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Article

Low-Frequency PPM1D Gene Mutations Affect Treatment Response to BCMA-Targeted CAR T-Cell Therapy in Multiple Myeloma

by
Katharina van der Weg
1,†,
Martina Bertschinger
1,†,
Ulrike Bacher
2,
Michele Hoffmann
1,
Henning Nilius
3,
Katja Seipel
4,‡ and
Thomas Pabst
1,*,‡
1
Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
2
Department of Hematology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
3
Department of Clinical Chemistry, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
4
Department for Biomedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
These authors also contributed equally to this work.
Cancers 2026, 18(13), 2032; https://doi.org/10.3390/cancers18132032
Submission received: 19 May 2026 / Revised: 19 June 2026 / Accepted: 22 June 2026 / Published: 23 June 2026
(This article belongs to the Special Issue CAR T-Cell Therapy and Multiple Myeloma)
Browse Figure
Versions Notes

Simple Summary

Multiple Myeloma is an incurable plasma cell disorder, which, despite major therapeutic advances, particularly with the development of CAR T-cell therapy, remains incurable. Clonal hematopoiesis with mutations in the PPM1D gene can develop after repeated treatments. These mutations have previously been linked to treatment resistance and poor survival in lymphoma patients receiving cellular therapies. This retrospective study analyzed patients treated with CAR T-cell therapy between 2022 and 2025 to evaluate the impact of PPM1D mutations on treatment outcomes. Genetic screening before CAR T-cell infusion assessed mutation status, which was correlated with clinical characteristics, toxicity, and survival. PPM1D mutations were detected in 14.5% of the relapsed refractory Multiple Myeloma patients. Mutated patients showed more advanced disease burden and adverse prognostic features and fewer prior high-dose chemotherapy. While mutation status did not affect initial response depth, it was associated with shorter treatment durability after CAR T-cell therapy.

Abstract

Background: BCMA-targeted Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized the treatment of Relapsed/Refractory Multiple Myeloma (RRMM). However, the disease is not curable and progression after CAR T-cell treatment remains a challenge. Clonal hematopoiesis, specifically mutations in the DNA damage response gene PPM1D, has been linked to therapy resistance and inferior survival in lymphoma patients undergoing cellular therapy. The impact of PPM1D mutations on MM patient outcome after CAR T-cell therapy remains undefined. Methods: We conducted a retrospective single-center study of 83 patients with RRMM patients treated with idecabtagene vicleucel or ciltacabtagene autoleucel between 2022 and 2025. Next-generation sequencing was performed on peripheral blood mononuclear cells collected prior to CAR T-cell infusion to identify PPM1D exon 6 mutations (variant allele frequency > 0.01). We analyzed associations between mutational status, clinical characteristics, toxicity, and survival. Results: PPM1D mutations were detected in 14.5% (12/83) of patients. PPM1D-mutated patients had fewer prior autologous stem cell transplantation compared to wild-type patients (50% vs. 82%, p = 0.02) and presented more advanced disease burden and adverse prognostic features (R-ISS stage III 58% vs. 20%, p = 0.05). Notably, PPM1D status did not impact initial efficacy; complete remission rates were comparable between groups (67% vs. 69%). However, PPM1D mutations were significantly associated with inferior progression-free survival (PFS) (median PFS: 6 months vs. 16 months, p = 0.04). Regarding toxicity, the mutated subgroup exhibited significantly higher rates of grade ≥2 cytokine release syndrome and a trend toward increased neurotoxicity (25% vs. 7%). Conclusions: PPM1D clonal hematopoiesis is frequent in RRMM and despite deep initial responses, patients harboring PPM1D mutations face a significantly higher risk of early relapse. PPM1D mutations may serve as a biomarker for poor durability of response and should be further evaluated in larger, prospective trials.

1. Introduction

Multiple Myeloma (MM) is a clonal plasma cell malignancy that accounts for about 10% of all hematological malignancies [1]. Over the past two decades, the introduction of novel agents including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and monoclonal antibodies (mAbs) has led to substantial improvements in outcomes for patients with newly diagnosed MM [2,3,4]. Standard first-line therapy typically consists of an induction regimen including a PI, an IMiD, and a mAb, followed by high-dose chemotherapy with autologous stem cell transplantation (HDCT/ASCT) in eligible patients [3,4]. Despite all the advantages, MM remains incurable, and almost all patients with MM eventually relapse [4]. The management of patients with relapsed or refractory MM (RRMM) remains a significant clinical challenge. With successive lines of therapy, the duration of response has shown to decrease with each therapy line [5]. In particular, patients refractory to multiple drug classes have limited treatment options and a poor prognosis [6,7,8].
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel immunotherapeutic approach for the treatment of RRMM. The clinically most advanced CAR T-cell products in RRMM target B-cell maturation antigen (BCMA), a surface antigen predominantly expressed on differentiated B-cells including malignant plasma cells [9]. Currently, two BCMA-targeted CAR T-cell products, idecabtagene vicleucel (ide-cel, Abecma®) and ciltacabtagene autoleucel (cilta-cel, Carvykti®), have received regulatory approval by the European Medicines Agency (EMA) for patients with RRMM who have received at least one prior line of therapy. Both products have demonstrated substantial clinical activity in heavily pretreated RRMM with median progression-free survival (PFS) of approximately 12 months for ide-cel and exceeding 30 months for cilta-cel [10,11,12,13,14,15,16,17,18,19]. Notably, the observed benefit was consistent even through high-risk subgroups [13,18,20]. Despite its efficacy, CAR T-cell therapy is frequently associated with clinically relevant toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), infections and prolonged cytopenias [21]. CRS and ICANS are managed according to established grading systems, with tocilizumab as first-line therapy for CRS and corticosteroids in cases of neurotoxicity or higher-grade CRS [22]. Across clinical trials, CRS has been reported in 75–95% of RRMM patients after CAR T-cell infusion and neurotoxicity in 15–42%, with the majority of events being grade 1 or 2 [11,12,13,15,17,18,23]. Hematologic toxicities, such as neutropenia, leukopenia, anemia and thrombocytopenia, represent the most frequent higher-grade (≥3) adverse events [13,15,18]. In indirect comparison of ide-cel and cilta-cel, Hansen et al. reported superior efficacy and survival with cilta-cel, albeit at the cost of higher rates of certain toxicities, including higher-grade CRS, infections, second primary malignancies, and delayed neurotoxicity [24]. Recently, studies including less heavily pretreated patients have demonstrated improved treatment responses and lower toxicity rates, supporting the evaluation of CAR T-cell therapy in earlier treatment lines [10,15,19,25].
Clonal hematopoiesis (CH) refers to the clonal expansion of hematopoietic stem cells harboring somatic mutations in the absence of overt hematologic malignancy, typically defined by a variant allele frequency (VAF) of ≥0.02. The prevalence of CH increases with age and is further enriched in patients with cancer, particularly following exposure to cytotoxic chemotherapy and radiotherapy [26,27]. CH is driven by mutations in genes that provide a selective advantage to hematopoietic stem cells. PPM1D, a gene involved in the DNA damage response (DDR), is a driver gene of CH [27,28]. The PPM1D gene is located on chromosome 17q and encodes the phosphatase Mg2+/Mn2+-dependent 1D protein (PPM1D, Wip1), a serin/threonine phosphatase that is transcriptionally upregulated in a p53-dependent manner in response to cellular stress, including DNA damage [29,30]. PPM1D negatively regulates p53 and other DDR proteins, thereby promoting termination of the DDR and restoration of cellular homeostasis [31]. By attenuating p53 signaling, PPM1D protects cells from apoptosis or senescence under genotoxic stress [32,33]. As long as PPM1D is not overexpressed, its role appears to be benign and vital in stem cell homeostasis [31,34]. In hematopoietic cells, PPM1D alterations predominantly consist of nonsense or frameshift mutations clustered in exon 6, resulting in C-terminally truncated protein products with preserved phosphatase activity and increased protein stability due to impaired proteasomal degradation [35,36]. These gain-of-function mutations lead to resistance to apoptosis under DNA-damaging conditions [37]. Multiple studies have demonstrated strong associations between PPM1D mutations and prior exposure to cytotoxic chemotherapy as well as radiotherapy, indicating therapy-driven clonal selection of PPM1D-mutated cells [26,30,38,39]. Consistently, PPM1D-mutant cells exhibit increased resistance to chemotherapy, likely mediated by enhanced protein stability and reduced apoptotic susceptibility [30,40].
CH is frequently detected in patients with lymphoma or MM undergoing CAR T-cell therapy or HDCT/ASCT, with reported prevalences ranging from 21% to over 50% [41,42,43]. In the HDCT/ASCT setting, CH—particularly involving DDR genes such as PPM1D—has been linked to inferior clinical outcomes, including faster disease progression, inferior survival and an increased risk of therapy-related myeloid neoplasms [42,44,45,46]. In MM patients undergoing HDCT/ASCT, truncating PPM1D mutations were more frequently detected after repeated transplantation and were associated with inferior PFS and OS [47]. We have previously demonstrated inferior survival outcomes following CD19-targeted CAR T-cell therapy in patients with large B-cell and mantle cell lymphoma harboring PPM1D mutations [48,49].
In this retrospective study, we determined the prevalence of PPM1D exon 6 mutations in peripheral blood mononuclear cells (PMBCs) of patients with MM undergoing BCMA-targeted CAR T-cell therapy and analyzed their association with clinical outcomes. Using next-generation sequencing (NGS) amplicon analysis, we evaluated correlations between PPM1D mutational status and treatment response, survival outcomes and therapy-related toxicities.

2. Materials and Methods

We conducted a retrospective single-center study at the Inselspital, University Hospital of Bern, Switzerland. The final study cohort comprised 83 patients with triple-class exposed RRMM, who received commercially available CAR T-cell therapy between June 2022 and October 2025. All patients provided written informed consent for the use of their personal data for research purposes. Clinical follow-up evaluations were scheduled at 3 and 6 months, at 1 year and annually thereafter following CAR T-cell infusion. In addition, clinical and laboratory data related to both the underlying disease and CAR T-cell therapy were collected.
Genomic DNA was extracted from mononuclear cells (PBMCs) isolated from the peripheral blood of 83 MM patients collected before CAR T-cell infusion and 8 healthy donors. NGS amplicon sequencing was performed. Library preparation included the construction of a Nextera two-step PCR library, followed by sequencing on an Illumina MiSeq platform using a MiSeq Reagent Kit v3 (600-cycle) with 2 × 300 bp paired-end reads (Ilumina, San Diego, CA, USA). Gene-specific primers covering exon 6 of the PPM1D gene were used (forward: 5′-GAGGATCCATGGCCAAGGG-3′; reverse: 5′-TTCCAATTTTCTTCTGGCCCC-3′; amplicon size: 505 bp). Sequencing was performed by Microsynth (Balgach, Switzerland).
Bioinformatic analysis included trimming of locus-specific Illumina adapter sequences, merging of paired-end reads, mapping of the trimmed and merged reads to human chromosome 17 for variant calling and annotation, and mapping to the selected PPM1D region (chr17:60,662,994–60,663,549) for coverage analysis. In addition, trimmed and merged reads were dereplicated. A total of 2,586,264 demultiplexed reads passed Illumina’s chastity filter, corresponding to 777,838,210 demultiplexed bases, with a mean read length of 301 bp. FastQC (version 0.11.9) was used to assess quality. The quality assessment returned a mean Q of 35, with 95% in Q20 and 89% in Q30. The method was described in detail by Seipel et al. [47]. As described in Seipel et al. the VAF of PPM1D gene mutations called in the DNA samples ranged from 0.01 to 0.05 [47]. We therefore applied a cutoff of 0.01 in the current study. NGS amplicon sequencing and bioinformatics followed previous descriptions [47,48].
The primary endpoints were survival outcomes. PFS and overall survival (OS) were defined as the time from CAR T-cell infusion to disease progression, death, or last follow-up, respectively. PFS and OS were censored at the last follow-up on 15 December 2025, which was also used as the data cutoff.
Parameters investigated for their potential prognostic significance were patient age, R-ISS stage, cytogenetic risk, number of prior treatment lines including HDCT/ASCT, prior radiotherapy, the need for bridging therapy before CAR T-cell infusion, remission status before and after CAR T-cell treatment, use of Abecma® or Carvykti® CAR T-cell products, the manifestation of a CRS and ICANS.
Kaplan–Meyer survival curves and univariate statistical analyses were performed using GraphPad Prism version 10 (GraphPad Software, San Diego, CA, USA). Categorical variables were summarized as frequencies and percentages, while continuous variables were reported as medians and ranges. Associations between categorical variables were analyzed using Fisher’s exact test. Comparisons of continuous variables between groups were performed using the Mann–Whitney U test. Survival differences between groups were assessed using the log-rank test. All statistical tests were two-sided. p values < 0.05 were considered significant.
Univariable and multivariable Cox proportional-hazards models were additionally fitted using the survival package (version 4.5.1) in R [50]. The multivariable models were adjusted for age, sex, R-ISS stage, high-risk cytogenetics, CAR-T product, and prior ASCT.

3. Results

3.1. Prevalence of PPM1D Mutations

NGS amplicon sequencing was performed to identify mutations in exon 6 of the PPM1D gene in PBMC obtained from 83 patients with MM prior to infusion of BCMA-targeted CAR T-cell therapies. Only PPM1D gene mutations with a VAF of >0.01 were included. Overall, 12 low-frequency PPM1D mutations were identified in 12 of 83 patients (14.5%), comprising 4 in-del, 7 nonsense and 1 missense mutations (Table 1). VAF of PPM1D mutations detected in PBMC-derived DNA samples ranged from 0.011 to 0.069 with a mean VAF of 0.032 and a median VAF of 0.017.

3.2. Baseline Clinical Characteristics

All 83 MM patients with available NGS data were admitted to CAR T-cell infusion. Clinical characteristics of the 83 patients are summarized in Table 2.
The median age at initial diagnosis was 58 years (range: 33–78) and the median age at CAR T-cell infusion was 67 years (range: 42–84), with no statistically significant difference between the PPM1Dwt and PPM1Dmut group. At initial diagnosis, Revised International Staging System (R-ISS) distribution differed between the subgroups, with a higher proportion of R-ISS stage III stage disease among PPM1Dmut patients compared with PPM1Dwt patients (58% vs. 20%, p = 0.05). Cytogenetic risk categories were similarly distributed between the groups, with high-risk cytogenetics observed in 42% of PPM1Dmut and 32% of PPM1Dwt patients (p = 0.68). Most patients were heavily pretreated prior to CAR T-cell therapy, with 60% of the overall cohort having received four or more prior lines of therapy, without differences between the PPM1D subgroups. Prior radiotherapy and the use of bridging therapy were comparable between PPM1Dwt and PPM1Dmut patients. In contrast, a significantly lower proportion of PPM1Dmut patients had undergone HDCT/ASCT compared with PPM1Dwt patients (50% vs. 82%, respectively; p = 0.02).

3.3. Disease Features and CAR T-Cell Treatment

Disease status at the time of CAR T-cell infusion and treatment-related characteristics are summarized in Table 3.
The median interval from initial diagnosis to CAR T-cell infusion was 76 months (range: 8–349 months) in the overall cohort, with no significant difference between the PPM1Dwt and PPM1Dmut group (82 vs. 66 months, p = 0.14). Disease status at infusion was comparable between subgroups, with progressive disease (PD) being the most frequent disease state in both PPM1Dwt (45%) and PPM1Dmut (50%) patients. As lymphodepleting chemotherapy, patients received either fludarabine/cyclophosphamide or bendamustine. Two different CAR T-cell products were used: Abecma® (Brisol Myers Squibb, Princeton, NJ, USA, idecabtagen vicleucel; 57%) and Carvykti® (Johnson & Johnson, New Brunswick, NJ, USA, ciltacabtagene autoleucel; 43%). Both the lymphodepleting chemotherapy regimens and the CAR T-cell products were used in comparable proportions across both subgroups.

3.4. Clinical Outcomes After CAR T-Cell Therapy

Clinical outcomes after CAR T-cell therapy are summarized in Table 4. CRS occurred in 87% of patients and was predominantly low grade. While CRS was more frequently observed in PPM1Dwt patients (90% vs. 67%), the distribution of CRS grades differed significantly between the subgroups (p = 0.04), with a higher proportion of grade 1 CRS in PPM1Dwt patients and a higher frequency of grade ≥2 CRS in the PPM1Dmut subgroup. ICANS was observed in 10% of the overall cohort and occurred more frequently in PPM1Dmut patients (25% vs. 7%, p = 0.07). Rates of admission to intermediate or intensive care units were low and comparable between subgroups. The median duration of hospitalization was similar in PPM1Dwt and PPM1Dmut patients (17 vs. 15.5. days, p = 0.24). Best response after CAR T-cell therapy did not differ between groups, with complete remission (CR) achieved in 69% of PPM1D and 67% of PPM1Dmut patients. Relapse or disease progression occurred in 39% of PPM1Dwt and 50% of PPM1Dmut patients (p = 0.54). Survival outcomes favored the PPM1Dwt subgroup, with significantly longer PFS (16 vs. 6 months, p = 0.04) and numerically longer OS (14 vs. 32 months, p = 0.27) compared to the PPM1Dmut patients (Figure 1).
In the multivariable Cox proportional-hazards model, PPM1D mutation was an independent risk factor for PFS (HR = 2.58, 95% CI 1.02–6.52, p = 0.044) but not for OS (HR = 1.78, 95% CI 0.50–6.34, p = 0.4) (Table S1).

4. Discussion

In this retrospective single-center study, we investigated the prevalence and clinical impact of PPM1D exon 6 mutations in patients with RRMM undergoing BCMA-targeted CAR T-cell therapy. To our knowledge, this is one of the first studies to specifically assess the prognostic value of PPM1D CH in the context of CAR T-cell therapy for MM. Our primary finding is that PPM1D mutations are present in a relevant proportion of this heavily pretreated patient population and are associated with significantly shorter PFS and a trend toward increased immunotoxicity, despite comparable initial treatment response rates.
The observed prevalence of PPM1D mutations in our cohort was 14.5%, which is slightly lower than rates reported in some broader CH studies involving lymphoma and MM patients [41,42,43]. This frequency underscores that PPM1D-mutant clones are a recurring feature of the hematopoietic landscape in patients exposed to chronic cytotoxic stress. Importantly, the presence of these mutations correlated with significantly shorter median PFS (6 months vs. 16 months for wild-type patients).
The impact of PPM1D mutations on clinical outcomes after CAR T-cell therapy has been documented across different hematological diseases. Notably, an evaluation of 85 patients with relapsed/refractory diffuse large B-cell lymphoma undergoing CD19-targeted CAR T-cell therapy revealed a PPM1D mutation prevalence of 20%; within this cohort, patients harboring these mutations exhibited significantly shorter PFS and OS [48]. This negative prognostic association was further elaborated by Seipel et al. in patients with mantle cell lymphoma receiving CD19-directed CAR T-cell treatment. This retrospective analysis similarly identified PPM1D mutations as a determinant of inferior survival outcomes [49]. These data concur with our present findings in patients with RRMM. The reproducibility of this negative prognostic signal across different hematologic malignancies and CAR T-cell targets suggests that PPM1D may represent a pan-disease biomarker of poor long-term outcomes in patients treated with CAR T-cell therapy.
We observed a dissociation between initial response and durability. We found no significant difference in the best overall response or CR rates between PPM1D-mutated and wild-type patients (67% vs. 69% CR rates). This suggests that the presence of PPM1D-mutant clones in the peripheral blood does not impair the immediate cytotoxic efficacy of the CAR T-cell product. However, the rapid relapse rate in the mutated cohort implies that PPM1D mutations may be indicative of an unfavorable host environment that fails to sustain remission or perhaps correlates with a more aggressive underlying myeloma biology, as suggested by the higher proportion of R-ISS stage III disease in the mutated group.
Mechanistically, the impact of PPM1D mutations on CAR T-cell therapy is likely multifactorial. Since CAR T-cells are autologous products manufactured from PBMCs, it is plausible that a fraction of the infused T-cells carries the PPM1D mutation.
While PPM1D truncating mutations confer apoptosis resistance—which theoretically could enhance T-cell persistence—they also dampen p53-mediated DNA damage responses [31,32,33,34]. This could lead to genomic instability within the T-cell compartment or functional exhaustion. Alternatively, PPM1D mutations in the myeloid compartment (monocytes/macrophages) may contribute to a pro-inflammatory microenvironment, which leads to immunosuppression. CH is well-documented to drive aberrant inflammation via the NLRP3 inflammasome [51,52]. Our toxicity data supports this “inflammatory host” hypothesis: PPM1D-mutated patients exhibited a significant shift toward higher-grade CRS and a trend toward higher rates of ICANS (25% vs. 7%). This suggests that PPM1D clones may amplify the cytokine storm associated with CAR T-cell engagement, potentially worsening the therapeutic index.
Interestingly, our study revealed a counter-intuitive inverse relationship between prior HDCT/ASCT and PPM1D status. While findings from other studies suggest that HDCT/ASCT exert selective pressure favoring PPM1D mutant expansion, our mutated cohort had significantly fewer prior HDCT/ASCTs compared to the wild-type group (50% vs. 82%) [42,44,47]. This discrepancy might be explained by clinical selection bias; patients harboring PPM1D mutations presented with higher-risk disease (R-ISS III) and may have been deemed ineligible for transplant earlier in their disease course due to comorbidities or refractory disease, leading to reliance on other alkylating agents or continuous therapy lines that drove clonal selection. Alternatively, this may indicate that in the RRMM setting, the cumulative dose of novel agents and continuous chemotherapy may select for PPM1D clones as effectively as single-event HDCT/ASCT.
This study has several limitations. First, the retrospective, single-center design and the relatively small number of patients with PPM1D mutations (n = 12) limit the statistical power for subgroup analyses, particularly regarding OS, which showed a numerical but non-significant trend. Due to the limited sample size, the results should be seen as exploratory and confirmed in a larger cohort. Second, we performed targeted sequencing of PBMCs without sorting specific cell lineages; therefore, we cannot definitively state whether the mutations reside primarily in the myeloid compartment, the T-cell compartment (including the CAR T-cells themselves), or residual circulating plasma cells, although the latter is less likely given the VAF thresholds used. Another limitation of this analysis is that only PPM1D mutations were evaluated. Other CHIP-associated mutations were not captured and could likewise have contributed to the observed associations, potentially influencing the results. Additionally, as we used unsorted PBMCs, the cellular origin of the mutations remains unknown. Since CAR T-cells are autologous products manufactured from PBMCs, it is plausible that a fraction of the infused T-cells carries the PPM1D mutation. Finally, the heterogeneity of prior treatment lines and the use of two different CAR T-cell products (ide-cel and cilta-cel) introduce variability, although distribution was balanced between groups.

5. Conclusions

PPM1D mutations are frequent in RRMM patients treated with CAR T-cell therapy, and in our analysis, they are associated with inferior PFS and increased toxicity. Unlike markers of primary refractory disease, PPM1D status does not appear to hinder initial remission induction, but in our observational study, it is associated with a lack of durable disease control. These findings should be evaluated in future larger studies.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers18132032/s1, Table S1: Univariate and multivariate analysis. ID = initial diagnosis, R-ISS = Revised International Staging System, ASCT = High-dose chemotherapy with autologous stem cell transplant.

Author Contributions

Conceptualization, T.P.; formal analysis, K.v.d.W. and K.S.; investigation, K.v.d.W. and M.B.; resources, K.v.d.W., M.B. and K.S.; writing/original draft preparation, K.v.d.W. and M.B.; writing/review and editing, K.v.d.W., M.B., U.B., M.H., H.N., K.S. and T.P.; visualization, K.v.d.W. and H.N.; supervision, T.P.; project administration, T.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by decisions of the local ethics committee of Bern, Switzerland (decision number 2024-01248, date of approval 8 August 2024).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Deidentified individual participant data are available from the corresponding author upon reasonable request.

Acknowledgments

The authors wish to thank the data management, the apheresis, the flow cytometry and the stem cell laboratory teams of the ASCT program at the University Hospital of Bern and its associated partner hospitals and collaborators for documentation of the data relevant for this study. During the preparation of this manuscript/study, the authors used AI GPT 5 for the purposes of proofreading the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
BCMAB-Cell maturation antigen
CARChimeric antigen receptor
RRMMRelapsed/refractory multiple myeloma
PPM1DProtein phosphatase Mg2+/Mn2+-dependent 1D
MMMultiple myeloma
R-ISSRevised International Staging System
PFSProgression-free survival
OSOverall survival
PIProteasome inhibitor
IMiDImmunomodulatory drugs
mAbMonoclonal antibodies
HDCTHigh-dose chemotherapy
ASCTAutologous stem cell transplantation
CRSCytokine release syndrome
ICANSImmune effector cell-associated neurotoxicity syndrome
CHClonal hematopoiesis
VAFVariant allele frequency
DDRDNA damage response
PMBCPeripheral blood mononuclear cell
NGSNext generation sequencing
wtWild type
mutMutated

References

  1. Rajkumar, S.V. Multiple Myeloma: Every Year a New Standard? Hematol. Oncol. 2019, 37, 62–65. [Google Scholar] [CrossRef] [PubMed]
  2. Kumar, S.K.; Rajkumar, S.V.; Dispenzieri, A.; Lacy, M.Q.; Hayman, S.R.; Buadi, F.K.; Zeldenrust, S.R.; Dingli, D.; Russell, S.J.; Lust, J.A.; et al. Improved Survival in Multiple Myeloma and the Impact of Novel Therapies. Blood 2008, 111, 2516–2520. [Google Scholar] [CrossRef] [PubMed]
  3. Dimopoulos, M.A.; Moreau, P.; Terpos, E.; Mateos, M.V.; Zweegman, S.; Cook, G.; Delforge, M.; Hájek, R.; Schjesvold, F.; Cavo, M.; et al. Multiple Myeloma: EHA-ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up†. Ann. Oncol. 2021, 32, 309–322. [Google Scholar] [CrossRef] [PubMed]
  4. Rajkumar, S.V. Multiple Myeloma: 2024 Update on Diagnosis, Risk-stratification, and Management. Am. J. Hematol. 2024, 99, 1802–1824. [Google Scholar] [CrossRef] [PubMed]
  5. Kumar, S.K.; Therneau, T.M.; Gertz, M.A.; Lacy, M.Q.; Dispenzieri, A.; Rajkumar, S.V.; Fonseca, R.; Witzig, T.E.; Lust, J.A.; Larson, D.R.; et al. Clinical Course of Patients With Relapsed Multiple Myeloma. Mayo Clin. Proc. 2004, 79, 867–874. [Google Scholar] [CrossRef] [PubMed]
  6. Mateos, M.-V.; Weisel, K.; De Stefano, V.; Goldschmidt, H.; Delforge, M.; Mohty, M.; Dytfeld, D.; Angelucci, E.; Vincent, L.; Perrot, A.; et al. LocoMMotion: A Study of Real-Life Current Standards of Care in Triple-Class Exposed Patients with Relapsed/Refractory Multiple Myeloma—2-Year Follow-up (Final Analysis). Leukemia 2024, 38, 2554–2560. [Google Scholar] [CrossRef] [PubMed]
  7. Kumar, S.K.; Dimopoulos, M.A.; Kastritis, E.; Terpos, E.; Nahi, H.; Goldschmidt, H.; Hillengass, J.; Leleu, X.; Beksac, M.; Alsina, M.; et al. Natural History of Relapsed Myeloma, Refractory to Immunomodulatory Drugs and Proteasome Inhibitors: A Multicenter IMWG Study. Leukemia 2017, 31, 2443–2448. [Google Scholar] [CrossRef] [PubMed]
  8. Gandhi, U.H.; Cornell, R.F.; Lakshman, A.; Gahvari, Z.J.; McGehee, E.; Jagosky, M.H.; Gupta, R.; Varnado, W.; Fiala, M.A.; Chhabra, S.; et al. Outcomes of Patients with Multiple Myeloma Refractory to CD38-Targeted Monoclonal Antibody Therapy. Leukemia 2019, 33, 2266–2275. [Google Scholar] [CrossRef] [PubMed]
  9. Manier, S.; Ingegnere, T.; Escure, G.; Prodhomme, C.; Nudel, M.; Mitra, S.; Facon, T. Current State and Next-Generation CAR-T Cells in Multiple Myeloma. Blood Rev. 2022, 54, 100929. [Google Scholar] [CrossRef] [PubMed]
  10. Swan, D.; Madduri, D.; Hocking, J. CAR-T Cell Therapy in Multiple Myeloma: Current Status and Future Challenges. Blood Cancer J. 2024, 14, 206. [Google Scholar] [CrossRef] [PubMed]
  11. Raje, N.; Berdeja, J.; Lin, Y.; Siegel, D.; Jagannath, S.; Madduri, D.; Liedtke, M.; Rosenblatt, J.; Maus, M.V.; Turka, A.; et al. Anti-BCMA CAR T-Cell Therapy Bb2121 in Relapsed or Refractory Multiple Myeloma. N. Engl. J. Med. 2019, 380, 1726–1737. [Google Scholar] [CrossRef] [PubMed]
  12. Munshi, N.C.; Anderson, L.D.; Shah, N.; Madduri, D.; Berdeja, J.; Lonial, S.; Raje, N.; Lin, Y.; Siegel, D.; Oriol, A.; et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N. Engl. J. Med. 2021, 384, 705–716. [Google Scholar] [CrossRef] [PubMed]
  13. Rodriguez-Otero, P.; Ailawadhi, S.; Arnulf, B.; Patel, K.; Cavo, M.; Nooka, A.K.; Manier, S.; Callander, N.; Costa, L.J.; Vij, R.; et al. Ide-Cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N. Engl. J. Med. 2023, 388, 1002–1014. [Google Scholar] [CrossRef] [PubMed]
  14. Sanoyan, D.A.; Seipel, K.; Bacher, U.; Kronig, M.-N.; Porret, N.; Wiedemann, G.; Daskalakis, M.; Pabst, T. Real-Life Experiences with CAR T-Cell Therapy with Idecabtagene Vicleucel (Ide-Cel) for Triple-Class Exposed Relapsed/Refractory Multiple Myeloma Patients. BMC Cancer 2023, 23, 345. [Google Scholar] [CrossRef] [PubMed]
  15. Ailawadhi, S.; Arnulf, B.; Patel, K.; Cavo, M.; Nooka, A.K.; Manier, S.; Callander, N.; Costa, L.J.; Vij, R.; Bahlis, N.J.; et al. Ide-Cel vs Standard Regimens in Triple-Class–Exposed Relapsed and Refractory Multiple Myeloma: Updated KarMMa-3 Analyses. Blood 2024, 144, 2389–2401. [Google Scholar] [CrossRef] [PubMed]
  16. Xu, J.; Wang, B.-Y.; Yu, S.-H.; Chen, S.-J.; Yang, S.-S.; Liu, R.; Chen, L.-J.; Hou, J.; Chen, Z.; Zhao, W.-H.; et al. Long-Term Remission and Survival in Patients with Relapsed or Refractory Multiple Myeloma after Treatment with LCAR-B38M CAR T Cells: 5-Year Follow-up of the LEGEND-2 Trial. J. Hematol. Oncol. 2024, 17, 23. [Google Scholar] [CrossRef] [PubMed]
  17. Berdeja, J.G.; Madduri, D.; Usmani, S.Z.; Jakubowiak, A.; Agha, M.; Cohen, A.D.; Stewart, A.K.; Hari, P.; Htut, M.; Lesokhin, A.; et al. Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Patients with Relapsed or Refractory Multiple Myeloma (CARTITUDE-1): A Phase 1b/2 Open-Label Study. Lancet 2021, 398, 314–324. [Google Scholar] [CrossRef] [PubMed]
  18. San-Miguel, J.; Dhakal, B.; Yong, K.; Spencer, A.; Anguille, S.; Mateos, M.-V.; Fernández De Larrea, C.; Martínez-López, J.; Moreau, P.; Touzeau, C.; et al. Cilta-Cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N. Engl. J. Med. 2023, 389, 335–347. [Google Scholar] [CrossRef] [PubMed]
  19. Jagannath, S.; Jackson, C.C.; Schecter, J.M.; Lendvai, N.; Sun, H.; Akram, M.; Patel, N.; Martin, T.G. Cilta-Cel, a BCMA-Targeting CAR-T Therapy for Patients with Multiple Myeloma. Expert Opin. Biol. Ther. 2024, 24, 339–350. [Google Scholar] [CrossRef] [PubMed]
  20. Patel, K.; Rodríguez-Otero, P.; Manier, S.; Baz, R.; Raab, M.S.; Cavo, M.; Callander, N.; Costa, L.; Moreau, P.; Solomon, S.; et al. S195: Idecabtagene Vicleucel (Ide-Cel) vs. Standard Regimens in Patients with Triple-Class–Exposed (Tce) Relapsed and Refractory Multiple Myeloma (Rrmm): A Karmma-3 Analysis in High-Risk Subgroups. HemaSphere 2023, 7, e369897b. [Google Scholar] [CrossRef]
  21. Chohan, K.L.; Siegler, E.L.; Kenderian, S.S. CAR-T Cell Therapy: The Efficacy and Toxicity Balance. Curr. Hematol. Malig. Rep. 2023, 18, 9–18. [Google Scholar] [CrossRef] [PubMed]
  22. Lin, Y.; Qiu, L.; Usmani, S.; Joo, C.W.; Costa, L.; Derman, B.; Du, J.; Einsele, H.; Fernandez De Larrea, C.; Hajek, R.; et al. Consensus Guidelines and Recommendations for the Management and Response Assessment of Chimeric Antigen Receptor T-Cell Therapy in Clinical Practice for Relapsed and Refractory Multiple Myeloma: A Report from the International Myeloma Working Group Immunotherapy Committee. Lancet Oncol. 2024, 25, e374–e387. [Google Scholar] [CrossRef] [PubMed]
  23. Jagannath, S.; Martin, T.G.; Lin, Y.; Cohen, A.D.; Raje, N.; Htut, M.; Deol, A.; Agha, M.; Berdeja, J.G.; Lesokhin, A.M.; et al. Long-Term (≥5-Year) Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma. J. Clin. Oncol. 2025, 43, 2766–2771. [Google Scholar] [CrossRef] [PubMed]
  24. Hansen, D.K.; Peres, L.C.; Dima, D.; Richards, A.; Shune, L.; Afrough, A.; Midha, S.; Dhakal, B.; Kocoglu, M.H.; Atrash, S.; et al. Comparison of Standard-of-Care Idecabtagene Vicleucel and Ciltacabtagene Autoleucel in Relapsed/Refractory Multiple Myeloma. J. Clin. Oncol. 2025, 43, 1597–1609. [Google Scholar] [CrossRef] [PubMed]
  25. Roex, G.; Timmers, M.; Wouters, K.; Campillo-Davo, D.; Flumens, D.; Schroyens, W.; Chu, Y.; Berneman, Z.N.; Lion, E.; Luo, F.; et al. Safety and Clinical Efficacy of BCMA CAR-T-Cell Therapy in Multiple Myeloma. J. Hematol. Oncol. 2020, 13, 164. [Google Scholar] [CrossRef] [PubMed]
  26. Bolton, K.L.; Ptashkin, R.N.; Gao, T.; Braunstein, L.; Devlin, S.M.; Kelly, D.; Patel, M.; Berthon, A.; Syed, A.; Yabe, M.; et al. Cancer Therapy Shapes the Fitness Landscape of Clonal Hematopoiesis. Nat. Genet. 2020, 52, 1219–1226. [Google Scholar] [CrossRef] [PubMed]
  27. Pich, O.; Reyes-Salazar, I.; Gonzalez-Perez, A.; Lopez-Bigas, N. Discovering the Drivers of Clonal Hematopoiesis. Nat. Commun. 2022, 13, 4267. [Google Scholar] [CrossRef] [PubMed]
  28. Warren, J.T.; Link, D.C. Clonal Hematopoiesis and Risk for Hematologic Malignancy. Blood 2020, 136, 1599–1605. [Google Scholar] [CrossRef] [PubMed]
  29. Fiscella, M.; Zhang, H.; Fan, S.; Sakaguchi, K.; Shen, S.; Mercer, W.E.; Vande Woude, G.F.; O’Connor, P.M.; Appella, E. Wip1, a Novel Human Protein Phosphatase That Is Induced in Response to Ionizing Radiation in a P53-Dependent Manner. Proc. Natl. Acad. Sci. USA 1997, 94, 6048–6053. [Google Scholar] [CrossRef] [PubMed]
  30. Husby, S.; Hjermind Justesen, E.; Grønbæk, K. Protein Phosphatase, Mg2+/Mn2+-dependent 1D (PPM1D) Mutations in Haematological Cancer. Br. J. Haematol. 2021, 192, 697–705. [Google Scholar] [CrossRef] [PubMed]
  31. Lu, X.; Nguyen, T.-A.; Moon, S.-H.; Darlington, Y.; Sommer, M.; Donehower, L.A. The Type 2C Phosphatase Wip1: An Oncogenic Regulator of Tumor Suppressor and DNA Damage Response Pathways. Cancer Metastasis Rev. 2008, 27, 123–135. [Google Scholar] [CrossRef] [PubMed]
  32. Lu, X.; Nannenga, B.; Donehower, L.A. PPM1D Dephosphorylates Chk1 and P53 and Abrogates Cell Cycle Checkpoints. Genes Dev. 2005, 19, 1162–1174. [Google Scholar] [CrossRef] [PubMed]
  33. Lindqvist, A.; De Bruijn, M.; Macurek, L.; Brás, A.; Mensinga, A.; Bruinsma, W.; Voets, O.; Kranenburg, O.; Medema, R.H. Wip1 Confers G2 Checkpoint Recovery Competence by Counteracting P53-dependent Transcriptional Repression. EMBO J. 2009, 28, 3196–3206. [Google Scholar] [CrossRef] [PubMed]
  34. Goloudina, A.R.; Kochetkova, E.Y.; Pospelova, T.V.; Demidov, O.N. Wip1 Phosphatase: Between P53 and MAPK Kinases Pathways. Oncotarget 2016, 7, 31563–31571. [Google Scholar] [CrossRef] [PubMed]
  35. Hsu, J.I.; Dayaram, T.; Tovy, A.; De Braekeleer, E.; Jeong, M.; Wang, F.; Zhang, J.; Heffernan, T.P.; Gera, S.; Kovacs, J.J.; et al. PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy. Cell Stem Cell 2018, 23, 700–713.e6. [Google Scholar] [CrossRef] [PubMed]
  36. Kleiblova, P.; Shaltiel, I.A.; Benada, J.; Evčík, J.; Pecháčková, S.; Pohlreich, P.; Voest, E.E.; Dundr, P.; Bartek, J.; Kleibl, Z.; et al. Gain-of-Function Mutations of PPM1D/Wip1 Impair the P53-Dependent G1 Checkpoint. J. Cell Biol. 2013, 201, 511–521. [Google Scholar] [CrossRef] [PubMed]
  37. Stoyanov, M.; Martinikova, A.S.; Matejkova, K.; Horackova, K.; Zemankova, P.; Burdova, K.; Zemanova, Z.; Kleiblova, P.; Kleibl, Z.; Macurek, L. PPM1D Activity Promotes Cellular Transformation by Preventing Senescence and Cell Death. Oncogene 2024, 43, 3081–3093. [Google Scholar] [CrossRef] [PubMed]
  38. Coombs, C.C.; Zehir, A.; Devlin, S.M.; Kishtagari, A.; Syed, A.; Jonsson, P.; Hyman, D.M.; Solit, D.B.; Robson, M.E.; Baselga, J.; et al. Therapy-Related Clonal Hematopoiesis in Patients with Non-Hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell 2017, 21, 374–382.e4. [Google Scholar] [CrossRef] [PubMed]
  39. Wong, T.N.; Miller, C.A.; Jotte, M.R.M.; Bagegni, N.; Baty, J.D.; Schmidt, A.P.; Cashen, A.F.; Duncavage, E.J.; Helton, N.M.; Fiala, M.; et al. Cellular Stressors Contribute to the Expansion of Hematopoietic Clones of Varying Leukemic Potential. Nat. Commun. 2018, 9, 455. [Google Scholar] [CrossRef] [PubMed]
  40. Kahn, J.D.; Miller, P.G.; Silver, A.J.; Sellar, R.S.; Bhatt, S.; Gibson, C.; McConkey, M.; Adams, D.; Mar, B.; Mertins, P.; et al. PPM1D-Truncating Mutations Confer Resistance to Chemotherapy and Sensitivity to PPM1D Inhibition in Hematopoietic Cells. Blood 2018, 132, 1095–1105. [Google Scholar] [CrossRef] [PubMed]
  41. Miller, P.G.; Sperling, A.S.; Brea, E.J.; Leick, M.B.; Fell, G.G.; Jan, M.; Gohil, S.H.; Tai, Y.-T.; Munshi, N.C.; Wu, C.J.; et al. Clonal Hematopoiesis in Patients Receiving Chimeric Antigen Receptor T-Cell Therapy. Blood Adv. 2021, 5, 2982–2986. [Google Scholar] [CrossRef] [PubMed]
  42. Mouhieddine, T.H.; Sperling, A.S.; Redd, R.; Park, J.; Leventhal, M.; Gibson, C.J.; Manier, S.; Nassar, A.H.; Capelletti, M.; Huynh, D.; et al. Clonal Hematopoiesis Is Associated with Adverse Outcomes in Multiple Myeloma Patients Undergoing Transplant. Nat. Commun. 2020, 11, 2996. [Google Scholar] [CrossRef] [PubMed]
  43. Panagiota, V.; Kerschbaum, J.F.; Penack, O.; Stein, C.M.; Arends, C.M.; Koenecke, C.; Strzelecka, P.M.; Kloos, A.; Wiegand, L.; Lasch, A.; et al. Clinical Implications and Dynamics of Clonal Hematopoiesis in Anti-CD19 CAR T-Cell Treated Patients. HemaSphere 2023, 7, e957. [Google Scholar] [CrossRef] [PubMed]
  44. Gibson, C.J.; Lindsley, R.C.; Tchekmedyian, V.; Mar, B.G.; Shi, J.; Jaiswal, S.; Bosworth, A.; Francisco, L.; He, J.; Bansal, A.; et al. Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J. Clin. Oncol. 2017, 35, 1598–1605. [Google Scholar] [CrossRef] [PubMed]
  45. Husby, S.; Favero, F.; Nielsen, C.; Sørensen, B.S.; Bæch, J.; Grell, K.; Hansen, J.W.; Rodriguez-Gonzalez, F.G.; Haastrup, E.K.; Fischer-Nielsen, A.; et al. Clinical Impact of Clonal Hematopoiesis in Patients with Lymphoma Undergoing ASCT: A National Population-Based Cohort Study. Leukemia 2020, 34, 3256–3268. [Google Scholar] [CrossRef] [PubMed]
  46. Schmid, C.N.; Sponagel, K.; Bacher, U.; Seipel, K.; Porret, N.; Wiedemann, G.; Hoffmann, M.; Daskalakis, M.; Pabst, T. Clonal Hematopoiesis and Outcomes After High-Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with AML, Myeloma, and Lymphoma. Int. J. Mol. Sci. 2025, 26, 8021. [Google Scholar] [CrossRef] [PubMed]
  47. Seipel, K.; Veglio, N.Z.; Nilius, H.; Jeker, B.; Bacher, U.; Pabst, T. Rising Prevalence of Low-Frequency PPM1D Gene Mutations after Second HDCT in Multiple Myeloma. Curr. Issues Mol. Biol. 2024, 46, 8197–8208. [Google Scholar] [CrossRef] [PubMed]
  48. Seipel, K.; Frey, M.; Nilius, H.; Akhoundova, D.; Banz, Y.; Bacher, U.; Pabst, T. Low-Frequency PPM1D Gene Mutations Affect Treatment Response to CD19-Targeted CAR T-Cell Therapy in Large B-Cell Lymphoma. Curr. Oncol. 2023, 30, 10463–10476. [Google Scholar] [CrossRef] [PubMed]
  49. Seipel, K.; Benninger, L.; Bacher, U.; Pabst, T. Low-Frequency PPM1D Gene Mutations Associated with Inferior Treatment Response to CD19 Targeted CAR-T Cell Therapy in Mantle Cell Lymphoma. Therapeutics 2024, 1, 95–105. [Google Scholar] [CrossRef]
  50. Therneau, T.M.; Grambsch, P.M. Modeling Survival Data: Extending the Cox Model; Statistics for Biology and Health; Springer: New York, NY, USA, 2000. [Google Scholar]
  51. Fuster, J.J.; MacLauchlan, S.; Zuriaga, M.A.; Polackal, M.N.; Ostriker, A.C.; Chakraborty, R.; Wu, C.-L.; Sano, S.; Muralidharan, S.; Rius, C.; et al. Clonal Hematopoiesis Associated with TET2 Deficiency Accelerates Atherosclerosis Development in Mice. Science 2017, 355, 842–847. [Google Scholar] [CrossRef] [PubMed]
  52. Yura, Y.; Miura-Yura, E.; Katanasaka, Y.; Min, K.-D.; Chavkin, N.; Polizio, A.H.; Ogawa, H.; Horitani, K.; Doviak, H.; Evans, M.A.; et al. The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice. Circ. Res. 2021, 129, 684–698. [Google Scholar] [CrossRef] [PubMed]
Cancers 18 02032 g001
Figure 1. Clinical outcomes in RRMM patients treated with BCMA-targeted CAR T-cell therapy. (a) PFS and (b) OS of RRMM patients receiving BCMA-targeted CAR T-cell therapy were analyzed using Kaplan–Meyer, stratified by PPM1D status.
Figure 1. Clinical outcomes in RRMM patients treated with BCMA-targeted CAR T-cell therapy. (a) PFS and (b) OS of RRMM patients receiving BCMA-targeted CAR T-cell therapy were analyzed using Kaplan–Meyer, stratified by PPM1D status.
Cancers 18 02032 g001
Table 1. PPM1D gene mutations detected in MM cohort.
Table 1. PPM1D gene mutations detected in MM cohort.
ClassificationLocusVAFNT ChangeAA Change
nonsensechr17:60,66633520.011G/TE540 *
nonsensechr17:60,66632920.013C/TQ520 *
nonsensechr17:60,66631820.018T/GL484 *
nonsensechr17:60,66630770.013T/GL450 *
nonsensechr17:60,66631360.012C/AS468 *
nonsensechr17:60,66633450.015T/GL538 *
nonsensechr17:60,66631580.014G/TE475 *
indelchr17:60,66630770.069AT/AL450fs
indelchr17:60,66633100.039GA/GI526fs
missensechr17:60,66630860.071G/AE451K
indelchr17:60,66630400.052TA/TR536fs
indelchr17:60,66632730.062AT/AL513fs
* nonsense mutation.
Table 2. Baseline clincal characteristics of the RRMM cohort, univariate analysis.
Table 2. Baseline clincal characteristics of the RRMM cohort, univariate analysis.
Cohort
(n = 83)		PPM1Dwt
(n = 71)		PPM1Dmut
(n = 12)		p-Value
Sex (female:male)26:5723:483:90.74
Median age at ID (years)58 (33–78)58 (33–78)63.5 (43–76)0.08
Median age at CAR T (years)67 (42–84)66 (42–82)70.5 (50–84)0.16
R-ISS stage at ID 0.05
I21 (25%)19 (27%)2 (17%)
II33 (40%)31 (44%)2 (17%)
III21 (25%)14 (20%)7 (58%)
no info8 (10%)7 (10%)1 (8%)
Cytogenetic abnormalities 0.68
standard risk32 (39%)27 (38%)5 (42%)
high risk28 (34%)23 (32%)5 (42%)
no info23 (28%)21 (30%)2 (17%)
Extramedullary disease17 (20%)15 (21%)2 (17%)>0.99
Number of treatment lines prior to CAR T-cell therapy >0.99
1–333 (40%)28 (39%)5 (42%)
≥450 (60%)43 (61%)7 (58%)
Radiotherapy44 (53%)36 (51%)8 (67%)0.36
Prior HDCT/ASCT64 (77%)58 (82%)6 (50%)0.02
Prior BCMA exposure7 (8%)6 (8%)1 (8%)>0.99
Bridging Therapy48 (58%)41 (58%)7 (58%)>0.99
ID = initial diagnosis, R-ISS = Revised International Staging System, HDCT/ASCT = High-dose chemotherapy with autologous stem cell transplant, BCMA = B-cell maturation antigen.
Table 3. Clinical characteristics and details of CAR T-cell treatment, univariate analysis.
Table 3. Clinical characteristics and details of CAR T-cell treatment, univariate analysis.
Cohort
(n = 83)		PPM1Dwt
(n = 71)		PPM1Dmut
(n = 12)		p-Value
LD Chemotherapy 0.35
Flu/Cy40 (48%)36 (51%)4 (33%)
Bendamustine43 (52%)35 (49%)8 (67%)
CAR T-cell product 0.76
Abecma®47 (57%)41 (58%)6 (50%)
Carvykti®36 (43%)30 (42%)6 (50%)
Stage at CAR T-cell infusion >0.99
CR6 (7%)5 (7%)1 (8%)
PR21 (25%)18 (25%)3 (25%)
SD18 (22%)16 (23%)2 (17%)
PD38 (46%)32 (45%)6 (50%)
Median interval ID to CAR T-cell infusion (months)76 (8–349)82 (11–224)66 (8–349)0.14
LD = lymphodepleting, Flu/Cy = fludarabine/cyclophosphamide, CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, ID = initial diagnosis.
Table 4. Clinical outcome after CAR T-cell treatment, univariate analysis.
Table 4. Clinical outcome after CAR T-cell treatment, univariate analysis.
Cohort
(n = 83)		PPM1Dwt
(n = 71)		PPM1Dmut
(n = 12)		p-Value
CRS72 (87%)64 (90%)8 (67%)0.04
grade 158 (70%)53 (75%)5 (42%)
grade 213 (16%)10 (14%)3 (25%)
grade 30 (0%)0 (0%)0 (0%)
grade 41 (1%)1 (1%)0 (0%)
ICANS8 (10%)5 (7%)3 (25%)0.07
grade 13 (4%)1 (1%)2 (17%)
grade 23 (4%)2 (3%)1 (8%)
grade 30 (0%)0 (0%)0 (0%)
grade 42 (2%)2 (3%)0 (0%)
Admissions to IMC/ICU7 (8%)6 (8%)1 (8%)>0.99
Median Hospitalization time (days)17 (8–93)17 (8–93)15.5 (9–21)0.24
Best remission status post CAR T-cell therapy 0.64
CR57 (69%)49 (69%)8 (67%)
PR11 (13%)9 (13%)2 (17%)
SD3 (4%)2 (3%)1 (8%)
PD12 (14%)11 (15%)1 (8%)
Relapse/Progression34 (41%)28 (39%)6 (50%)0.54
Median survival time
PFS (months)141660.04
OS (months)2932140.27
CRS = cytokine release syndrome, ICANS = immune effector cell-associated neurotoxicity syndrome, IMC = intermediate care unit, ICU = intensive care unit, CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, PFS = progression free survival, OS = overall survival.
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van der Weg, K.; Bertschinger, M.; Bacher, U.; Hoffmann, M.; Nilius, H.; Seipel, K.; Pabst, T. Low-Frequency PPM1D Gene Mutations Affect Treatment Response to BCMA-Targeted CAR T-Cell Therapy in Multiple Myeloma. Cancers 2026, 18, 2032. https://doi.org/10.3390/cancers18132032

AMA Style

van der Weg K, Bertschinger M, Bacher U, Hoffmann M, Nilius H, Seipel K, Pabst T. Low-Frequency PPM1D Gene Mutations Affect Treatment Response to BCMA-Targeted CAR T-Cell Therapy in Multiple Myeloma. Cancers. 2026; 18(13):2032. https://doi.org/10.3390/cancers18132032

Chicago/Turabian Style

van der Weg, Katharina, Martina Bertschinger, Ulrike Bacher, Michele Hoffmann, Henning Nilius, Katja Seipel, and Thomas Pabst. 2026. "Low-Frequency PPM1D Gene Mutations Affect Treatment Response to BCMA-Targeted CAR T-Cell Therapy in Multiple Myeloma" Cancers 18, no. 13: 2032. https://doi.org/10.3390/cancers18132032

APA Style

van der Weg, K., Bertschinger, M., Bacher, U., Hoffmann, M., Nilius, H., Seipel, K., & Pabst, T. (2026). Low-Frequency PPM1D Gene Mutations Affect Treatment Response to BCMA-Targeted CAR T-Cell Therapy in Multiple Myeloma. Cancers, 18(13), 2032. https://doi.org/10.3390/cancers18132032

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