Перепрофилирование функциональной миэломы высокого риска в контексте четырехкратной терапии и аутологической трансплантации стволовых клеток.

INTRODUCTION

Multiple myeloma is the second most common hematologic malignancy and has very heterogenous outcomes. The current risk stratification based on the International Staging System (ISS) and the revised ISS (R‐ISS) include disease burden and high‐risk cytogenetics determined by fluorescence in situ hybridization studies at diagnosis. 1 Additional high‐risk features at presentation, including plasma cell leukemia and the presence of extramedullary disease, add to risk prediction but do not fully capture the dynamic disease biology and heterogeneity of outcomes.

Functional high‐risk (FHR) myeloma is commonly defined as disease relapsing within 18 months of treatment initiation, 2 which includes primary refractory disease as well as disease relapsing early (typically 12 months) after autologous stem cell transplantation (ASCT), as used across multiple studies. 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 FHR multiple myeloma is associated with poor outcomes irrespective of baseline risk stratification, and the term was originally coined to identify a population with subsequent overall survival (OS) of less than 2 years. 6 , 12 , 13

The use of quadruplet induction therapy (QUAD), incorporating anti‐CD38 antibodies, proteasome inhibitors), immunomodulatory agents, and dexamethasone followed by upfront ASCT, has resulted in significant improvements in the depth of response as well as progression‐free survival(PFS). 14 , 15 , 16 , 17 , 18 , 19 However, outcomes of patients treated with QUAD + ASCT who experience early disease progression are not well characterized, and it is unknown whether the previous definition of FHR properly captures the poor prognosis of this population because they may carry worse biology that overcame more effective therapy.

We leveraged data from a prospective clinical trial and a prospectively curated institutional database to explore the optimal definition of FHR in the era of QUAD + ASCT and to identify patterns of responses to subsequent therapy, specifically examining the use of T‐cell–redirecting therapies (TCRTs) and their effect on outcomes.

MATERIALS AND METHODS

Study population

We combined data from the previously published MASTER trial (ClinicalTrials.gov identifier NCT03224507 ) 15 and a prospectively maintained database at the University of Alabama at Birmingham. MASTER was a single arm, multicenter, phase 2, minimal residual disease (MRD) response–adapted trial for patients with newly diagnosed multiple myeloma (NDMM), with enrichment for patients who had high‐risk chromosome abnormalities. Briefly, participants received four cycles of induction therapy with daratumumab, carfilzomib, lenalidomide, and dexamethasone followed by ASCT. After ASCT, participants received zero, four, or eight cycles of daratumumab, carfilzomib, lenalidomide, and dexamethasone according to their MRD status. Patients who did not achieve two consecutive MRD results <10 −5 received single‐agent lenalidomide until they developed progression. In addition to patients from the MASTER trial, we included patients from the University of Alabama at Birmingham database who had received standard‐of‐care induction therapy with daratumumab, bortezomib, lenalidomide, and dexamethasone for four cycles; ASCT; and the same parameters for post‐ASCT consolidation. Treatment cessation was suggested for patients who had two consecutive MRD results <10 −5 and standard cytogenetic risk. Maintenance strategy was usually single‐agent lenalidomide but varied according to existing toxicities and patient and physician preference. Patients were retrospectively classified according to the second revision of the ISS (R2‐ISS) 20 and the 2025 International Myeloma Society/International Myeloma Working Group (IMS/IMWG) consensus definition of high‐risk multiple myeloma. 21 All patients had a similar pattern of disease monitoring, and those evolving with disease progression were offered the best available therapy, including clinical trials that used agents with new mechanisms of action, if available. Clinical trial participants provided written informed consent, and nonclinical trial participants provided written informed consent to have their data collected in the database.

End points

For the entire study population, we described the cumulative incidence of disease progression, as defined by the standard IMWG criteria. 22 Subsequently, we gradually tested more inclusive cohorts of possible FHR cutoff points according to the time to progression <12 months (FHR12), <18 months (FHR18), <24 months (FHR24), and <36 months (FHR36) measured from the onset of induction therapy. For each of the cohorts, we described second‐line therapy and characterized outcomes in terms of second progression‐free survival (2PFS) defined as the time from progression after initial therapy until IMWG‐defined disease progression on second‐line therapy or death, and overall survival (OS) defined as time from progression after initial therapy until death from any cause. We established a priori that, consistent with historical data and the accepted concept of FHR, the optimal definition would be one demarcating a population with an OS of approximately 2 years postprogression.

Because the nature of second‐line therapy was not predetermined and given the emergence of data suggesting a transformative effect of TCRTs in relapsed and refractory multiple myeloma, we also analyzed PFS and OS for the various definitions of FHR according to whether the second line of therapy included TCRT, either an autologous chimeric antigen receptor T‐cell (CAR T‐cell) therapy or a bispecific T‐cell engager.

Statistical analysis

We described the cumulative incidence of progression using Kaplan–Meier estimates with events defined as IMWG‐defined progression, and patients were censored at last follow‐up or death not preceded by progression. Other time‐to‐event end points, namely, 2PFS and OS, were described using the Kaplan–Meier method and were compared using the log‐rank test. We compared proportions using the Fisher exact test. To test whether the use of TCRT in the next line of therapy affected the outcomes of patients who progressed after QUAD + ASCT, we performed multivariable analysis by inputting either the duration of first treatment response or FHR status and the receipt of TCRT as independent variables. We explored the association of those variables with the overall response rate using binary logistic regression and with 2PFS and OS using Cox regression with bootstrapping validation (with 2000 samples). Given the relatively small sample sizes, additional variables were not included in the analysis to avoid overfitting. All p values were two‐sided, and the level of significance was chosen as .05.

RESULTS

Overall, 310 patients received QUAD induction plus ASCT. The median patient age was 62 years (interquartile range, 56–68 years), 171 were men (55%), 95 were from a racial‐ethnic minority (31%), 114 (37%) had one high‐risk chromosome abnormality, and 44 (14%) had two or more high‐risk chromosome abnormalities (del[17p], t[4;14], t[14;16], gain/amp[1q]). The median duration of follow‐up was 41.8 months. Patient characteristics are displayed in Table 1 . Patient characteristics in the MASTER trail and from the University of Alabama at Birmingham database were similar, except that they reflected the MASTER trial design with planned enrichment for high‐risk disease (see Table S1 )

There were 66 patients who had disease progression. Among those who progressed, the estimated cumulative incidence of progression within each FHR definition was 2.6% for FHR12, 6.2% for FHR18, 10.1% for FHR24, and 16.4% for FHR36 (Figure 1 ). Death not preceded by progression was rare ( n = 2). There were no meaningful differences in baseline patient or disease characteristics between the groups according to different possible FHR definitions (Table 1 ). Across all FHR cutoff points, patients were more likely to have R2‐ISS stage III–IV disease or IMS/IMWG high‐risk disease compared with patients who did not progress.

The next treatment included TCRT in 11 patients (17%). Their median 2PFS was 3.0 months (95% confidence interval [CI], 2.2–3.7 months) for FHR12, 2.7 months (95% CI, 2.3–3.1 months) for FHR18, 3.3 months (95% CI, 2.3–4.3 months) for FHR24, and 5.8 months (95% CI, 2.4–9.3 months) for FHR36. The median OS was 8.1 months (95% CI, not estimated to 17.1 months) for FHR12, 8.1 months (95% CI, 5.5–10.7 months) for FHR18, 15.7 months (95% CI, 5.2–26.1 months) for FHR24, and 23.8 months (95% CI, 16.2–31.3 months) for FHR36 (see Figure S1 ). These findings point to FHR36 as a more appropriate definition of FHR than the historical FHR18 (Figure 2A,B ). Indeed, the median 2PFS for patients with FHR36 was 5.8 versus 8.1 months for patients who progressed beyond 36 months ( p = .003), whereas OS was 23.8 months versus not reached ( p = .005; see Figure S1 ), respectively.

