Impact of Newer Agents on Progression Free Survival of Multiple Myeloma in the 2nd 3rd and 4th Line Setting- a Systematic Review
Authors: Sardar Muhammad , Jose Jemin Aby , Shah Zunairah , Sohail Chaudhry Saad , Selene Insija Ilyas , Shafqat Madeeha , Qureshi Anum , Naseer Raza , Khan Ali Younas , Malik Saad Ullah , Anwer Faiz 
Published: October 2019

Abstract
Background: Multiple Myeloma (MM) remains incurable. Majority of the patients ultimately relapse with a lower median event free survival after each successive line of therapy. For newly diagnosed MM patients, the median progression free survival (PFS) has improved drastically with the advent of novel agents. Aim of our review is to discuss median PFSnwith novel agents in the 2nd 3rd and 4th line of treatment in MM.
Methods: A comprehensive literature search was done in accordance with the PRISMA guidelines from Jan 1st 2010 to May 30th 2018 using the following 4 databases: PubMed/ Medline, Elsevier/Embase, Wiley/Cochrane and clinicaltrials.gov. Inclusion criteria consisted of all prospective clinical trials that a) included patients with 1-3 prior lines of therapies b) received novel therapeutic agents as an intervention c) outcome was reported as median PFS. We excluded case series, retrospective/observational studies, systematic reviews/meta-analysis. We identified 4777 records through initial database search. After removing duplicates and further screening, 59 full-text articles were assessed for eligibility. 50 articles were subsequently excluded with reason and 9 articles constituting 4937 patients were selected for data extraction and final analysis.
Result In a randomized clinical trial (RCT) by Dimopolous et al (2017), 396 patients (median age: 64) in the carfilzomib, lenalidomide and dexamethasone (KRD) arm had median PFS of 26.3 m. In comparison, 396 patients in the control group (median age: 65) that received RD regimen had a median PFS of 17.6 m. Percentage of patients with prior bone marrow transplant (BMT) and high-risk (HR) cytogenetics was 54.8% and 12.1% respectively in the KRD regimen and 57.8% and 13.1% respectively in the RD regimen. The median prior number of therapies was 2 in each group. In the trial by Avet-Loiseau et al 2017, patients in the Ixazomib-RD arm (n=360; HR cytogenetics=21%) had a median PFS of 20.6m as compared to 14.7 m in the control group (RD) arm (n=362; HR cytogenetics=17%). Median prior number of therapies was 2 in each group and 59% and 57% of the patients had prior BMT respectively. Lonial et al (2015) showed that the group (n=321; median age 67) that received elotuzumab-RD regimen had median PFS of 19.4m compared to 14.5m in the control group (n=325; median age 66) that received RD regimen. Prior median therapies were 2 in each arm and BMT was done in 52% and 57% of the patients respectively. A RCT of two drug regimen by Chang et al (2017) showed that patients (n= 464) who received KD had a higher median PFS (18.7m) as compared to patients (n= 465) who received bortezomib(V)-D (9.4 m). KD arm had 37.2% patients with prior BMT as compared to 49.6% in the VD arm whereas the median prior number of therapies was 2 in each arm. HR cytogenetics were present in 21% and 24% respectively. In the trial by Orlowski et al (2015), there was no improvement in the median PFS with the addition of Siltuximab to V as compared to V alone. Similarly, no significant improvement in median PFS was noted by Dimopolus et al (2017) in the combination regimen of Vorinostat-V as compared to placebo-V. In the trial by white et al (2017), the median PFS was 6.2 with bevacizumab-V as compared to 5.1m with placebo-V. In a trial by Richardson et al (2016), Panobinostat-VD had a median PFS of 11.99 which was higher than 8.08 with placebo-VD.
Conclusion: Regimen consisting of KRD has the highest median PFS in MM patients with multiple prior lines of therapy followed by IRD based regimen. Limitations of our analysis include a heterogeneous patient population and exclusion of data with daratumumab based regimen because of unavailability of median PFS specifically in the 2nd 3rd and 4th line setting in the published clinical trials.

Disclosures
No relevant conflicts of interest to declare.