Yousaf, Muhammad Abdullah

Background: Carfilzomib (Car), a second-generation proteasome inhibitor (PI), has been approved by the US Food and Drug Administration (FDA) as therapy for relapsed and /or refractory multiple myeloma (RRMM), either as a single agent or in combination with other agents. It has proven to be superior in many ways compared to the the first generation PI, bortezomib, both in terms of superior efficacy and neuropathy related adverse effect profile. Carfilzomib has lower rate of peripheral neuropathy. In this review, we gathered data from trials which studied Carfilzomib for newly diagnosed MM (NDMM). Carfilzomib based two and three drug combination as induction regimens for the management of NDMM is an emerging approach. Through this systematic review, we explore efficacy, adverse effect profile of Car based regimens for NDMM. Methods: Per PRISMA guidelines, a thorough database search was conducted on 06/24/2019 using the following search engines; PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov. We included all published trials that used carfilzomib as an induction agent in NDMM patients and had at least response rates after induction. Results: The total number of articles identified with initial search were 1131, out of which 19 articles met our selection / eligibility criteria (n=2286). The overall response rates (ORR) after induction therapy with carfilzomib based regimens was very impressive (range: 84.3% - 100%). Two drug combination using carfilzomib and dexamethasone (n=72) had an ORR of 90% and a greater than very good partial response rate (>VGPR) of 84%. Three drug combinations used for induction therapy included carfilzomib/dexamethasone with immunomodulators (n=391) and alkylating agents (n=308). The combination of carfilzomib/dexamethasone with lenalidomide (n=189, ORR: 97% - 98%, >VGPR: 69% - 98%) and thalidomide (n=202, ORR: 90% - 94%, >VGPR: 66% - 68%) showed the best response. Alkylating agents used in combination with carfilzomib were melphalan (n=98, ORR: 90% - 93%, >VGPR: 58% - 70%), cyclophosphamide (n=192, ORR: 87% - 95%, >VGPR: 39% - 71%) and bendamustine (n=18, ORR; 100%, >VGPR: 89%). Four drug combinations with carfilzomib used were daratumumab/lenalidomide/dexamethasone (n=22, ORR: 100%, >VGPR: 90%, 12m PFS: 95%) and cyclophosphamide / thalidomide / dexamethasone (n=64, ORR; 91%, >VGPR: 69%, 24m PFS: 76%). One trial directly compared carfilzomib/melphalan/dexamethasone (n=478, ORR: 84%, >VGPR: 61%, PFS: 22.3m) with bortezomib/melphalan/dexamethasone (n=477, ORR: 79%, >VGPR: 49%, PFS: 22.1m). Another trial compared the combination of carfilzomib / dexamethasone with lenalidomide (n=315) or cyclophosphamide (n=159) that showed similar ORR (97% vs 91%) though >VGPR rate was better with lenalidomide (75% vs 60%). Efficacy data including progression free survival (PFS) for carfilzomib based regimens is reported in table 1. Most common >grade 3 hematological adverse effects reported were anemia (2% - 35%), lymphopenia (5% - 76%), thrombocytopenia (4% - 28%) and neutropenia (1% - 38%). Most Common >grade 3 non-hematological adverse events included cardiac events (5% - 10%), respiratory disorders (8% - 16%), infections (2% - 9%), hypertension (6% - 17%), renal events (9% - 10%) and hyperglycemia (6% - 23%). (Table 1) Conclusion: The overall efficacy and favorable adverse effect profile of Carfilzomib-based induction regimens seem very promising for the treatment of NDMM. Car is now approved for weekly dosing which is convenient. Due to cardiovascular toxicity seen in upto 10% cases, Car should be used very judiciously in patients with cardiovascular risk factors and heart failure. Several ongoing phase 3 clinical trials are studying Carfilzomib in various combinations will help to establish foundation for future standard therapy as well as next phase of drug development through clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction Amyloidosis is a rare disease and there are currently no FDA approved therapies for AL amyloidosis. Most of the therapeutic and disease data come from expert guidelines, consensus and retrospective