Rationale:

1. Strength and Reliability of Data:

• The meta-analysis includes data from four studies, three of which are randomized controlled trials (RCTs), providing a high level of evidence. The inclusion of a large sample size (3,327 patients) enhances the reliability of the findings.
• The systematic review and meta-analysis were conducted following Cochrane Collaboration and PRISMA guidelines, ensuring methodological rigor.
• The statistical significance of the results is strong, with pooled hazard ratios indicating a substantial improvement in both overall survival (OS) and progression-free survival (PFS) with daratumumab-based regimens.

2. Comparison to Current Standard-of-Care:

• The current standard induction therapy for TE-NDMM patients typically involves triplet regimens. The addition of daratumumab to these regimens (forming quadruplet regimens) has shown significant improvements in survival outcomes.
• The pooled hazard ratios for OS (0.60) and PFS (0.49) suggest a meaningful clinical benefit over existing triplet regimens, indicating a potential shift in the standard of care.

3. Clinical Relevance and Feasibility:

• The findings are clinically relevant as they provide evidence supporting the use of daratumumab-based quadruplet regimens as a superior first-line treatment option for TE-NDMM patients.
• The feasibility of incorporating daratumumab into existing regimens is supported by previous studies demonstrating its safety and efficacy in combination with other agents.

Given the robust evidence from multiple RCTs, the significant improvement in survival outcomes, and the feasibility of integrating daratumumab into current treatment protocols, these findings are strong enough to warrant a change in clinical practice for the treatment of transplant-eligible newly diagnosed multiple myeloma patients.

• The CEPHEUS study is a multicenter, open-label, randomized, phase 3 trial, which provides a high level of evidence due to its robust design.
• The sample size is substantial, with 395 patients randomized, ensuring adequate power to detect differences between the treatment groups.
• The statistical significance of the findings is strong, with P-values <0.0001 for MRD-negativity rates and sustained MRD negativity, indicating a high level of confidence in the results.

• The study compares D-VRd (Daratumumab with VRd) to the current standard VRd regimen in transplant-ineligible or deferred patients with newly diagnosed multiple myeloma (NDMM).
• D-VRd demonstrated superior outcomes in terms of MRD-negativity rates and progression-free survival (PFS), with a hazard ratio of 0.57 for PFS, indicating a 43% reduction in the risk of progression or death compared to VRd.
• The improvement in MRD-negativity rates at both 10^–5 and 10^–6 thresholds suggests a deeper and more durable response, which is associated with better long-term outcomes.

• The findings are clinically relevant as they provide evidence for a new standard of care in a specific patient population (transplant-ineligible or deferred NDMM patients).
• The use of Daratumumab in combination with VRd is feasible in clinical practice, given its established use and manageable safety profile.
• The significant improvement in PFS and MRD-negativity rates supports the immediate incorporation of D-VRd into clinical practice for the specified patient group.

• The study is a phase III randomized trial, which is a robust design for evaluating the efficacy of new treatments.
• The sample size is substantial, with 1056 patients undergoing induction randomization, providing a strong basis for statistical analysis.
• The study reports a significant improvement in progression-free survival (PFS) with a hazard ratio (HR) of 0.69 (95% CI 0.60, 0.80, p<0.001) for the KRdc group compared to the triplet therapies, indicating a strong effect size.
• The overall survival (OS) analysis, although initially underpowered due to early trial closure, was adjusted for temporal changes and still showed a significant improvement (HR 0.80, 95% CI 0.67, 0.95, p=0.011).

• The current standard-of-care for newly diagnosed multiple myeloma (NDMM) often involves triplet regimens. The addition of carfilzomib to a triplet regimen (KRdc) represents an intensified induction approach.
• The study demonstrates that KRdc not only improves PFS but also shows a significant OS benefit when adjusted for temporal trends, which is a critical endpoint in oncology.
• The achievement of minimal residual disease (MRD) negativity was higher in the KRdc group, which is increasingly recognized as an important prognostic marker in multiple myeloma.

• The findings are clinically relevant as they suggest a new standard for induction therapy in NDMM, particularly for patients with high-risk cytogenetic profiles.
• The regimen is feasible in clinical practice, as carfilzomib is already an approved drug for multiple myeloma, and the combination with lenalidomide, dexamethasone, and cyclophosphamide is manageable in terms of administration and toxicity.
• The study emphasizes the importance of early and aggressive treatment, which could lead to changes in treatment guidelines, especially for high-risk patients.

