Maintenance Therapy in Newly Diagnosed and Transplant Ineligible Multiple Myeloma Patients: A Meta-Analysis

Introduction:

Multiple myeloma (MM) is an incurable plasma cell disorder with more than two-thirds of the newly diagnosed multiple myeloma (NDMM) patients being ≥65 years of age. Recent advancements in the treatment of MM with novel agents and autologous stem cell transplantation (ASCT) have significantly improved survival in those patients. However, the management of NDMM in many elderly patients remains a challenge due to frailty, multiple comorbidities, and their ineligibility for ASCT. Our aim in this study is to review and analyze the safety and efficacy of different maintenance regimes for NDMM patients who are ineligible for ASCT.

Methods:

A comprehensive literature search was done on four databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). A search was performed without the use of filters and using MeSH terms for multiple myeloma and maintenance therapy (MT). Studies involving transplant-ineligible NDMM patients which reported overall response rate (ORR), complete response (CR), very good partial response (VGPR), or partial response (PR) along with adverse effects were included. A pooled analysis of the extracted data was performed using the “meta” package by Schwarzer et al. in the R programming language (version 4.0.2). The event rates were pooled using the inverse variance method and logit transformation. The between-studies variance was calculated using the DerSimonian-Laird estimator. The random-effects model was used for the analysis.

Results:

Lenalidomide based MT: Four studies involving 950 transplant-ineligible NDMM patients were included. All patients received lenalidomide (R) based MT following induction therapy. A pooled analysis of these studies showed ORR of 88% (95% confidence interval (CI): 81%-93%, p < 0.01) with 67% of the patients showing ≥VGPR (95% CI: 48%-82%, p <0.01) (Figure 1 A). The most common ≥ grade 3 hematological adverse effects (AE) included neutropenia, anemia, and thrombocytopenia while most common ≥ grade 3 non-hematological AE were infections, diarrhea, and fatigue (Table 1).

Bortezomib based MT: Five clinical trials involving 1171 NDMM patients who received bortezomib (V) based MT were included and evaluated in our study (Figure 1 B). Pooled analysis showed ORR of 84% (95% CI: 74%-91%, p <0.01) with 32% patients showing CR (95% CI: 25%-41%, p <0.01). The most common ≥ grade 3 hematological and non-hematological AE’s are reported in table 1.

Ixazomib based MT: A total of 202 transplant-ineligible NDMM patients were evaluated for a response after receiving ixazomib (I) based MT in 5 clinical trials (Figure 1 C). A pooled analysis of these trials showed an ORR of 86% (95% CI: 69%-94%, p: <0.01) with 60% patients having ≥ VGPR (95% CI: 40%-76%, p <0.01 ). The most common ≥ grade 3 hematological AE included anemia (9%), neutropenia (15%), and thrombocytopenia (3%). (Table 1)

Conclusion: V, R and I based MT has shown promising efficacy with an acceptable safety profile in transplant-ineligible NDMM patients. R based MT has shown superior ORR compared to V or I based MT. However, data from more clinical trials are needed.