, which did not include routine thrombosis prophylaxis, the overall rate of TEEs in the LD groups were 8 and 14% versus 4% for those treated with DP. Here we describe an unexpectedly higher incidence of TEEs among the first 21 pts enrolled in a Southwest Oncology Group (SWOG) double-blinded Phase III study (S0232) comparing LD to DP in NDMM pts. Methods: Pts received L/P 25 mg/day on days 1–28 plus D 40 mg/day on days 1–4, 9–12, 17–20 for three 35-day induction cycles, followed by L/P 25 mg/day on days 1–21 plus D 40 mg/day on days 1–4, 15–18 in repeating 28-day maintenance cycles. The incidence of TEEs for pts on LD and DP were compared using Fisher’s exact test (two-sided). Baseline clinical data were compared for pts who developed thromboses versus those who did not. Baseline labs, including hemoglobin, platelet count, PT, PTT, D-dimers, fibrinogen, vWF activity, Protein C, Protein S, activated protein C resistance, factor VIII level, and thrombin-antithrombin complexes, were also assessed. Results: Nine of 12 NDMM pts (75%) randomized to LD developed TEEs, compared to zero of 9 (0%) treated with DP (p = 0.0011). All events were lower extremity deep vein thromboses except for one ischemic stroke. Events occurred after a median of 50 days of therapy. There was no association between myeloma stage, pt age or gender, or M-protein Ig subtype and the risk of thrombosis. Although baseline fVIII and vWF levels were elevated in the majority of pts (median 169 and 164.5, respectively) neither these nor other coagulation lab findings correlated with the risk of thrombosis. In all cases except the one pt who suffered a stroke, LD was resumed after full anticoagulation was instituted. Discussion: The 75% incidence of thrombosis for the first 12 newly diagnosed pts treated with LD on S0232 was much higher than expected. No other predictive risk factors, including coagulation-related laboratory abnormalities, were identified. The incidence of thrombosis for pts with NDMM treated on a prior Phase II study of LD administered in 28-day cycles with daily ASA prophylaxis (325 mg/day) was extremely low. This experience, plus evidence that ASA (81 mg/day or 325 mg/day) reduces the risk of TEEs in pts treated with TD or T plus chemotherapy, prompted us to amend the protocol to include ASA 325 mg daily for all pts. The impact of ASA prophylaxis on the incidence of TEEs in pts enrolled subsequent to the 21 pts described here will be reported at the meeting.

Description: Background: Bone disease in myeloma occurs as a result of complex interactions between myeloma cells and the bone marrow microenvironment. To date, no studies have evaluated the potential impact of genetic polymorphisms upon and/or within this microenvironment. Patients and Methods: Peripheral blood DNA from 282 patients enrolled in the Total Therapy 2 (TT2) protocol was studied using the previously reported Affymetrix 3k BOAC custom chip to evaluate relevant genetic polymorphisms. DKK1 gene expression and high risk GEP gene signatures were assessed as previously reported (Blood109:4470–4477 and 109:2276–2284 2007). Patients were classified using both full skeletal x-rays and MRI findings. The lower cut-off used was absence of focal abnormalities on x-ray and/or

Description: Purpose: Deep vein thrombosis (DVT) is increasingly recognized as a major complication of thalidomide (T; Thal) and lenalidomide (R; Rev) based therapy for multiple myeloma. Estimated incidence varies widely in the literature. There is no consensus on specific risk factors, indications for thromboprophylaxis or the agent of choice for DVT prophylaxis. The purpose of this study was to develop a consensus among members of the IMWG. Patients and Methods: A survey was electronically mailed to 67 IMWG members on July 21, 2006 and consisted of 24 multiple-choice questions. Results: Twenty-three IMWG members (34%) sent in their responses by the cut-off date. All (100%) felt that DVT was an important question, but most (95%) did not avoid Thal/Rev based therapy because of the DVT risk. Overall results are summarized in the Table below. A majority of physicians felt that concomitant therapy with high dose dexamethasone (90% of physicians), alkylators (55%), doxorubicin/liposomal doxorubicin (90%), and erythropoietin (75%) increase the risk of DVT associated with Thal or Rev based therapy. Aspirin (81 mg or 325 mg per day) was the preferred choice of prophylaxis when necessary. However, 65% of respondents preferred warfarin to a therapeutic INR or LMW heparin if either doxorubicin or liposomal doxorubicin was added to the regimens. Most (95–100%) felt that DVT prophylaxis was not indicated for: VAD, MP, bortezomib +/− dexamethasone regimens. Seventy-five percent felt it to be safe to resume therapy with Thal/Rev after therapeutic anticoagulation. Most (95%) believed randomized trials were needed. Conclusion: DVT is recognized as a major clinical problem associated with Thal/Rev containing regimens. Most respondents felt that the DVT risk did not warrant any prophylaxis when either Thal or Rev were used as single agents. Aspirin was the preferred form of DVT prophylaxis for most Thal/Rev containing regimens, except when doxorubicin/liposomal doxorubicin or melphalan were added. Additional responses will be analyzed both electronically and by conference call prior to the meeting. Therapy Estimated incidence of DVT (% respondents) Choice of thromboprophylaxis (% respondents) Single agent thal

Description: Introduction: Between 2009 and 2015, use of novel therapies (immunomodulating drugs and proteasome inhibitors) in multiple myeloma (MM) increased. Regimens initiated during this time frame may help project near-term future treatment patterns. Connect® MM is the first and largest prospective, observational, US-based, multicenter disease registry designed to characterize treatment patterns and outcomes for patients (pts) with newly diagnosed MM (NDMM). Pts with NDMM were enrolled in 2 sequential cohorts from Sep 2009 to Apr 2016. This noninterventional registry did not prescribe or limit therapy choices. Study sites represented all census regions, with 89% and 11% split between community and academic sites, respectively. This allowed a reasonable generalizability to patterns for the US. Methods: Connect® MM enrollment was initiated in Sep 2009 at 250 community and academic sites. Pts were enrolled within 2 months of diagnosis. Cohort 1 enrolled 1493 NDMM pts from Sep 2009 to Dec 2011, and Cohort 2 enrolled 1518 NDMM pts from Dec 2012 to Apr 2016. Data were collected at a baseline visit and quarterly visits thereafter until death or discontinuation. The current analysis was conducted for the population of treated pts (N=2848) as of May 2016. This study examined recorded treatment choice of first-line regimen, maintenance therapy, and second-line regimen in 6-month intervals. Trends in regimens were graphically represented using "Tepee" plots (Srinivasan, Shankar. Resource Tepee. Patent US 7,495,673 B1. 24 Feb 2009). Briefly, all pts who initiated treatment during each 6-month interval are represented horizontally, with each horizontal line indicating 100% of all treatment used in that period. The regimens are represented by gray shading with wider bands signifying the more frequently used regimens at each time interval. Results: Median follow‐up for all pts was 39.3 months (0.03‐78.4) in Cohort 1 and 15.4 months (0.2-40.1) in Cohort 2. For the treated population, the median age was 67 years (range 24‐94), 58% were male, 83% were white, and 38% of those reporting International Staging System stage had stage III MM. By US geographical region, 329 (11.6%) pts were from the Northeast, 1036 (36.4%) from the Midwest, 1117 (39.2%) from the South, 360 (12.6%) from the West, 4 (0.1%) from Puerto Rico, and 2 missing (0.05%). Most pts (2285; 80.2%) were from community sites, and 397 (13.9%) were from academic sites with the remaining from government sites. A total of 1416 (47.4%) reported an intent to transplant (stem cell transplant [SCT]) at the initiation of therapy. A total of 666 (25.8%) have progressed and entered second line. Tepee plots of treatment patterns for start of induction for those pts with and without SCT intent are provided in Figure 1A and 1B, respectively. The year 2012 does not feature in these induction plots, as this period corresponds to a time when pts were not enrolled-Cohort 1 had been completed and Cohort 2 had not yet opened. The 4 most common induction regimens for SCT intent, from left to right, in order of decreasing frequency of use, were lenalidomide (R), bortezomib (V), dexamethasone (D) combined (RVD); VD; cyclophosphamide plus VD (CyBorD); and RD. The 5 most common induction regimens for those without SCT intent, from left to right, in order of decreasing frequency of use, were VD, RD, RVD, CyBorD, and V. Triplet therapy in first-line induction pts increased in frequency from 2009 to 2014. The 4 most frequent maintenance regimens for those with SCT intent were R monotherapy, V monotherapy, RD, and RVD. The 4 most common maintenance regimens for pts who did not intend to receive SCT were R monotherapy, RD, VD, and V monotherapy. The most prevalent regimens in the second line were VD, RD, V, and RVD. Additional graphs including treatment patterns by age group (≤ 70 vs 〉 70 years) and maintenance by conduct of first-line SCT will be presented. Conclusions: Our work utilizes Tepee plots to outline induction and maintenance treatment patterns over time, for both SCT and non-SCT intent pts, using the largest, prospective, noninterventional registry study in the US. Triplet therapy use increased in the time period studied, with RVD being the most frequently used triplet for pts with or without SCT intent. The most common maintenance regimens included R as monotherapy or in combination. Disclosures Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen/ONYX: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Gasparetto:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria. Jagannath:Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Terebelo:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Consultancy. Kitali:Celgene: Employment, Equity Ownership. Zafar:Celgene: Employment. Srinivasan:Celgene: Employment; Individual Patent: Patents & Royalties: US7,495,673B1 Used for MM-Connect Treatment Patterns Abstract.. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: Background: Treatment of multiple myeloma has evolved considerably in the past few years with availability of several news drugs as well as increasing use of multidrug combinations. These changes have no doubt led to the improved survival seen among patients with MM. We have previously shown that outcomes of patients intolerant or refractory to one of the IMiDs and bortezomib had a poor outcome. Since that time, other drugs of the same class as well as new classes of drugs have been introduced for the treatment of MM. We designed this retrospective study to estimate the outcomes in patients with relapsed myeloma, who have become refractory to the current generation IMiDs and proteasome inhibitors. Patients and Methods: Patients with relapsed multiple myeloma who have received at least 3 prior lines of therapy, is refractory to both an IMiD (lenalidomide or pomalidomide) AND a proteasome inhibitor (bortezomib or carfilzomib), and has been exposed to an alkylating agent were identified from multiple centers. The time patients met the above criteria was defined as T0, and details of all treatment regimens before and after T0 were collected using electronic CRFs. The study was approved by the IRB at the respective centers. Results: 543 patients were enrolled in this study; median age was 62 years (31-87) and 61% were males. Patients were enrolled from centers in North America (n=181), Europe (n=318), and Asia Pacific (n=44). Patients were diagnosed between 2006 and 2014, the median duration between diagnosis of myeloma and study entry (T0) was 3.1 years (0.3 to 9). The median (95% CI) estimated follow up from diagnosis and from T0 were 61 (57, 66) months and 13 (11, 15) months respectively. The median number of lines of therapy prior to T0 was 4 (3-13), 48% had a prior transplant. The median OS from T0 for the entire cohort was 13 (11, 15) months. For these 462 patients, the median number of recorded regimens was 2 (1-9). The overall response and the depth of response to each line of treatment following T0 are as shown in the table. The median (95% CI) PFS and OS from T0 was 5 (4, 6), and 15.2 (13, 17), respectively. The overall survival for the 81 patients with no treatment post T0 was only 2.1 months. In a multivariate analysis, duration from diagnosis to T0, ISS stage III and number of lines of therapy were all associated with inferior PFS, as well as OS, and in addition, serum creatinine〉2 mg/dL at T0 also predicted inferior OS. Conclusions: The study provides the expected outcome following development of myeloma that is refractory to a PI and an IMiD. The outcomes of these patients appear to be better than we had seen historically in patients refractory/ intolerant to bortezomib and IMiDs, highlighting the increased treatment options available for these patients. However, there is decreasing response rate to sequential regimens highlighting the development of drug resistance. The data provides a bench mark for comparison of new therapies that are being evaluated in this disease. Table Table. Disclosures Dimopoulos: Janssen: 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; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Hillengass:Sanofi: Research Funding; Novartis: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; LeoPharma: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Pierre Fabre: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Cavo:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Shire: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Karyopharma: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. van de Donk:Amgen: Research Funding; Janssen: Research Funding; BMS: Research Funding; Celgene: Research Funding. Mark:Onyx: Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ludwig:Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Janssen: Speakers Bureau. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Usmani:Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Dytfeld:Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Lee:Amgen: Membership on an entity's Board of Directors or advisory committees. Shustik:Janssen: 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; Millenium: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Celgene: Consultancy; Bristol Myers: Consultancy; Amgen,: Consultancy; Janssen: Consultancy. Durie:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy.

