Multiple Myeloma Group

  • Albert oriol
Campus ICO-Germans Trias i Pujol

IMPPC Building ICO-GTiP Campus
Ctra. de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona, Spain

Directions

Research

The group is focused on translational research and most specifically in the analysis of the biological processes leading to the development of resistance of myeloma to specific drugs. We are linking biological and clinical research by the study by gene expression profiling and other methods of myeloma and immune cells from patients receiving specific treatments. We expect that type of research will ultimately lead to the understanding of mechanisms by which myeloma cells develop resistance to certain drugs, identify biomarkers to predict the risk of development of resistance and finally develop therapeutic strategies able to prevent the development of chemoresistance. 

Our current research project aims to detect gene expression profiling biomarkers in myeloma cells and in normal lymphocytes of patients that predict early progression or long term response to lenalidomide in patients with relapsed multiple myeloma. New focus of interest are to study patients immune response to treatment with antibodies anti-PD1 and PDL1 in combination with immunomodulatory drugs.

Affiliations – Institut Català d’Oncologia. Hospital Germans Trias i Pujol. Institut Germans Trias i Pujol.

Collaborations

The group aims to develop collaborative projects with the pharmaceutical industry and academic research organizations. 

People

NamePosition
Albert OrioloriolPrincipal Investigator
Paula GomezPgomez_3xTechnician
Isabel Granada
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Postdoctoral Investigator
Mar MalloMmallo_3xPostdoctoral Investigator
Cristina Motlló
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PhD Student
Neus Ruiz
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PhD Student

Selected publications

Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P

Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma.

Blood 1 Sep 2016, 128 (9) 1174-80. Epub 20 Jul 2016
The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391.
More information
Paiva B, Mateos MV, Sanchez-Abarca LI, Puig N, Vidriales MB, López-Corral L, Corchete LA, Hernandez MT, Bargay J, de Arriba F, de la Rubia J, Teruel AI, Giraldo P, Rosiñol L, Prosper F, Oriol A, Hernández J, Esteves G, Lahuerta JJ, Bladé J, Perez-Simon JA, San Miguel JF

Immune status of high-risk smoldering multiple myeloma patients and its therapeutic modulation under LenDex: a longitudinal analysis.

Blood 3 Mar 2016, 127 (9) 1151-62. Epub 14 Dec 2015
There is significant interest in immunotherapy for the treatment of high-risk smoldering multiple myeloma (SMM), but no available data on the immune status of this particular disease stage. Such information is important to understand the interplay between immunosurveillance and disease transformation, but also to define whether patients with high-risk SMM might benefit from immunotherapy. Here, we have characterized T lymphocytes (including CD4, CD8, T-cell receptor γδ, and regulatory T cells), natural killer (NK) cells, and dendritic cells from 31 high-risk SMM patients included in the treatment arm of the QUIREDEX trial, and with longitudinal peripheral blood samples at baseline and after 3 and 9 cycles of lenalidomide plus low-dose dexamethasone (LenDex). High-risk SMM patients showed at baseline decreased expression of activation-(CD25/CD28/CD54), type 1 T helper-(CD195/interferon-γ/tumor necrosis factor-α/interleukin-2), and proliferation-related markers (CD119/CD120b) as compared with age-matched healthy individuals. However, LenDex was able to restore the normal expression levels for those markers and induced a marked shift in T-lymphocyte and NK-cell phenotype. Accordingly, high-risk SMM patients treated with LenDex showed higher numbers of functionally active T lymphocytes. Together, our results indicate that high-risk SMM patients have an impaired immune system that could be reactivated by the immunomodulatory effects of lenalidomide, even when combined with low-dose dexamethasone, and support the value of therapeutic immunomodulation to delay the progression to multiple myeloma. The QUIREDEX trial was registered to www.clinicaltrials.gov as #NCT00480363.
More information
Paiva B, Cedena MT, Puig N, Arana P, Vidriales MB, Cordon L, Flores-Montero J, Gutierrez NC, Martín-Ramos ML, Martinez-Lopez J, Ocio EM, Hernandez MT, Teruel AI, Rosiñol L, Echeveste MA, Martinez R, Gironella M, Oriol A, Cabrera C, Martin J, Bargay J, Encinas C, Gonzalez Y, Van Dongen JJ, Orfao A, Bladé J, Mateos MV, Lahuerta JJ, San Miguel JF

Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients.

Blood 23 Jun 2016, 127 (25) 3165-74. Epub 26 Apr 2016
The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible patients than in elderly patients. Because an optimal balance between treatment efficacy and toxicity is of utmost importance in patients with elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used second-generation 8-color multiparameter-flow cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study. The transition from first- to second-generation MFC resulted in increased sensitivity and allowed us to identify 3 patient groups according to MRD levels: MRD negative (<10(-5); n = 54, 34%), MRD positive (between <10(-4) and ≥10(-5); n = 20, 12%), and MRD positive (≥10(-4); n = 88, 54%). MRD status was an independent prognostic factor for time to progression (TTP) (hazard ratio [HR], 2.7; P = .007) and overall survival (OS) (HR, 3.1; P = .04), with significant benefit for MRD-negative patients (median TTP not reached, 70% OS at 3 years), and similar poorer outcomes for cases with MRD levels between <10(-4) and ≥10(-5) vs ≥10(-4) (both with a median TTP of 15 months; 63% and 55% OS at 3 years, respectively). Furthermore, MRD negativity significantly improved TTP of patients >75 years (HR, 4.8; P < .001), as well as those with high-risk cytogenetics (HR, 12.6; P = .01). Using second-generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate, and favorable outcomes (25%, 61%, and 100% OS at 3 years, respectively; P = .01), the later patients being characterized by an increased compartment of mature B cells. Our results show that similarly to transplant candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespectively of age or cytogenetic risk. This trial was registered at www.clinicaltrials.gov as #NCT01237249.
More information
Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Bladé J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM

Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.

Lancet 9 Apr 2016, 387 (10027) 1551-60. Epub 7 Jan 2016
New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma.
More information
Paiva B, Puig N, Cedena MT, de Jong BG, Ruiz Y, Rapado I, Martinez-Lopez J, Cordon L, Alignani D, Delgado JA, van Zelm MC, Van Dongen JJ, Pascual M, Agirre X, Prosper F, Martín-Subero JI, Vidriales MB, Gutierrez NC, Hernandez MT, Oriol A, Echeveste MA, Gonzalez Y, Johnson SK, Epstein J, Barlogie B, Morgan GJ, Orfao A, Blade J, Mateos MV, Lahuerta JJ, San-Miguel JF

Differentiation stage of myeloma plasma cells: biological and clinical significance.

Leukemia 16 Sep 2016, . Epub 16 Sep 2016
The notion that plasma cells (PCs) are terminally differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+) and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR: 1.7; P=0.005) and overall survival (HR: 2.1; P=0.006). Longitudinal comparison of diagnostic vs minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (for example: PAX5), and show distinct mutation profile vs fully differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harbouring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles.Leukemia advance online publication, 16 September 2016; doi:10.1038/leu.2016.211.
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Current projects

Correlation between response kinetics of response to lenalidomide treatment and gene expression profiles (GEP) in multiple myeloma

Project leader:Albert Oriol
Funding:
Start date:01/01/2016
End date:31/12/2016