Characteristics of the included studies
Finally, 58 articles were included in the study (Supplementary Figure S1), with 68 trials and a total sample size of 3124. Eleven types of treatment strategies are involved, including monotherapy (chemotherapy, targeted therapy, and immunotherapy) and combination therapy (chemotherapy + immunotherapy, chemotherapy + ASCT, targeted therapy + targeted therapy, immunotherapy + immunotherapy, targeted therapy + immunotherapy, chemotherapy + targeted therapy + immunotherapy, chemotherapy + immunotherapy + immunotherapy, and chemotherapy + immunotherapy + ASCT). A total of 63 specific treatment regimens were used in this study. The number of studies, number of trials, and sample size for each treatment regimen and the reported percentages of the three efficacy indicators of OS, PFS, and ORR for each treatment regimen are shown in Supplementary Figure S2. The median age of the included studies was 66 years, the median male percentage was 61%, and the median number of treatments received since diagnosis was 2.3 times. Details of the included trials are provided in Supplementary Table S1.
Model establishment and evaluation
The results show that the lognormal model can better describe the characteristics of PFS and OS data than the other three hazard functions; the OFV is the smallest, and the relative standard error (RSE) % of the model parameters is also smaller. Therefore, a lognormal hazard model was selected to fit the OS and PFS data.
The model parameters are presented in Table 1. The results showed that the RSE% of the final model parameters of OS and PFS were both within 30%, indicating that the estimated values of the model parameters were relatively stable. The 1,000-time bootstrap-replaceable repeated sampling method successfully converged 997 times and 962 times, respectively, with 95% CIs that are extremely close to the parameter estimates of the final models of OS and PFS, indicating that the final models are robust and relatively less affected by individual study data (Table 1). The goodness-of-fit plots and individual fit plots of the final model showed that the model fits the measured data well (Supplementary Figure S3) and no systematic bias was observed. The VPC chart of the final model shows that the measured data generally fell within the 95% CI predicted by the model, indicating that the model had good predictability (Figure 1).
The results of the covariate analysis showed that patients who received monotherapy or combination therapy had a significant impact on OS. Combination therapy was associated with a 1.67-fold reduction in the 1-year risk of death for OS compared to monotherapy. Furthermore, combination therapy and chemotherapy had a significant impact on PFS. The 1-year PFS risk of combination therapy was 2.56 times lower than that of monotherapy, and the 1-year PFS risk of patients who received chemotherapy was 2.34 times lower than that of patients who did not receive chemotherapy.
Typical value of OS
Based on the final model, the effects of monotherapy or combination therapy on OS were simulated. The results showed that the typical median OS rates were 8.8 (95% CI, 6.9, 11.4) months and 14 (95% CI, 10.6, 19.6) months for monotherapy and combination therapy, respectively (Figure 2A). The 1-year OS for monotherapy and combination therapy were 38.5% (95% CI, 29.9%, 47.9%) and 57.2% (95% CI, 44.9%, 65.9%), respectively.
The typical OS curves for each type of treatment strategy are shown in Figure 3A. Among them, chemotherapy + immunotherapy + ASCT, immunotherapy + immunotherapy, chemotherapy + ASCT, chemotherapy + immunotherapy and chemotherapy + immunotherapy + immunotherapy have better efficacy, and the median OS were 28.5, 16.5, 15.5, 14 and 13.9 months, respectively (Figure 4).
Specific to each treatment regimen, R-inotuzumab ozogamicin, R-BEAM+ASCT, R-ESHAP-L, iodine-131 tositumomab + BEAM + ASCT, and chemotherapy + CAR-T had the best efficacy on OS, and the median OS was > 2 years, and 1-year OS rate was > 80% (Figure 5).
Moreover, we summarized the median OS of the different targets of targeted therapy and immunotherapy, and the results are shown in Supplementary Figure S5.
Typical value of PFS
Based on the final model, PFS can be simulated in four scenarios depending on whether patients received combination therapy and whether patients received chemotherapy. Since there were only two studies on chemotherapy used alone, it simulates only three scenarios: monotherapy without chemotherapy, combination therapy and chemotherapy, and combination therapy without chemotherapy. The results (Figure 2B) showed that the median PFS were 2.7 (95% CI, 2.3, 3.3) months, 7.3 (95% CI, 4.4, 12.4) months and 5.0 (95% CI, 3.3, 7.7) months for monotherapy without chemotherapy, combination therapy and chemotherapy, and combination therapy without chemotherapy, respectively. The 1-year PFS were 3.4% (95% CI, 1.64%, 6%) months, 35.6% (95% CI, 22.3%, 51.8%) months, and 21.5% (95% CI, 11.7%, 34.5%) months for monotherapy without chemotherapy, combination therapy and chemotherapy, and combination therapy without chemotherapy, respectively.
The typical PFS curves for each treatment strategy are shown in Figure 3B. Among them, chemotherapy + immunotherapy + ASCT, chemotherapy + immunotherapy + immunotherapy, immunotherapy + immunotherapy, chemotherapy + ASCT, and chemotherapy + immunotherapy have better efficacy, with median PFS of 23, 9, 6.5, 5.9 and 4.9 months, respectively (Figure 4).
Specific to each treatment regimen, yttrium-90 ibritumomab tiuxetan + BEAM + ASCT, R-ESHAP-lenalidomide, R-BEAM + ASCT, iodine-131 tositumomab + BEAM + ASCT, and tafasitamab + lenalidomide had the best efficacy, and the median PFS was > 10 months (Figure 5).
Furthermore, we summarized the median PFS rates for different targets of targeted therapy and immunotherapy, and the results are shown in Supplementary Figure S5.
ORR
The ORR of combination therapy was significantly higher than that of monotherapy, which were 49% (95% CI, 41%, 58%) and 23% (95% CI, 17%, 29%), respectively (Supplementary Figure S4). The efficacy of different types of treatment strategies can be roughly divided into three categories, among which chemotherapy + immunotherapy + ASCT, chemotherapy + ASCT, and chemotherapy + immunotherapy + immunotherapy have higher ORR, which was > 70%; chemotherapy + immunotherapy, chemotherapy used alone, chemotherapy + immunotherapy + targeted therapy, and immunotherapy + immunotherapy have moderate ORR, which range from 41% to 58%; immunotherapy used alone, targeted therapy + targeted therapy, targeted therapy + immunotherapy, and targeted therapy used alone have lower ORR, which range from 15% to 20%. These results suggest that chemotherapy is involved in two categories with better efficacy, indicating that the ORR is higher in regimens with chemotherapy than in those without chemotherapy.
Specific to novel treatment options, such as CAR-T cell therapy, HDC+ASCT, R+ADC, CD3/CD19-targeting bispecific antibodies, and ADCs, the ORR were 82% (95% CI, 75%, 89%), 70% (95% CI, 60%, 79%), 48% (95% CI, 32%, 67%), 43% (95% CI, 22%, 64%), and 33% (95% CI, 19%, 46%), respectively.
Moreover, we summarized the ORR of different targets of targeted therapy and immunotherapy, and the results are shown in Supplementary Figure S5.
Grade 3–5 adverse events
A total of 25 trials reported the incidence of grade 3–5 adverse events, and the results showed that the incidence of grade 3–5 neutropenia, leukopenia, and thrombocytopenia was higher in chemotherapy used alone, chemotherapy + immunotherapy, chemotherapy + immunotherapy + immunotherapy, and chemotherapy + targeted therapy + immunotherapy and the incidence rate was > 30%. (Figure 4).
Correlation between ORR, PFS, and OS
The correlations between the ORR, PFS, and OS are shown in Figure 6. The results showed that 6-month PFS was moderately correlated with 2-year OS (R2 = 0.746), and the equations were as follows: y = 0.8005x + 0.0192; that is, for every 10% increase in 6-month PFS, 2-year OS would increase by 8.0%. Subgroup analysis showed a strong correlation between the 6-month PFS and 2-year OS with combination therapy (R2 = 0.948).
Moderate correlations were found between 1-year PFS and 2-year OS (R2 = 0.743) and between ORR and 2-year OS (R2 = 0.754). Moreover, weaker associations were found between ORR and 6-month PFS (R2 = 0.684) and between ORR and 1-year PFS (R2 = 0.623).