Isatuximab, Pomalidomide, and Dexamethasone (IsaPd) As Salvage Therapy for Patients with Multiple Myeloma: Multicenter, Retrospective Clinical Experience with 262 Cases Outside of Controlled Clinical Trials

This preliminary study investigates the real-world efficacy and safety of Isatuximab (Isa) combined with pomalidomide (P) and dexamethasone (d) (IsaPd) as a salvage therapy for relapsed/refractory multiple myeloma (RRMM) patients treated outside of controlled clinical trials according to marketing approval. A cohort of 262 RRMM patients from 50 Italian centers received at least one cycle of IsaPd as salvage treatment between January 2021 and June 2024. To qualify as responsive, patients were required to achieve at least a partial remission (PR). At the initiation of IsaPd therapy, 143 patients (54.6%) were males, with 14.1% classified as stage III according to the International Staging System (ISS). The median number of prior therapies was 2 (range 2-7), with 24.8% of patients exhibiting refractory disease. Furthermore, 38.9% of patients had undergone autologous stem cell transplant (ASCT), and 16.8% had prior exposure to daratumumab. Cytogenetic data from FISH analysis data were available for 142 patients (54.2%), with 69.7% showing favorable cytogenetic profiles, while 30.3% were categorized as high-risk due to aberrations such as t(4;14), t(14;16), and del(17p). As of June 2024, all patients were evaluable for response. The median number of IsaPd cycles administered was 11 (range 1-37). The overall response rate (ORR) was 73.7%, including 11 stringent complete responses (sCR, 4.2%), 28 complete responses (CR, 10.7%), and 77 very good partial responses (VGPR, 29.4%). Significant grade 3/4 adverse events included neutropenia (56.1%), anemia (14.1%), and thrombocytopenia (16.4%). Infection rates were 48%, with pneumonia occurring in 26.7% of cases. After a median follow-up of 23.5 months (range 1-35), disease progression or death occurred in 105 patients, yielding a median progression-free survival (PFS) of 15.4 months. Univariable analyses showed no significant impact on PFS from age, gender, number of previous therapies, or prior ASCT. However, elevated LDH (HR=1.8; P=0.004), high-risk cytogenetic abnormalities (HR=2.57; P<0.0001), refractory disease (HR=1.52; P=0.02), ISS stage III (HR=2.48; P<0.0001) and previous daratumumab exposure (HR=2.12; P<0.0001) were associated with a significantly shorter PFS. Cox multivariable analysis identified high-risk cytogenetic abnormalities (HR=2.87; P<0.0001), elevated LDH (HR=2.35; P=0.003), and previous daratumumab exposure (HR=2.44; P=0.003) as independent prognostic factors for PFS. The 2-year-overall survival (OS) probability was 66.3%. Univariable analyses identified elevated LDH (HR=2.3; P=0.01), high-risk cytogenetic abnormalities (HR=1.92; P=0.042), creatinine clearance <60 ml/min (HR=1.52; P=0.02), ISS stage III (HR=2.51; P<0.0001), prior daratumumab exposure (HR=1.95; P=0.013), and more than 2 previous therapies (HR=1.57; P=0.041) as adverse prognostic factors. In Cox multivariable analysis, high-risk cytogenetic abnormalities (HR=2.12;P=0.023), elevated LDH (HR=3.3; P=0.001) and creatinine clearance <60 ml/min (HR=2.48;P=0.007) maintained independent prognostic significance for OS. Previous daratumumab exposure was trendily associated with OS (HR=2.48; P=0.07). In conclusion, this comprehensive real-world study confirms the safety and efficacy of IsaPd as a viable salvage therapy for RRMM who have undergone at least two treatment regimens. The ORR of 73.7% is noteworthy. Nonetheless, when making therapeutic decisions on the IsaPd triplet regimen, a number of prognostic factors that have a detrimental effect on outcomes should be taken into account.