• The DREAMM-7 trial is a global, randomized, open-label, phase 3 study, which provides a high level of evidence due to its robust design.
• The study included a substantial sample size of 494 patients, ensuring adequate power to detect differences between the treatment arms.
• The primary endpoint of progression-free survival (PFS) was met with a highly statistically significant hazard ratio (HR) of 0.41 (95% CI, 0.31-0.53; P<.00001), indicating a strong treatment effect favoring the belantamab mafodotin, bortezomib, and dexamethasone (BVd) regimen over the daratumumab, bortezomib, and dexamethasone (DVd) regimen.

• The BVd regimen demonstrated a median PFS of 36.6 months compared to 13.4 months with DVd, which is a substantial improvement over the current standard-of-care.
• BVd also showed higher rates of complete response or better plus minimal residual disease (MRD) negativity (25% vs 10%) and a more favorable duration of response (DOR) than DVd.
• The observed trend towards improved overall survival (OS) with BVd, with an HR of 0.57 (95% CI, 0.40-0.80), further supports its potential superiority.

• The findings suggest that BVd could become a new standard of care for patients with relapsed/refractory multiple myeloma (MM) after at least one prior line of therapy, given its significant efficacy benefits.
• The study's results are clinically meaningful, showing not only improved PFS but also a trend towards better OS, which is crucial for patient outcomes.
• The anticipated presentation of updated OS data at ASH 2024 is expected to further solidify the practice-changing potential of the BVd regimen.

• The study is a phase 3 randomized controlled trial (RCT), which is the gold standard for clinical research, providing high-quality evidence.
• A substantial sample size of 390 patients was randomized, ensuring adequate power to detect differences between the treatment and control groups.
• The statistical significance of the primary endpoint, progression-free survival (PFS), was robust (HR, 0.49; 95% CI, 0.36-0.67; P < 0.0001), indicating a strong effect of daratumumab (DARA) in delaying progression to multiple myeloma (MM).
• Secondary endpoints, such as overall response rate (ORR) and time to first-line MM treatment, also showed significant improvements with DARA, further supporting the primary findings.

• Currently, high-risk smoldering multiple myeloma (SMM) is managed with active monitoring, with no approved treatments to delay progression to MM.
• The study demonstrates that DARA monotherapy significantly prolongs PFS compared to active monitoring, with a median PFS not reached in the DARA group versus 41.5 months in the control group.
• The ORR was markedly higher in the DARA group (63.4% vs. 2.0%), indicating a substantial therapeutic benefit.
• These results suggest a paradigm shift in the management of high-risk SMM, providing a proactive treatment option that could alter the disease course.

• DARA is already approved for use in other stages of MM, suggesting that its safety profile is well understood and manageable.
• The treatment regimen (subcutaneous administration) is feasible and aligns with existing clinical practices for MM, facilitating integration into current healthcare settings.
• The low incidence of grade 3/4 treatment-emergent adverse events (TEAEs) and treatment discontinuations due to adverse events supports the tolerability of DARA in this patient population.

• The IFM2017-03 trial is a phase 3, prospective, randomized, open-label study, which is a robust design for evaluating the efficacy and safety of new treatment regimens.
• The sample size of 295 patients is adequate, and the study includes a well-defined frail elderly population with NDMM, which is often underrepresented in clinical trials.
• The primary endpoint, progression-free survival (PFS), showed a statistically significant improvement with a hazard ratio (HR) of 0.51 and a p-value of <0.0001, indicating a strong reduction in the risk of progression or death with the DR regimen compared to Rd.
• Secondary endpoints, including overall survival (OS) and overall response rate, also demonstrated significant benefits for the DR arm, with a HR for OS of 0.46 and a p-value of 0.0001.

• The current standard-of-care for elderly frail patients with NDMM often includes lenalidomide and dexamethasone (Rd). However, long-term dexamethasone use is associated with significant side effects, particularly in frail patients.
• The DR regimen, which reduces dexamethasone exposure, not only improves PFS and OS but also maintains a favorable safety profile, addressing a critical need for safer treatment options in this population.
• The study demonstrates that the DR regimen provides superior outcomes compared to the standard Rd regimen, with a significant reduction in the risk of progression or death and improved health-related quality of life (HRQoL).