We subsequently approached the impact of second‐line therapy on outcomes of the study population. The overall response rate was 55% for the 66 patients who had progression at any time and 44% for patients with FHR36. The overall response rate was 91% for patients who received TCRT and 47% for patients who did not receive TCRT as part of next therapy ( p = .009). TCRT was associated with improved 2PFS (Figure 2C ), with a 1‐year 2PFS rate of 80% versus 23%. OS at 12 months was 90% versus 73% for patients treated with and without TCRT, respectively (Figure 2D ). To adjust for the impact of duration of first response/FHR status on outcomes of second‐line therapy, we performed multivariable analysis inputting either the duration of first remission as continuous variable or as categorical variable represented by FHR36 status. With both strategies, the receipt of TCRT as next‐line therapy was associated with substantially improved 2PFS (Table 2 ; see Table S2 ).

DISCUSSION

In our current study, of 310 patients who received QUAD induction, 66 had disease progression at a median follow up of 41.8 months. PFS was uniformly poor across all FHR cutoff points examined. Survival analysis pointed to FHR36 as the optimal definition to describe a population, corresponding to 16.4% of all treated patients, with postprogression OS approaching 2 years. In the era of QUAD + ASCT, FHR36, corresponding to approximately one in six patients, defines a population of patients with poor outcomes using conventional therapy, apparently improved outcomes with TCRT, and who, with unmet medical needs, are prime candidates for clinical trials with the early introduction of agents that have novel mechanisms of action.

Response to treatment and time to progression are well established prognostic factors in patients with multiple myeloma. Before the introduction of anti‐CD38 monoclonal antibodies in the NDMM setting, early relapse (defined as relapse within 12–18 months of treatment initiation) was reported in 9%–16% of patients. 6 , 12 In a large, retrospective data set analysis from the Mayo Clinic with 512 patients who had NDMM, 82 patients (16%) relapsed within 1 year. 12 The majority of patients in that study, however, received a doublet regimen with either bortezomib plus dexamethasone or lenalidomide plus dexamethasone. Among patients who had an early relapse, 78% received subsequent therapy; however, the median PFS (8 vs. 30.2 months) and the median OS (21 months vs. not reached) remained significantly lower compared with patients who had later progression. Similar results have been reported from a Center for International Blood and Marrow Transplant Research study, 3 which included 3256 patients with NDMM who underwent ASCT within 1 year of diagnosis, including 959 (29.5%) who received triplet induction. After relapse, the median OS for patients who progressed within 24 months of ASCT was 16.4 months for those treated before 2005 and 24.7 months for those progressing after 2005. Similar results of poor survival outcomes with early relapse are noted across multiple studies. 4 , 6 However, nearly all published literature on early progression is from studies in patients who received doublet or triplet induction.

With the advent of QUAD induction followed by ASCT, initial response rates and survival outcomes have significantly improved, with approximately two thirds of patients achieving MRD‐negative status in multiple phase 2 and 3 trials. 14 , 15 , 18 Yet the results are inferior for patients who have multiple high‐risk chromosome abnormalities, with nearly one half of these patients progressing in the first 3 years. 15 , 18 , 23 , 24 Progression in 16.4% of patients at 36 months, as observed in our analysis, is well aligned with prospective trials, exemplified by 16% of progression or death at 4 years seen in the PERSEUS trial (ClinicalTrials.gov identifier NCT03710603 ). 18 Although R2‐ISS stage, IMS/IMWG high‐risk status, and the presence of one or multiple high‐risk chromosome abnormalities are predictors of progression in the setting of QUAD + ASCT, they fail to capture all early relapses. Indeed, in our current study, 35% patients with FHR36 had R2‐ISS stage I or II disease, and 52% had IMS/IMWG standard‐risk disease, confirming the role of the FHR concept in capturing biologically adverse disease not yet identified by established prognostic systems. It is important to note that, once early progression is established, the original risk classification does not seem to independently affect outcomes (Table 2 ; see Figure S2 ). Additional approaches, including multiparameter predictive models 25 and gene expression profiling, 26 , 27 have contributed to the prediction of FHR, but they lack validation in the context of QUAD + ASCT. The presence of circulating tumor cells improves prognostic models in the setting of QUAD, 28 an observation that needs to be confirmed and operationalized.