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Journal
Blood
Published
2024-11-05
DOI
https://doi.org/10.1182/blood-2024-206008
Primary Topic
Multiple Myeloma Research and Treatments
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article

Isatuximab, Pomalidomide, and Dexamethasone (IsaPd) As Salvage Therapy for Patients with Multiple Myeloma: Multicenter, Retrospective Clinical Experience with 262 Cases Outside of Controlled Clinical Trials

Giovanni Reddiconto, Concetta Conticello, Giuseppina Uccello, Flavia Lotti et al.
Blood
Multiple Myeloma Research and Treatments
article

Isatuximab, Pomalidomide, and Dexamethasone (IsaPd) As Salvage Therapy for Patients with Multiple Myeloma: Multicenter, Retrospective Clinical Experience with 262 Cases Outside of Controlled Clinical Trials

Giovanni Reddiconto, Concetta Conticello, Giuseppina Uccello, Flavia Lotti, Gabriele Buda, Pietro Benvenuti, Nicola Di Renzo, Enrica Antonia Martino, Emiliano Barbieri, Annalisa Citro, Massimo Gentile, Alessandro Maggi, Ombretta Annibali, Lorenzo De Paoli, Cirino Botta, Claudio De Magistris, Angela Rago, Fortunato Morabito, Daniela Roccotelli, Rosario Bianco, Velia Bongarzoni, Alessandro Gozzetti, Raffaele Fontana, Francesco Di Raimondo, Marta Coscia, Anna Maria Cafro, Antonella Bruzzese, Antonino Neri, Marino Brunori, Silvia Mangiacavalli, Pellegrino Musto, Angela Amendola, Giuseppe Mele, Giuseppe Bertuglia, Francesca Farina, Alessandra Lombardo, Mario Monachesi, Valerio De Stefano, Elena Zamagni, Roberta Della Pepa, Antonio Lazzaro, Salvatore Palmieri, Sara Aquino, Anna Mele, Santo Neri, Gloria Margiotta Casaluci, Renato Zambello, Vittorio Montefusco, Massimiliano Arangio Febbo, Carmine Liberatore, Gregorio Barilà, Daniele Derudas, Elisabetta Antonioli, Nicola Sgherza, Anna Furlan, Massimo Offidani, Claudio Cerchione, Catello Califano, Ernesto Vigna, Jacopo Micozzi, Paola Stefanoni, Sofia Terlizzi, Elena Rossi
article en

Abstract

This preliminary study investigates the real-world efficacy and safety of Isatuximab (Isa) combined with pomalidomide (P) and dexamethasone (d) (IsaPd) as a salvage therapy for relapsed/refractory multiple myeloma (RRMM) patients treated outside of controlled clinical trials according to marketing approval. A cohort of 262 RRMM patients from 50 Italian centers received at least one cycle of IsaPd as salvage treatment between January 2021 and June 2024. To qualify as responsive, patients were required to achieve at least a partial remission (PR). At the initiation of IsaPd therapy, 143 patients (54.6%) were males, with 14.1% classified as stage III according to the International Staging System (ISS). The median number of prior therapies was 2 (range 2-7), with 24.8% of patients exhibiting refractory disease. Furthermore, 38.9% of patients had undergone autologous stem cell transplant (ASCT), and 16.8% had prior exposure to daratumumab. Cytogenetic data from FISH analysis data were available for 142 patients (54.2%), with 69.7% showing favorable cytogenetic profiles, while 30.3% were categorized as high-risk due to aberrations such as t(4;14), t(14;16), and del(17p). As of June 2024, all patients were evaluable for response. The median number of IsaPd cycles administered was 11 (range 1-37). The overall response rate (ORR) was 73.7%, including 11 stringent complete responses (sCR, 4.2%), 28 complete responses (CR, 10.7%), and 77 very good partial responses (VGPR, 29.4%). Significant grade 3/4 adverse events included neutropenia (56.1%), anemia (14.1%), and thrombocytopenia (16.4%). Infection rates were 48%, with pneumonia occurring in 26.7% of cases. After a median follow-up of 23.5 months (range 1-35), disease progression or death occurred in 105 patients, yielding a median progression-free survival (PFS) of 15.4 months. Univariable analyses showed no significant impact on PFS from age, gender, number of previous therapies, or prior ASCT. However, elevated LDH (HR=1.8; P=0.004), high-risk cytogenetic abnormalities (HR=2.57; P<0.0001), refractory disease (HR=1.52; P=0.02), ISS stage III (HR=2.48; P<0.0001) and previous daratumumab exposure (HR=2.12; P<0.0001) were associated with a significantly shorter PFS. Cox multivariable analysis identified high-risk cytogenetic abnormalities (HR=2.87; P<0.0001), elevated LDH (HR=2.35; P=0.003), and previous daratumumab exposure (HR=2.44; P=0.003) as independent prognostic factors for PFS. The 2-year-overall survival (OS) probability was 66.3%. Univariable analyses identified elevated LDH (HR=2.3; P=0.01), high-risk cytogenetic abnormalities (HR=1.92; P=0.042), creatinine clearance <60 ml/min (HR=1.52; P=0.02), ISS stage III (HR=2.51; P<0.0001), prior daratumumab exposure (HR=1.95; P=0.013), and more than 2 previous therapies (HR=1.57; P=0.041) as adverse prognostic factors. In Cox multivariable analysis, high-risk cytogenetic abnormalities (HR=2.12;P=0.023), elevated LDH (HR=3.3; P=0.001) and creatinine clearance <60 ml/min (HR=2.48;P=0.007) maintained independent prognostic significance for OS. Previous daratumumab exposure was trendily associated with OS (HR=2.48; P=0.07). In conclusion, this comprehensive real-world study confirms the safety and efficacy of IsaPd as a viable salvage therapy for RRMM who have undergone at least two treatment regimens. The ORR of 73.7% is noteworthy. Nonetheless, when making therapeutic decisions on the IsaPd triplet regimen, a number of prognostic factors that have a detrimental effect on outcomes should be taken into account.