• The findings are highly relevant for clinical practice, particularly for the management of frail elderly patients with NDMM, who are at higher risk of adverse events and treatment discontinuation.
• The DR regimen is feasible for implementation in clinical settings, as it involves the use of daratumumab, which is already an approved agent for multiple myeloma, and lenalidomide, a standard treatment.
• The improved HRQoL and reduced dexamethasone-related side effects make the DR regimen an attractive option for this vulnerable patient population.

• The study is a randomized, phase 3 trial (CARTITUDE-4), which is a robust design for evaluating clinical interventions.
• The sample size is substantial, with 419 patients randomized, providing a strong basis for statistical analysis.
• The results show statistically significant improvements in both progression-free survival (PFS) and overall survival (OS) with cilta-cel compared to standard of care (SoC), with hazard ratios of 0.26 for PFS and 0.55 for OS, both with highly significant p-values (<0.0001 and 0.0009, respectively).

• Cilta-cel demonstrated a significant improvement in MRD-negativity rates compared to SoC, with a more than threefold increase in MRD-negativity rates at both the 10^-5 and 10^-6 thresholds.
• The achievement of MRD-negative complete response (≥CR) at 12 months was significantly higher in the cilta-cel arm (44% vs 8% in the SoC arm), which is a strong prognostic marker for prolonged survival.
• The sustained MRD-negativity rates were also significantly higher with cilta-cel, indicating a durable response.

• The findings are clinically relevant as they demonstrate that cilta-cel can achieve deeper and more sustained responses in patients with lenalidomide-refractory multiple myeloma, a population with limited treatment options.
• The treatment regimen, involving a single infusion of cilta-cel after apheresis and lymphodepletion, is feasible and represents a significant advancement over existing therapies.
• The improvement in both PFS and OS, along with the high rates of MRD negativity, suggests that cilta-cel could become a new standard of care for this patient population.

• The study is a phase 3 randomized controlled trial (RCT), which is the gold standard for clinical research, providing high-quality evidence.
• The sample size is robust, with 355 patients in the D-VRd-DR group and 354 in the VRd-R group, enhancing the reliability of the findings.
• The statistical significance of the primary endpoint, progression-free survival (PFS), is strong, with a hazard ratio of 0.42 and a p-value of <0.001, indicating a substantial reduction in the risk of progression or death with the addition of daratumumab.
• The median follow-up of 47.5 months is adequate to assess long-term outcomes and durability of response.

• The current standard-of-care for transplantation-eligible newly diagnosed multiple myeloma (NDMM) often includes the VRd regimen. The addition of daratumumab (D) to this regimen (D-VRd-DR) shows a significant improvement in PFS, with a 48-month PFS of 84.3% compared to 67.7% for VRd-R.
• The study demonstrates that the addition of daratumumab does not compromise health-related quality of life (HRQoL), which is a critical consideration in the management of multiple myeloma, where treatment-related toxicity can significantly impact patient well-being.

• The findings are clinically relevant as they suggest that the quadruplet regimen (D-VRd-DR) can be adopted as a new standard of care, offering superior efficacy without compromising HRQoL.
• The regimen is feasible for clinical practice, given that daratumumab is already an approved and widely used agent in multiple myeloma treatment, and the subcutaneous formulation is associated with manageable side effects.
• The study's results align with the goal of improving both survival outcomes and quality of life for patients, making it a compelling option for clinicians.

• The study is a phase 3 randomized controlled trial (RCT), which is the gold standard for clinical research, providing high-quality evidence.
• A substantial sample size of 419 patients enhances the reliability of the findings.
• The statistical significance of the results is robust, with hazard ratios (HR) indicating a strong reduction in risk for progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT) compared to standard of care (SOC).

• Cilta-cel demonstrated superior outcomes in terms of PFS and OS compared to SOC regimens, which include pomalidomide, bortezomib, dexamethasone, and daratumumab.
• The hazard ratio for PFS (0.26) and OS (0.55) indicates a significant improvement over existing treatments, suggesting a meaningful advancement in therapeutic options for lenalidomide-refractory multiple myeloma.