Description: Up to now no systematic analysis on the impact of different age categories on survival in patients with multiple myeloma has been reported. Information on possible correlations of host and tumor related prognostic factors with different age categories are lacking. We studied these parameters in a large cohort of patients with multiple myeloma (n=10.750) submitted by participating institutions and groups in the international staging system (ISS) project. Prognostic factors were recorded and age was calculated at start of initial chemotherapy. Patients were grouped into 6 age cohorts (

Description: Lenalidomide (Len) is an immunomodulatory drug approved for use with high-dose dexamethasone (HD) as therapy for relapsed-refractory multiple myeloma (RRMM). Preliminary data suggest Len+HD may be even more active versus newly-diagnosed myeloma (NDMM). SWOG conducted a randomized, double-blinded, placebo-controlled trial (S0232) comparing Len+HD to HD alone. Methods: Original study design: enrollment of 500 pts with NDMM (measurable disease, Cr ≤ 2.5 mg/dL, ineligible for/declining immediate autologous stem cell transplant), with interim analysis after accrual of 300 pts. The trial was closed after 198 pts were enrolled, due to external data affecting acceptability of HD as the control arm. Pts were randomized to Len 25 mg/d (28 of 35 days for 3 induction cycles, then 21 of 28 days as maintenance thereafter) plus HD (40 mg days 1–4, 9–12, 17–20 induction, then days 1–4, 15–18 maintenance) or HD (same induction and maintenance schedules) plus placebo. Therapy was unblinded for disease progression; pts on HD could crossover to Len+HD. After a high initial rate of thrombosis (TEE) was seen in pts on Len+HD, aspirin (ASA) 325 mg/d was mandated. Pts were stratified by ISS stage and SWOG performance status (PS). The primary endpoint is progression-free survival (PFS). Secondary endpoints reported here are overall response rate (ORR), major response rate (MRR), overall survival (OS), and toxicity. Results: Between Oct 2004 and Mar 2007, 100 pts were randomized to Len+HD (arm A) and 98 pts to HD plus placebo (arm B), with no differences in age (median 64.6 yrs overall), sex, race, PS, or stage distribution between arms. As of July 18, 2007, 61 pts on arm A and 72 pts on arm B were assessable for response. Estimated 1-yr PFS was 77% (arm A), vs 55% (arm B) (p=0.002). The ORR was 85.3% (≥ MR 79.4%, CR 22.1%) vs 51.3% (≥ MR 26.2%, CR 3.8%) on arms A and B, respectively (p = 0.001). OS was high in both arms (93% vs 91% at 1 yr; p=NS). Forty pts on arm B crossed over to arm A. Of these, 23 are assessable for response: ORR is 70.4% (14.8% CR). Grade 3–4 neutropenia was more frequent on arm A (13.5% vs 2.4%; p=0.010), as were infections (arm A: n=38, Gr 3–4=13, Gr 5=1; arm B: n=23, Gr 3–4=8, Gr 5=0; p= 0.003). There were 20 TEEs on arm A (14 on ASA prophylaxis) and 12 on arm B (all on ASA; 5 after crossover to Len+HD). Thus, 25 TEEs occurred during either blinded or open-label Len+HD vs 7 on HD alone (p=0.089). Discussion: In NDMM, Len+HD is superior in terms of ORR, MRR, and PFS compared to HD alone. The 1-yr OS in both arms of this study is among the highest reported. ASA at this dose may not be optimal thromboprophylaxis for pts with NDMM treated with Len+HD, although pt compliance with ASA on this study is not known. With recent evidence that dex intensity may affect TEE risk, this study was modified to include lower dose dex (40 mg q wk) with no change in TEE prophylaxis.

Description: 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.

