Autologous Peripheral Blood Stem Cell Transplantation as Front-Line Therapy for Myeloma with Double-Hit and Triple-Hit in a Real-World Study
Multiple myeloma (MM), a plasma cell malignancy, represents approximately 10% of all hematologic cancers. In China alone, over 16,500 new cases were diagnosed in 2016, with 10,300 deaths attributed to the disease. Despite advancements in novel therapies, including proteasome inhibitors and immunomodulatory drugs, a subset of patients continues to exhibit poor prognoses, with median overall survival (OS) under two years. The revised Mayo Clinic Stratification for Myeloma and Risk-Adapted Therapy 3.0 (mSMART 3.0) guidelines introduced in 2020 classify patients with two or three high-risk cytogenetic abnormalities as “double-hit” or “triple-hit” myeloma, respectively. These subgroups are associated with aggressive disease biology and shorter survival. However, the role of autologous peripheral blood stem cell transplantation (APBSCT) as front-line therapy for these high-risk groups remains understudied. This real-world analysis evaluated the efficacy of APBSCT in improving outcomes for myeloma patients with double-hit and triple-hit abnormalities.
Study Design and Patient Characteristics
The study retrospectively reviewed medical records of 240 newly diagnosed MM (NDMM) patients who underwent APBSCT as front-line therapy between January 2010 and December 2019 at Beijing Chao-Yang Hospital. Eligibility required completion of induction therapy containing at least one novel agent, such as bortezomib, thalidomide, or lenalidomide, followed by high-dose chemotherapy and APBSCT. Patients were stratified into three subgroups based on interphase fluorescence in situ hybridization (iFISH) results: standard-risk (no high-risk abnormalities, n=110), high-risk (one abnormality, n=96), and double-hit/triple-hit (two or three abnormalities, n=34). Baseline demographics, disease characteristics, and treatment responses were independently verified by multiple researchers.
Induction therapy consisted of a median of four cycles (range: 2–13), with 90% of patients receiving bortezomib-based regimens. Post-APBSCT, most patients initiated maintenance therapy by day 100. Responses were assessed post-induction and post-transplantation using International Myeloma Working Group criteria, with stringent complete remission (sCR) as the highest response tier.
Clinical Outcomes and Subgroup Analyses
Response Rates
Post-induction, 71.7% of the cohort (172/240) achieved ≥very good partial remission (VGPR), with no significant difference across subgroups (standard-risk: 70.0%, high-risk: 75.0%, double/triple-hit: 67.6%; P=0.149). By day 100 post-APBSCT, the ≥VGPR rate improved to 84.6%, again without subgroup variation (standard-risk: 82.7%, high-risk: 84.5%, double/triple-hit: 79.5%; P=0.070). A notable 30.3% (73/240) of patients achieved further remission post-transplant, irrespective of cytogenetic risk.
Survival Outcomes
With a median follow-up of 33.5 months (range: 12–132), the overall cohort demonstrated a median progression-free survival (PFS) of 41 months and median OS of 89 months. However, striking disparities emerged between subgroups:
- Standard-risk: Median PFS 82 months; median OS 107 months.
- High-risk: Median PFS 33 months; median OS 70 months.
- Double/triple-hit: Median PFS 28 months; median OS 44 months (P<0.001 for both PFS and OS comparisons) [Figure 1].
The double/triple-hit subgroup exhibited significantly inferior outcomes despite comparable response rates, underscoring the aggressive nature of these cytogenetic profiles.
Comparative Real-World Evidence
The study benchmarked its findings against published data where subsets of double/triple-hit patients did not receive APBSCT. In those cohorts, median PFS ranged from <6 to 19.7 months, and median OS from 6 to 22.2 months—markedly shorter than the 28-month PFS and 44-month OS observed in this APBSCT-treated cohort. Notably, the 2-year OS rate for double/triple-hit patients here was 79.2%, surpassing the 63.9%–72.3% rates reported by Shah et al. (2020). These comparisons suggest that APBSCT may partially mitigate the adverse prognosis associated with high-risk cytogenetics.
Multivariate Predictors of Survival
Cox regression analyses identified independent prognostic factors:
- PFS: High-risk (HR=3.444, 95% CI: 2.130–5.571; P<0.001) and double/triple-hit status (HR=5.146, 95% CI: 2.832–9.349; P<0.001) predicted shorter PFS, while post-APBSCT further remission reduced progression risk (HR=0.428, 95% CI: 0.276–0.662; P<0.001).
- OS: High-risk (HR=2.908, 95% CI: 1.539–5.493; P=0.001) and double/triple-hit status (HR=5.549, 95% CI: 2.532–11.715; P<0.001) correlated with shorter OS, whereas deeper post-transplant responses prolonged survival (HR=0.386, 95% CI: 0.216–0.688; P=0.001).
Additional adverse factors included IgA/IgD/Igλ subtype, advanced ISS stage, extramedullary disease, and failure to achieve sCR post-APBSCT.
Implications for Clinical Practice
This study reinforces APBSCT as a cornerstone of front-line therapy for high-risk MM, even in the novel-agent era. For double/triple-hit patients, transplantation appears to confer a survival advantage over chemotherapy-alone approaches, though outcomes remain suboptimal. The 44-month median OS in this subgroup—though dismal compared to standard-risk patients—represents a clinically meaningful improvement over historical controls.
Emerging strategies, such as tandem APBSCT or autologous-allogeneic transplantation, may further enhance outcomes. A European Society for Blood and Marrow Transplantation study demonstrated that tandem APBSCT improved PFS in high-risk patients, particularly those with extramedullary disease. Similarly, autologous-allogeneic approaches have shown promise in achieving durable remission, albeit with increased toxicity.
Conclusion
Double-hit and triple-hit myeloma represent distinct biological entities with markedly poor prognoses. This real-world analysis demonstrates that APBSCT, when integrated into front-line therapy, improves survival for these patients compared to novel-agent regimens alone. However, the persistent gap between high-risk and standard-risk groups underscores the need for advanced therapeutic strategies, such as tandem transplantation or targeted agents. Future research must prioritize elucidating the molecular drivers of double/triple-hit disease to enable precision medicine approaches.
doi.org/10.1097/CM9.0000000000001678
Was this helpful?
0 / 0