Survival Following Quadruplet and Triple Therapy in Transplant in-Eligible Multiple Myeloma - a Meta-Analysis of Recent Clinical Trials
Authors: Atodaria Kuldeepsinh , Sripathi Keerthi , Varma Samyukta , Parvataneni Tarun , Biswas Navanita , Yarlagadda Bhavya Raja Gopal , Panchal Megha , Pilathodan Hashwin , Arunachalam Janani , Rawal Shalin , Sandhu Jujhar , Patel Urvish 
Published: December 2024

INTRODUCTION
In the management of transplant-ineligible multiple myeloma (TIMM), therapeutic strategies are crucial for improving patient outcomes. Recent clinical trials have explored the efficacy of Quadruplet therapy and Triplet therapy in this context. Quadruplet therapy, involving an additional drug, has been proposed to offer enhanced benefits in overall survival and progression-free survival.
AIM
This meta-analysis aimed to evaluate the comparative effectiveness (overall survival [OS] and progression-free survival [PFS]) of Quadruplet vs Triplet therapy in TIMM regimens to inform clinical decision-making and optimize patient care.
METHODS
Type of Study: Meta-analysis of Phase 3 clinical trials
Endpoint: Evaluate OS and PFS in Quadruplet vs Triplet therapy
Search strategy: PRISMA protocol using keywords ((“multiple myeloma”[Title/Abstract] AND (“quadruple therapy”[Title/Abstract] OR “triple therapy”[Title/Abstract] OR (“bortezomib-lenalidomide-dexamethasone”[All Fields] AND “VRd”[Title/Abstract]) OR (“lenalidomide-dexamethasone”[All Fields] AND “Rd”[Title/Abstract]) OR (“bortezomib-melphalan-prednisone”[All Fields] AND “VMP”[Title/Abstract]) OR (“CD38-targeted”[All Fields] AND “antibody”[Title/Abstract]))) NOT “Transplant-eligible”[All Fields]) AND ((y_10[Filter]) AND (clinicaltrial[Filter] OR clinicaltrialphasei[Filter] OR clinicaltrialphaseii[Filter] OR clinicaltrialphaseiii[Filter] OR clinicaltrialphaseiv[Filter] OR multicenterstudy[Filter] OR observationalstudy[Filter] OR randomizedcontrolledtrial[Filter]) AND (fft[Filter]) AND (humans[Filter]) AND (english[Filter])) to identify clinical trials from last 10 years. Inclusion criteria: Only Clinical trials recruited TIMM patients in the last 10 yearsExclusion criteria: Studies other than clinical trials, non-human, non-English, and non-full text studies were excluded.
Study selection & Data extraction: Using eligibility criteria and keywords, we screened the abstracts and evaluated them for their inclusion in our meta-analysis. From screen abstracts, full-length articles were obtained and studied individually for their eligibility in quantitative analysis (meta-analysis). Data on study name, design, country, duration, sample size, population characteristics [country, mean/median age, sex], type of intervention, and outcomes (OS and PFS) were collected.
Statistical analysis: Review Manager 5.3 software was used to analyze the data. We performed random effects models to estimate the pooled effect size (pooled odds ratio) and 95% confidence interval (95% CI). Forest plots were obtained. p&lt;0.05 was considered statistically significant. Heterogeneity (I2 values) was identified and I2&gt;75% represented high heterogeneity. Risk of bias analysis was performed using the Newcastle-Ottawa Scale.
RESULTS
Out of 51 studies, fulfilling the criteria, nine studies had data on the management of TIMM, of which five studies had data on outcomes of Quadruplet vs Triplet therapy. ALCYONE, IMROZ, and OCTANS were the main multicenter, randomized, and open-label clinical trials covering 160+ sites in 25+ countries. We found 607 patients (of 1196) on Quadruplet and 368 patients (of 1142) on Triplet therapy. Quadruplet therapy had 88% higher odds of OS [OR: 1.88, 95%CI: 1.51-2.35, p&lt;0.00001, I2: 0%] and 178% higher odds of PFS [2.78, 0.83-9.33, p=0.1, I2: 92%] in compared to Triplet therapy. [Pooled OR for survival: 2.30, 1.36-3.87, p=0.002, I2: 0%]. Quadruplet therapy had higher odds of MRD negative [4.04, 2.32-7.03, p&lt;0.00001, I2: 52%] and RR [2.25, 1.66-3.05, p&lt;0.00001, I2: 0%] in compared to Triplet therapy. NOS suggested a moderate risk of bias.
CONCLUSION
In conclusion, our meta-analysis demonstrates that Quadruplet therapy significantly outperforms Triplet therapy in transplant-ineligible multiple myeloma patients, with notable improvements in overall survival and progression-free survival. The Quadruplet regimen also enhances the likelihood of achieving minimal residual disease negativity and a higher response rate. These findings underscore the potential benefits of integrating an additional drug into treatment regimens for better clinical outcomes.