• The findings are clinically relevant as they address a critical need for effective treatments in lenalidomide-refractory multiple myeloma patients who have limited options after 1-3 prior lines of therapy.
• The single infusion of cilta-cel offers a practical and potentially more convenient treatment option compared to continuous SOC regimens.
• The significant delay in TTNT and improvement in patient-reported outcomes (PROs) such as symptom control and quality of life further support its clinical applicability and benefit to patients.

• The study is a phase 3 randomized controlled trial (RCT), which is the gold standard for clinical research, providing high-quality evidence.
• The analysis included a substantial sample size with 155 patients in the cilta-cel arm and a total of 280 patients across comparator arms, ensuring robust statistical power.
• The use of inverse probability of treatment weighting (IPTW) to adjust for key prognostic baseline covariates enhances the reliability of the comparative efficacy results.

• Cilta-cel demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS) compared to standard regimens (DVd, DKd, Kd, Pd), with hazard ratios indicating a substantial reduction in risk of progression or death.
• The response rates, particularly the complete response (CR) rates, were markedly higher for cilta-cel, with adjusted response rate ratios showing a significant advantage over all comparator regimens.
• These results suggest cilta-cel offers a superior therapeutic option for patients with relapsed and refractory multiple myeloma (RRMM) who have received 1-3 prior lines of therapy.

• The findings are clinically relevant as they provide a new, highly effective treatment option for a challenging patient population (RRMM refractory to lenalidomide).
• The significant OS benefit and high response rates support the incorporation of cilta-cel into clinical practice, particularly in settings where current standard regimens are less effective.
• The study's results are consistent across sensitivity analyses, reinforcing the robustness and applicability of the findings.

• The OPTIMUM/MUKnine trial is a well-designed, prospective study with a substantial sample size of 107 ultra-high risk (UHiR) multiple myeloma (MM) patients, including 9 with plasma cell leukemia (PCL). The study's follow-up period of over 5 years provides robust long-term data.
• The statistical significance of the findings is strong, with a hazard ratio (HR) of 0.325 for progression-free survival (PFS) and 0.467 for overall survival (OS) compared to the Myeloma XI (MyXI) trial, both with highly significant p-values (p<0.0001 and p=0.0006, respectively).

• The OPTIMUM trial demonstrates superior outcomes compared to the MyXI trial, which represents a current standard-of-care approach for UHiR MM. The PFS and OS improvements are substantial, with PFS estimates at 60 months being 61.4% for OPTIMUM versus 23% for MyXI.
• The trial's tailored approach, including quintuplet induction therapy and extended consolidation and maintenance phases, shows a marked improvement over existing treatments, particularly for patients with ≥2 high-risk cytogenetic abnormalities (HRCA).

• The findings are clinically relevant as they address a significant unmet need in the treatment of UHiR MM, a group with historically poor outcomes.
• The integration of genetic and gene expression profiling (GEP) to stratify patients and tailor treatment regimens is feasible and aligns with precision medicine approaches increasingly adopted in oncology.
• The study identifies subgroups of patients who benefit exceptionally from the OPTIMUM regimen, as well as those with ongoing unmet needs, such as PCL patients, guiding future research and treatment strategies.

• The study is a randomized, multicenter phase 3 trial, which is a strong study design for evaluating clinical interventions.
• The sample size is substantial, with 660 patients included in the intention-to-treat analysis, providing a robust dataset.
• The statistical significance of the findings is well-supported, with p-values <0.001 for key outcomes, indicating strong evidence for the observed effects.

• The study investigates the addition of isatuximab (Isa) to the standard RVd regimen, which is a well-established treatment for transplant-eligible NDMM.
• The addition of Isa significantly increased MRD negativity rates, which is associated with improved survival outcomes.
• However, the PFS benefit was primarily observed in patients who remained MRD positive, suggesting that Isa may be particularly beneficial for this subgroup.

• Achieving MRD negativity is an important goal in multiple myeloma treatment, and the study confirms the prognostic value of MRD negativity and continued MRD negativity for PFS.
• The findings suggest that Isa-RVd may be more beneficial for patients who do not achieve MRD negativity, which could guide treatment decisions.
• However, the similar PFS outcomes in MRD-negative patients between the Isa-RVd and RVd arms indicate that the addition of Isa may not be necessary for all patients, limiting the immediate impact on clinical practice.