Description: Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups:

Description: Background :Carfilzomib (CFZ) is a novel irreversible proteasome inhibitor (PI) approved for relapsed/refractory multiple myeloma, but its safety and efficacy in AL amyloidosis is not known. We report updated results of an investigator-initiated, multi-center, Phase I/II study of CFZ in AL (NCT01789242), including additional patients (pts) treated in the expansion cohort. Methods: Eligible pts (relapsed or refractory AL after ≥1 prior therapy; Mayo cardiac stage I or II; LVEF ≥40%; CrCl≥30; CFZ-naive) received CFZ over 30 minutes on days 1, 2, 8, 9, 15, 16 every 28 days, for 8 cycles, given at 20 mg/m2 on days 1, 2 of cycle 1, then at 27, 36, or 45 mg/m2 (depending on cohort) thereafter. Pre-CFZ hydration was recommended during cycle 1, but could be modified or omitted at investigator discretion. Responding pts could continue on a day 1, 2, 15, 16 schedule at investigator discretion. Dexamethasone 20mg with each CFZ dose was added if no VGPR after cycle 4. Primary objectives were safety and determination of MTD. A 3+3 dose escalation design was used, with a planned expansion cohort at MTD. Responses were based on updated AL consensus guidelines. Pts completing ≥2 cycles (or progressing before 2 cycles) were evaluable for response; all treated pts were evaluated for safety. Cardiac function was monitored in all pts by serial NT-proBNP and echocardiograms. Data cutoff was 6/23/16. Results: From June 2013 - June 2016, 28 eligible pts were enrolled and treated. Median age was 64 (range 43 - 81); 64% were male. Median time from diagnosis was 31 mos., with median of 2 prior regimens (range 1-5), including bortezomib (96%), IMiDs (43%) and stem cell transplant (46%). Thirteen (46%) were refractory to last therapy, and 10 (36%) were PI-refractory (9 bortezomib, 1 ixazomib). Involved organs included kidney (64%), heart (50%), nerve (25%), GI tract (21%), soft tissue (14%), and liver (11%); 13 pts had ≥2 major organs involved. Median baseline NT-proBNP was 542 pg/ml (range 20 - 13571), and median baseline difference in free light chains (dFLC) was 138 mg/L (range 44 - 4709). There were no DLTs at 20/27 and 20/36 mg/m2. At 20/45 mg/m2, there were 2 first-cycle DLTs of grade 3 fatigue ≥7 days, making 20/36 mg/m2 the MTD. Eighteen more pts have enrolled at MTD. Median number of cycles is 6 (range 1-25+), with 10 pts completing the planned 8 cycles (7 continuing on maintenance), 3 ongoing before cycle 8, and 15 stopping early (9 for AE's, 4 for no response, 2 other). Most common drug-related AE's to date are fatigue (36%), increased creatinine (29%), nausea (25%), dyspnea (18%), anemia (18%), diarrhea (14%), pyrexia, chills, and hypertension (11% each). Grade 3/4 AEs (all-cause) occurred in 20 (71%) pts, including several grade 3/4 cardiac or pulmonary AEs: hypoxia (n=1), lung infection (n=2), chest pain (n=1), hypotension (n=1), hypertension (n=3), decreased ejection fraction/CHF (n=3), and symptomatic ventricular tachycardia (n=2, 1 with cardiac arrest requiring defibrillation). There have been no grade 5 AEs. Of 24 response-evaluable pts, 15 (63%) have responded hematologically (3 CR, 8 VGPR, 4 PR), including 6 of 8 evaluable PI-refractory pts (1 CR, 2 VGPR, 3 PR). Responses have occurred at all dose levels (Table). Dex was added in 5 pts, with 3 response upgrades. Five (21%) pts have had organ responses (3 kidney, 1 GI, 1 liver) to date. With median follow-up of 16 mos. (range 0.5 - 32), 9 pts have had hematologic progression, and 2 have died. To date, 11 pts have had NTproBNP increases of ≥30% and ≥300 pg/ml on CFZ. For 5 this correlated with progressive clinical and/or echocardiographic signs of cardiac dysfunction; the other 6 lacked objective signs of worsening cardiac function, with either no symptoms (n=4) or progressive fatigue (n=2). Conclusions: CFZ monotherapy is feasible and effective in relapsed/refractory AL amyloidosis, with MTD identified as 20/36 mg/m2 as a 30-minute infusion. Hematologic response rates are promising in this bortezomib-exposed population, including in PI-refractory pts. Cardiac, pulmonary, and renal toxicities were common, warranting close monitoring and dose reductions as appropriate. Similar to IMiDs, NT-proBNP can increase in pts receiving CFZ, without always correlating with progressive cardiac dysfunction, potentially confounding its use as a marker of cardiac response/progression in this setting. Disclosures Cohen: Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Landau:Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx/Amgen: Research Funding; Janssen: Consultancy. Scott:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Kaufman:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Vesole:Janssen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Lentzsch:BMS: Consultancy; Celgene: Consultancy, Honoraria. Gomes:Criterium, Inc: Employment. Comenzo:Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Durie:Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy.