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. 2025 May 5;6(3):203-216.
doi: 10.1158/2643-3230.BCD-24-0274.

Dynamics of Mutant Hematopoietic Progenitor Cells Are Not Associated with Clinical Outcomes in Multiple Myeloma

Camila Guerrero #  1 , Maria-Jose Larrayoz #  1 , Irache Erdozain  1 , Noemi Puig  2 , Maria-Teresa Cedena  3 , Catarina Maia  1 , Amagoia Mañu  1 , Natalia Gordillo  1 , Oihane Churruca  1 , Diego Alignani  1 , Sarai Sarvide  1 , Iria Vazquez  1 , Cristina Perez  1 , Albert Oriol  4 , Laura Rosinol  5 , Rafael Ríos-Tamayo  6 , Marta-Sonia Gonzalez-Perez  7 , Ana-Pilar Gonzalez-Rodriguez  8 , Felipe de Arriba  9 , Jose M Moraleda  10 , Jesus Martin  11 , Luis Palomera  12 , Valentin Cabañas  10 , Maria-Jose Calasanz  1 , Joaquin Martinez-Lopez  3 , Maria-Victoria Mateos  2 , Joan Bladé  5 , Juan-Jose Lahuerta  3 , Jesus F San-Miguel  1 , Bruno Paiva  1
Affiliations

Dynamics of Mutant Hematopoietic Progenitor Cells Are Not Associated with Clinical Outcomes in Multiple Myeloma

Camila Guerrero et al. Blood Cancer Discov. .

Abstract

SPMs that develop in patients with multiple myeloma have a deleterious impact on survival. Patients with CH may be at risk of developing SPMs, which could potentially be avoided through individualized treatment. However, our results suggest that screening for CH at diagnosis has limited utility.

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Conflict of interest statement

N. Puig reports personal fees from Amgen, Bristol Myers Squibb, Takeda, The Binding Site, Sanofi, and Menarini and grants from Pfizer outside the submitted work. M.-T. Cedena reports personal fees from Johnson&Johnson and Sobi outside the submitted work. A. Oriol reports personal fees from Sanofi, Pfizer, Amgen, GlaxoSmithKline, Bristol Myers Squibb, Johnson&Johnson, and Oncopeptides outside the submitted work. L. Rosinol reports other support from Janssen, Bristol Myers Squibb, Sanofi, Takeda, GlaxoSmithKline, Menarini Stemline, and Pfizer outside the submitted work. F. de Arriba reports personal fees and nonfinancial support from Janssen-Cilag, Bristol Myers Squibb/Celgene, Amgen, GlaxoSmithKline, and Sanofi outside the submitted work. V. Cabañas reports grants and personal fees from Johnson&Johnson and personal fees from Bristol Myers Squibb, Amgen, Biogene, GlaxoSmithKline, Menarini, and Sanofi outside the submitted work. M.-V. Mateos reports personal fees from Johnson&Johnson, Bristol Myers Squibb, GlaxoSmithKline, Sanofi, Pfizer, Kite, Stemline, Oncopeptides, AbbVie, and Roche outside the submitted work. J.F. San-Miguel reports other support from Abbvie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Pfizer, Takeda, Regeneron, Roche, Sanofi, and SecuraBio outside the submitted work. B. Paiva reports personal fees from Adaptive, Amgen, and Becton Dickinson, grants and personal fees from Sanofi, Takeda, Bristol Myers Squibb–Celgene, and Janssen, and personal fees from Merck, Novartis, and Roche outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Mutational landscape of HPCs in untreated patients. A, Detection of mutant HPCs identified using a customized pan-myeloid panel targeting 56 genes recurrently mutated in myeloid neoplasms in 232 BM samples from untreated patients with multiple myeloma. Those carrying mutant HPCs were subdivided according to the presence of isolated and concomitant gene mutations defined with a minimum VAF of ≥2%. B, Frequency of mutations and VAFs in individual genes observed in the 232 untreated patients with multiple myeloma. C, Percentage of patients ages <45–55, 56–65, and >66 years carrying mutant HPCs and enumeration of mutated genes. The corrected χ2 test was used to identify statistical associations.
Figure 2.
Figure 2.
Mutant HPCs and clinical outcomes. A and B, Progression-free survival (PFS) and OS of 167 newly diagnosed patients with active multiple myeloma (MM) with vs. without mutant HPCs at diagnosis. Patients with high-risk smoldering MM enrolled in the GEM-CESAR trial and those with active MM enrolled in the GEM2021MENOS65 trial were excluded from survival analysis due to the singular disease setting and limited follow-up, respectively. C, Forest plots visualizing log ORs with 95% confidence intervals (CI) of multivariate logistic regression model integrating tumor microenvironmental characteristics in 167 newly diagnosed patients with active MM having normal vs. mutated HPCs.
Figure 3.
Figure 3.
Mutational landscape of HPCs in treated patients. A, Detection of mutant HPCs in the 211 treated patients with multiple myeloma (MM) analyzed in this study. Those carrying mutant HPCs were subdivided according to the presence of isolated and concomitant gene mutations identified using a customized pan-myeloid panel targeting 56 genes. B, Frequency of detected mutations in the last available sample and VAFs in individual genes observed in the 211 treated patients with MM. C, Frequency of mutant HPCs and VAFs of mutated genes in the 555 longitudinal BM HPC samples collected at diagnosis and throughout treatment in the 348 patients with MM analyzed in this study. Corrected χ2 test was used to identify statistical associations. EoT, end of treatment; PD, progressive disease.
Figure 4.
Figure 4.
The effect of treatment in the mutational landscape of HPCs. Patient-paired analysis of mutations in HPCs detected at diagnosis and after (A) induction (n = 52), (B) intensification (i.e., either at day 100 after HDT followed by ASCT or after consolidation, n = 35), and (C) during maintenance (n = 32). Of note, comparisons are performed per patient, and one patient can have more than one sample available. D, VAF of genes mutated at diagnosis with the same variant found after induction, intensification, or maintenance in paired BM HPC samples.
Figure 5.
Figure 5.
Temporal dynamics of mutant HPCs. Longitudinal analysis of mutant HPCs in 48 BM samples from transplant-eligible patients with three or more samples available at any time point. Colored rectangles represent available BM HPC samples, with gray indicating the absence of detected mutations. Within each colored rectangle, the VAF of the identified mutation is displayed. As multiple mutations can be present within a single sample, the rectangles are subdivided accordingly. EoT/PD, end of treatment or progressive disease; Maint. Year 1-5, years after beginning of maintenance therapy; N., number of; Pre-Maint., pre-maintenance therapy.
Figure 6.
Figure 6.
Presence of mutant HPCs and SPM risk. Time-chart of the 29 patients developing SPMs and of mutant HPCs detected at any time from diagnosis throughout treatment. Colored rectangles represent available BM HPC samples, with gray indicating the absence of detected mutations. Within each colored rectangle, the VAF of the identified mutation is displayed. As multiple mutations can be present within a single sample, the rectangles are subdivided accordingly. SPMs with OS events are further stratified according to the cause of death: SPM in red and multiple myeloma (MM) in purple. EoT/PD, end of treatment or progressive disease; Maint. Year 1–5, years after beginning of maintenance therapy; N., number of; SPM, second primary malignancies; TE, transplant eligibility.
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References

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