• The study is based on two phase 1b trials, which are early-phase studies primarily designed to assess safety, tolerability, and preliminary efficacy. While these studies provide valuable insights, they are not typically sufficient to change clinical practice due to their exploratory nature.
• The sample size is relatively small (27 patients), which limits the generalizability of the findings. Larger, randomized controlled trials would be necessary to confirm these results and establish a new standard of care.
• The follow-up period is reasonably long for a phase 1b study (median of 25.8 months), providing a good duration to assess the durability of responses.

• The combination of teclistamab with daratumumab and pomalidomide (tec-DP) shows a high overall response rate (88.5%) and a promising progression-free survival (median of 26.5 months). These results are encouraging, especially for patients with relapsed/refractory multiple myeloma (RRMM) who have limited treatment options.
• However, the study lacks a control group, making it difficult to directly compare these outcomes to existing therapies. Without comparative data, it is challenging to determine if tec-DP offers a significant advantage over current standard treatments.

• The high incidence of infections, including serious and fatal cases, highlights a significant safety concern. While the implementation of an intensified infection prophylaxis plan appears to have mitigated this risk, it underscores the need for careful management of infection risks in clinical practice.
• The feasibility of implementing tec-DP in clinical practice would require robust infection prophylaxis protocols, which may not be readily available in all treatment settings.

• The study is a phase 3 randomized controlled trial, which is a strong study design for evaluating the efficacy of a treatment. The sample size of 200 patients is reasonable, but not large, which may limit the generalizability of the findings.
• The primary endpoint, MRD-negative conversion rate, is a relevant and increasingly recognized surrogate marker for progression-free survival (PFS) in multiple myeloma.
• The statistical significance of the MRD-negative conversion rates across various subgroups is compelling, with odds ratios indicating a clear benefit of the D-R combination over R alone.

• The current standard of care for transplant-eligible newly diagnosed multiple myeloma (NDMM) patients includes induction/consolidation therapy followed by maintenance therapy with lenalidomide (R). The addition of daratumumab (DARA) to R maintenance shows improved MRD-negative conversion rates and favorable PFS hazard ratios.
• However, while the MRD-negative conversion rates are promising, the PFS hazard ratios, although favoring D-R, do not reach statistical significance in most subgroups, which is a critical factor for practice-changing recommendations.

• The findings are clinically relevant as they suggest a potential benefit of adding DARA to R maintenance therapy in improving MRD-negative rates and possibly PFS in certain subgroups of patients.
• The increased incidence of grade 3/4 treatment-emergent adverse events (TEAEs) with D-R, particularly in younger patients and across racial groups, raises concerns about the safety and tolerability of this regimen, which may limit its immediate adoption in clinical practice.

• The study is a well-designed, randomized controlled trial (RCT) involving 660 patients, which provides a robust level of evidence. The sample size is adequate, and the study design is appropriate for evaluating the efficacy of the addition of isatuximab (Isa) to the RVd regimen.
• The statistical significance of the primary endpoint (MRD negativity) and the secondary endpoint (PFS) is strong, with p-values <0.001 and 0.0184, respectively. The hazard ratio (HR) for PFS (0.70) indicates a meaningful reduction in the risk of progression or death with Isa-RVd compared to RVd alone.

• The current standard-of-care for transplant-eligible NDMM often includes RVd induction therapy followed by ASCT. The addition of anti-CD38 monoclonal antibodies, such as daratumumab, has been explored in other studies, showing improved outcomes.
• This study demonstrates that adding Isa to RVd improves PFS, which is an important finding. However, overall survival (OS) data is not yet mature, and the 3-year OS rates are similar between the two arms, which limits the immediate impact on clinical practice.

• The findings are clinically relevant as they suggest a potential improvement in PFS with the addition of Isa. However, the lack of mature OS data and the absence of a significant benefit in high-risk cytogenetic subgroups and patients with poor performance status suggest that further follow-up and analysis are needed.
• The feasibility of incorporating Isa into standard practice would depend on factors such as cost, availability, and potential side effects, which are not detailed in the abstract.

• The study is a retrospective chart review, which inherently has limitations compared to prospective randomized controlled trials (RCTs). While the use of inverse probability of treatment weighting (IPTW) and propensity score matching helps balance covariates and reduce bias, these methods cannot fully account for all potential confounders.
• The sample size is relatively large (641 patients leukapheresed, 586 infused), which adds robustness to the findings. However, the retrospective nature and potential for selection bias remain concerns.
• The statistical significance of the findings, particularly the superior progression-free survival (PFS) and overall survival (OS) for cilta-cel, is compelling (e.g., PFS HR=0.47, p<0.001; OS HR=0.63, p=0.02).

• Both cilta-cel and ide-cel are already approved CAR T-cell therapies for relapsed/refractory multiple myeloma (RRMM), and this study provides a direct comparison in a real-world setting.
• The study suggests cilta-cel may offer superior efficacy in terms of response rates and survival outcomes compared to ide-cel. However, this comes with a higher incidence of certain toxicities, such as grade ≥ 3 cytokine release syndrome (CRS) and delayed neurotoxicity (NT).
• The findings are valuable for informing treatment decisions and patient counseling, particularly in weighing the benefits of improved efficacy against the risks of increased toxicity.

• The study's results are clinically relevant as they provide insights into the comparative effectiveness and safety profiles of two CAR T-cell therapies in a real-world setting.
• However, the increased toxicity associated with cilta-cel may limit its applicability to certain patient populations, and careful patient selection and monitoring would be necessary.
• The conclusion emphasizes the need for further validation through prospective studies or additional real-world data to confirm these findings and enhance their applicability in clinical practice.

• The study is a Phase 2 trial, which provides a moderate level of evidence. While promising, Phase 2 trials are generally not sufficient alone to change clinical practice without further validation in larger Phase 3 trials.
• The sample size of 58 patients is relatively small, which limits the generalizability of the findings.
• The follow-up period is relatively short (median of 10.3 months), which may not fully capture long-term efficacy and safety outcomes.
• The reported outcomes, such as the overall response rate (ORR) of 95% and a complete response/stringent complete response (CR/sCR) rate of 62%, are impressive, but longer follow-up is needed to confirm durability.

• The results are promising, especially in a heavily pre-treated, high-risk population (triple- and penta-class refractory multiple myeloma), where treatment options are limited.
• The high ORR and MRD negativity rates suggest that anito-cel could be a potent option for patients with relapsed/refractory multiple myeloma.
• However, current standard-of-care treatments for multiple myeloma are well-established, and new therapies typically require robust evidence from Phase 3 trials to demonstrate superiority or significant benefit over existing options.

• The safety profile appears manageable, with most cytokine release syndrome (CRS) events being Grade 1, and a low incidence of immune effector cell-associated neurotoxicity syndrome (ICANS).
• The occurrence of Grade 5 CRS and treatment-emergent adverse events leading to death highlight the need for careful patient monitoring and management.
• The feasibility of implementing CAR T-cell therapies like anito-cel in clinical practice involves considerations of cost, manufacturing time, and infrastructure, which are not addressed in the abstract.

• The study is a Phase 3 trial, which is a strong design for evaluating clinical interventions. However, the data presented are initial results, and the follow-up period is relatively short (median follow-up of 14.4, 5.0, and 4.9 months for the cohorts).
• The sample size of 94 patients is modest, and while the cohorts are balanced in terms of baseline characteristics, the results are preliminary and not yet mature.
• The study reports on safety and early efficacy outcomes, but longer-term efficacy data, particularly progression-free survival (PFS) and overall survival (OS), are not yet available.

• Lenalidomide (Len) maintenance after autologous stem cell transplantation (ASCT) is the current standard of care for newly diagnosed multiple myeloma (NDMM) and is known to improve progression-free and overall survival.
• The addition of Tec (teclistamab), a bispecific antibody, to Len is novel and shows promise in deepening responses, as evidenced by the 100% MRD negative CR rate in Cohort 1. However, without mature data on PFS or OS, it is difficult to determine if this combination offers a significant advantage over Len alone.

• The study suggests that Tec-Len can be safely administered, with a trend towards improved safety outcomes with less frequent dosing. This is clinically relevant as it may reduce treatment-related adverse events.
• The high rate of MRD negativity is promising, but the clinical significance of MRD negativity in terms of long-term outcomes needs further validation.
• The feasibility of incorporating Tec into routine practice will depend on further data, including cost-effectiveness, long-term safety, and survival benefits.