review papers. There is a paucity of data specifically for relapsed/refractory AL amyloidosis (RRAL). We conducted this systematic review of clinical trials, retrospective and prospective cohort studies to evaluate patterns of relapse and therapeutic options for RRAL. Methods PubMed and Clinicaltrials.gov were searched for clinical trials, retrospective and prospective cohort studies on RRAL. Studies were selected according to PRISMA guidelines. Cross-trial comparison of included studies and meta-analysis could not be performed for a number of reasons but mainly due to a limited number of studies on one particular treatment regimen. Results From a total of 511 studies, 11 studies (n= 698 patients) met our inclusion criteria. Five were phase I/II clinical trials, five retrospective cohort studies, and one prospective cohort study. Most studies had less than 50 patients. The largest study, a retrospective cohort by Tandon et al. included 366 patients. Mean age was 61.2. Three studies reported 2 median prior lines of therapy (n= 22, 28, and 84 patients); two reported 3 median prior lines of therapy (n= 25 and 24) and 6 studies didn't specify this data. Prior treatment options included proteasome inhibitors (PI), most commonly bortezomib (n= 259), followed by melphalan (n=211), high dose melphalan and stem cell transplant (HDM/SCT [n= 207]) and IMiDs most commonly lenalidomide (n=154). Time to progression (TTP) from first-line treatment was reported in only 4 studies as 1 month, 5 months, 5 months and 34 months respectively. The study reporting a TTP of 34-months had 11 patients who received HDM/SCT as first line treatment. Three studies reported information about their criteria for initiation of subsequent treatment. Subsequent treatment was mostly a combination regimen with dexamethasone or an alkylating agent. The only agent evaluated as single agent was bortezomib in a phase I/II clinical trial by Reece et al. Therapeutic options for RRAL are PI (non-specific) based therapy (n= 145), lenalidomide (n= 105), bortezomib (n= 99), IMiD (non-specific) based therapy (n=83), melphalan based therapy (n= 33), carfilzomib (n=28), pomalidomide (n=27), ASCT (n= 25), daratumumab (n=25) and bendamustine (n=22). Efficacy: Hematologic responses were reported to be following: bortezomib + dexamethasone/melphalan (85%, n=17/20), daratumumab + dexamethasone (76%, n= 19/25), HDM/ASCT (73%, n= 8/11), single agent bortezomib (67%, n=23/34), carfilzomib ± dexamethasone (63%, n= 15/24), lenalidomide + dexamethasone (61%, n=51/84), bendamustine + dexamethasone (55%, 11/22) and pomalidomide + dexamethasone (50%, 12/24). Five of eleven studies reported organ responses which ranged from 18% to 23%. The studies which reported organ responses had evaluated the following agents: single agent bortezomib, carfilzomib ± dexamethasone, lenalidomide + dexamethasone, and bendamustine + dexamethasone. Best survival outcomes were seen with bortezomib with median overall survival (OS) 62 months. With bendamustine and dexamethasone (retrospective cohort study n=22) median OS was 31 months. With lenalidomide + dexamethasone (prospective cohort study n=24 ) median OS was 14 months. For the remaining studies, the median OS was either not reported or not reached at the time of presentation of data. Conclusion AL amyloidosis patients progressing after front line therapy show good responses with bortezomib (median overall survival of 62 months). Novel combinations using lenalidomide, pomalidomide, carfilzomib, daratumumab, and bendamustine show promising efficacy. Ongoing trials of daratumumab (AMYDARA trial) and ixazomib (TOURAMALINE-AL1) will bring further insight into therapeutic armamentarium for RRAL patients. After relapse, a salvage HDM/ASCT can be considered. Comparisons of regimen efficacy between studies are not practical because of multiple factors which include but are not limited to heterogenous nature of AL patients, small sample sizes, variable prior treatments, exposure to novel agents, observational study versus clinical trial and variable endpoints. Table Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau.