Carfilzomib Based Regimens for Treatment of Newly Diagnosed Multiple Myeloma: A Systematic Review
Authors: Khan Maimoona , Waheed Asma , Jannat Rida Ul , Farooqui Arafat Ali Ali , Farooqi Muhammad Saad , Khan Ali Younas , Shafqat Madeeha , Ahmad Muhaddis Ejaz , Yousaf Muhammad Abdullah , Syed Tariq Iqtidar Sadiq , Abdullah Syed Maaz , Kotapati Sravanthi , Riaz Irbaz , Anwer Faiz 
Published: November 2019

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.