BloodVol. 144(Supplement 1)
University of Siena (IT), University of Pisa (IT), University of Insubria (IT), Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), University of Padua (IT), University of Perugia (IT), Azienda Ospedaliera San Giovanni Addolorata (IT), Casa Sollievo della Sofferenza (IT), Policlinico Umberto I (IT), Ospedale di Circolo e Fondazione Macchi (IT), Agostino Gemelli University Polyclinic (IT), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), University of Catania (IT), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Ospedale Antonio Cardarelli (IT), Ospedale San Paolo (IT), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), ASL Roma (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT), Ospedale San Carlo (IT), Azienda Ospedaliera di Cosenza (IT), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Ospedale A. Perrino (IT), Ospedale Papa Giovanni XXIII (IT), Ospedali Riuniti di Ancona (IT), Ospedale di Santo Spirito (IT), Istituto Oncologico Veneto (IT), Azienda Ospedaliera S.Giuseppe Moscati (IT), Ospedale Santa Maria (IT), Federico II University Hospital (IT), Istituto di Ematologia di Bologna (IT), Presidio Ospedaliero (IT), Azienda Ospedaliera Sant'Andrea (IT), Ospedale Annunziata di Cosenza (IT), IRCCS Ospedale San Raffaele (IT), Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona (IT), Guglielmo da Saliceto Hospital (IT), Ospedale Pediatrico Giovanni XXIII (IT), Campus Bio Medico University Hospital (IT), Azienda di Rilievo Nazionale ed Alta Specializzazione (IT), Ca' Foncello Hospital (IT), Ospedale Policlinico San Martino (IT), Policlinico San Matteo Fondazione (IT), Ospedale San Bortolo (IT), Ospedale Vito Fazzi (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Azienda Sanitaria Locale Roma 3 (IT), Gruppo Italiano per il Trapianto di Midollo Osseo (IT), Azienda Ospedaliera Ospedale Civile di Legnano (IT), Azienda Ospedaliera Ospedali Riuniti Papardo Piemonte (IT), Aziende Socio Sanitarie Territoriale dei Sette Laghi, Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo, University of Florence (IT), University of Calabria (IT), University of Bari Aldo Moro (IT), University of Brescia (IT), Sapienza University of Rome (IT), University of Palermo (IT), University of Bologna (IT)
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