Most therapies available for the treatment of relapsed and refractory multiple myeloma were not systematically studied in triple‐class exposed myeloma, particularly as second line option. The B‐cell maturation antigen–directed CAR T‐cell cilta‐cel was studied as second‐line, third‐line, and fourth‐line therapy in the CARTITUDE‐4 trial, including 15% of patients who had triple‐class refractory disease (ClinicalTrials.gov identifier NT04181827). Although the superior PFS and OS attained with cilta‐cel also were observed in the subset of patients who had progression within 18 months of prior transplantation (or 24 months from the onset of therapy if prior ASCT was not received), 29 very few of those patients were exposed or refractory to anti‐CD38 monoclonal antibody. Our analysis indicates that patients with FHR36 disease have a dismal prognosis with conventional subsequent therapy, yet TCRT carries the potential to modify the natural history of this meaningful, small proportion of patients with myeloma who do not enjoy the typical long and sustained disease control achieved with QUAD + ASCT. These findings, however, should be interpreted with great caution because they are based on a small number of progression events and lack external validation.

This study has important limitations. It combined patients from a prospective clinical trial with patients who were treated according to institutional guideline. Although this approach introduces heterogeneity, we are reassured by the relatively long follow‐up and the similar patterns of monitoring. There was also some variation in the proteasome inhibitor used for induction and consolidation and in the use and choice of consolidation and maintenance. This is mitigated by the lack of a large difference in the efficacy of proteasome inhibitors when used in the NDMM setting 30 and the uncertainty around post‐ASCT therapy in the era of QUADs. 31 Sensitivity analysis indicated that the type of proteasome inhibitor used and the traditional IMWG response category did not affect the risk of FHR36 or subsequent outcomes. The overall sample size was relatively small, limiting the ability to establish inferences, including in the multivariable analysis. We also did not include the rare patients who had progression before ASCT. There was substantial heterogeneity in the treatments received, and only 11 patients received TCRT in the next line. Although the use of TCRT was influenced mostly by trial availability and timing of progression (because TCRT only recently became available as second‐line therapy outside clinical trials), it is possible that TCRT is in part a surrogate for fitness and organ function, biasing the comparisons with conventional regimens. Of interest, 53% of patients who did not receive TCRT in the second‐line but experienced subsequent progression did receive TCRT in the third line or beyond.

To our knowledge, ours is one of the first studies that has explored outcomes according to FHR status in the setting of QUAD induction followed by upfront ASCT. We believe there is need for more data on the outcomes of patients who have FHR36 disease after QUAD + ASCT, and the rising use of TCRT in this setting will provide real‐world evidence that may confirm its transformative effect. We also believe that FHR36 should be a standard definition for FHR going forward and that the safety and efficacy of experimental agents should be reported in this important subset of patients or dedicated trials should be designed and conducted for this special population. Future clinical trials or real‐world analyses, including patients who have relapsed and refractory multiple myeloma and previously received QUAD induction, should list the proportion of patients with FHR36 disease. Our analysis also questions the prioritization of lines of therapy over exposure and refractoriness for guideline recommendations and regulatory approvals. Indeed, the outcomes of patients who have FHR36 disease, particularly if treated with conventional regimens, are similar to the outcomes of patients who had triple‐class exposed multiple myeloma in the LocoMMotion study (ClinicalTrials.gov identifier NCT04035226 ) 32 and the Mammoth (Monoclonal Antibodies in Multiple Myeloma: Outcomes after THerapy failure) study 33 with multiple prior lines of therapy.

In summary, the current analysis provides validation of FHR36 as the optimal classification for FHR multiple myeloma in the era of QUAD + ASCT, providing a benchmark for future therapies to be explored in this setting. We believe future trials reporting outcomes of second‐line therapy after QUAD + ASCT should indicate the proportion of patients with FHR36 status. This study also provides preliminary indication that these patients should be prioritized for early receipt of TCRT. Currently, cilta‐cel 34 and teclistamab + daratumumab 35 are approved by the US Food and Drug Administration for second‐line therapy, and other TCRTs are expected to gain approval for use in earlier lines of therapy in the near future. Finally, future efforts should focus on better risk‐predictive models for NDMM that would support the optimization of therapy and a further reduction in the proportion of patients with FHR multiple myeloma.

AUTHOR CONTRIBUTIONS

Gayathri Ravi : Data curation; writing—original draft; formal analysis; conceptualization; investigation; and writing—review and editing. Binod Dhakal : Conceptualization; data curation; writing—review and editing; and investigation. Natalie S. Callander : Conceptualization; writing—review and editing; data curation; and investigation. Eva Medvedova : Conceptualization; writing—review and editing; data curation; and investigation. Bhagirathbhai R. Dholaria : Data curation; writing—review and editing; conceptualization; and investigation. Kelly N. Godby : Conceptualization; investigation; writing—review and editing; and data curation. Susan Bal : Conceptualization; investigation; writing—review and editing; and data curation. Forest Huls : Investigation; writing—review and editing; and data curation. Rebecca W. Silbermann : Conceptualization; investigation; writing—review and editing; and data curation. Luciano J. Costa : Data curation; supervision; conceptualization; investigation; writing—original draft; writing—review and editing; formal analysis; methodology; visualization; and project administration.

CONFLICT OF INTEREST STATEMENT

Gayatri Ravi reports personal/consulting fees from Guidepoint Global outside the submitted work. Binod Dhakal reports personal/consulting fees or honoraria/speaking fees from AbbVie Inc., Arcellx, Bristol Myers Squibb Company, Genentech, GlaxoSmithKline, Janssen Biotech, Karyopharm Therapeutics, Kite Pharma, Natera, Pfizer, and Sanofi outside the submitted work. Eva Medvedova reports grants/contracts from AbbVie Inc., Alexion Pharmaceuticals Inc., Celgene, and Janssen Research and Development; and personal/consulting fees from Prothena outside the submitted work. Bhagirathbhai R. Dholaria reports institutional research funding from Adicet, AlloVir, Angiocrine, Bristol Myers Squibb Company, Janssen Biotech, MEI, Molecular Template, Orcabio, Pfizer, Poseida, and Wugen; and personal/consulting or advisory fees from Accrotech, ADC Therapeutics, AstraZeneca, Autolus, F. Hoffmann‐La Roche, Gilead/Kite, Janssen Biotech, MJH BioScience, and Poseida outside the submitted work. Susan Bal reports grants/contracts from AbbVie, BeiGene Ltd., Bristol Myers Company, and Fate Therapeutics; and personal/consulting fees or honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb Company, Janssen Global Services LLC, Kite Pharma, and Pfizer outside the submitted work. Rebecca W. Silbermann reports grants/contracts from Sanofi Aventis and personal/consulting or advisory fees from Genentech, Janssen Pharmaceuticals, and Sanofi and Genzyme US Companies outside the submitted work. Luciano J. Costa reports grants/contracts from AbbVie, Amgen, Bristol Myers Squibb Company, Caribou Biosciences Inc., Genentech, and Janssen Biotech; personal/consulting fees from AbbVie, Adaptive Biotechnologies Corporation, Amgen Inc., Caribou Biosciences Inc., Genentech, Janssen Biotech, Pfizer, and Regeneron Pharmaceuticals Inc.; and support for other professional activities from Bristol Myers Squibb Company and Sanofi Pasteur Inc. outside the submitted work. The remaining authors disclosed no conflicts of interest.

Supporting information

Supplementary Material

Supplementary Material

Supplementary Material

Supplementary Material

Supplementary Material

ACKNOWLEDGMENTS

Johnson & Johnson and Amgen provided partial support for the work reflected in this article.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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