Response rates and minimal residual disease outcomes as potential surrogates for progression-free survival in newly diagnosed multiple myeloma

Daniele, Patrick; Mamolo, Carla; Cappelleri, Joseph C.; Bell, Timothy J.; Neuhof, Alexander; Tremblay, Gabriel; Musat, Mihaela; Forsythe, Anna

doi:10.1371/journal.pone.0267979

Cited by 10 publications

(4 citation statements)

References 33 publications

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“…We next examined whether patients with VGPR or CR had an improved progression-free survival. Response has been associated with PFS in studies of overt MM 28 . However, this has not been previously shown in studies of smoldering myeloma partially because the previous studies using lenalidomide and dexamethasone had few cases of CR and partially for the short follow-up period of the quadruplet regimens being currently assessed in SMM.…”

Section: Resultsmentioning

confidence: 99%

Long-Term Follow-Up Defines the Population That Benefits from Early Interception in a High-Risk Smoldering Multiple Myeloma Clinical Trial Using the Combination of Ixazomib, Lenalidomide, and Dexamethasone

Nadeem,

Aranha,

Redd

et al. 2024

Preprint

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Background: Early therapeutic intervention in high–risk SMM (HR–SMM) has demonstrated benefit in previous studies of lenalidomide with or without dexamethasone. Triplets and quadruplet studies have been examined in this same population. However, to date, none of these studies examined the impact of depth of response on long–term outcomes of participants treated with lenalidomide–based therapy, and whether the use of the 20/2/20 model or the addition of genomic alterations can further define the population that would benefit the most from early therapeutic intervention. Here, we present the results of the phase II study of the combination of ixazomib, lenalidomide, and dexamethasone in patients with HR–SMM with long-term follow–up and baseline single-cell tumor and immune sequencing that help refine the population to be treated for early intervention studies. Methods: This is a phase II trial of ixazomib, lenalidomide, and dexamethasone (IRD) in HR–SMM. Patients received 9 cycles of induction therapy with ixazomib 4mg on days 1, 8, and 15; lenalidomide 25mg on days 1 to 21; and dexamethasone 40mg on days 1, 8, 15, and 22. The induction phase was followed by maintenance with ixazomib 4mg on days 1, 8, and 15; and lenalidomide 15mg d1 to 21 for 15 cycles for 24 months of treatment. The primary endpoint was progression–free survival after 2 years of therapy. Secondary endpoints included depth of response, biochemical progression, and correlative studies included single–cell RNA sequencing and/or whole–genome sequencing of the tumor and single-cell sequencing of immune cells at baseline. Results: Fifty–five patients, with a median age of 64, were enrolled in the study. The overall response rate was 93%, with 31% of patients achieving a complete response (CR) and 45% achieving a very good partial response (VGPR) or better. All patients that achieved a CR sustained it for greater than 6 months. The most common grade 3 or greater treatment-related hematologic toxicities were neutropenia (16 patients; 29%), leukopenia (10 patients; 18%), lymphocytopenia (8 patients; 15%), and thrombocytopenia (4 patients; 7%). Non-hematologic grade 3 or greater toxicities included hypophosphatemia (7 patients; 13%), rash (5 patients; 9%), and hypokalemia (4 patients; 7%). After a median follow–up of 50 months, the median progression–free survival (PFS) was 48.6 months (95% CI: 39.9 – not reached; NR) and median overall survival has not been reached. The median progression–free survival in the sustained CR group was not reached, compared to 38 months in the non–CR group (p = 0.0018). Similarly, patients achieving VGPR or better had a significantly better progression-free survival (p<0.001) compared to those who did not achieve VGPR (median PFS 58.2 months vs. 31.3 months). Biochemical progression preceded or was concurrent with the development of SLiM–CRAB criteria in eight patients during follow–up, indicating that biochemical progression is a meaningful endpoint that correlates with the development of end–organ damage. High–risk 20/2/20 participants had the worst PFS compared to low- and intermediate–risk participants. The use of whole genome or single–cell sequencing of tumor cells identified high–risk aberrations that were not identified by FISH alone and aided in the identification of participants at risk of progression. scRNA–seq analysis revealed a positive correlation between MHC class I expression and response to proteasome inhibition and at the same time a decreased proportion of GZMB+ T cells within the clonally expanded CD8+ T cell population correlated with suboptimal response. Conclusions: Ixazomib, lenalidomide, and dexamethasone in HR-SMM demonstrates significant clinical activity with an overall favorable safety profile. Achievement of sustained CR and VGPR or greater led to significant improvement in time to progression, suggesting that achieving deep response is beneficial in HR–SMM. Biochemical progression correlates with end-organ damage. Patients with high–risk FISH and lack of deep response had poor outcomes. ClinicalTrials.gov identifier: (NCT02916771)

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Section: Resultsmentioning

confidence: 99%

Long-Term Follow-Up Defines the Population That Benefits from Early Interception in a High-Risk Smoldering Multiple Myeloma Clinical Trial Using the Combination of Ixazomib, Lenalidomide, and Dexamethasone

Nadeem,

Aranha,

Redd

et al. 2024

Preprint

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“…In spite of the doubled 5-year overall survival rate for MM to above 50% over the past decade ( Daniele et al, 2022 ), as our understanding for the disease biology advances, the treatment strategies for MM have been, and will keep, evolving with persisting demands for more appropriate therapeutics. As an example, current treatment options, such as the proteasome inhibitor bortezomib and immunomodulatory agent lenalidomide, are subject to development of drug resistance in almost all patients ( Zhang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…In spite of the doubled 5-year overall survival rate for MM to above 50% over the past decade (Daniele et al, 2022), as our understanding for the disease biology advances, the treatment strategies for MM have been, and will keep, evolving with Apoptosis of RPMI8226 cells induced by RGD-IONP/CAPE within 24 h in the TW model. Dose-dependent induction of RPMI8226 apoptosis was observed in the presence of HS-5 cells (A).…”

Section: Discussionmentioning

confidence: 99%

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Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities

Smith,

Li,

Fields

et al. 2024

Front. Pharmacol.

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Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells preferentially in the bone marrow. Currently, emerging chemotherapy drugs with improved biosafety profiles, such as immunomodulatory agents and protease inhibitors, have been used in clinics to treat MM in both initial therapy or maintenance therapy post autologous hematopoietic stem cell transplantation (ASCT). We previously discovered that caffeic acid phenethyl ester (CAPE), a water-insoluble natural compound, inhibited the growth of MM cells by inducing oxidative stress. As part of our continuous effort to pursue a less toxic yet more effective therapeutic approach for MM, the objective of this study is to investigate the potential of CAPE for in vivo applications by using magnetic resonance imaging (MRI)-capable superparamagnetic iron oxide nanoparticles (IONP) as carriers. Cyclo (Arg-Gly-Asp-D-Phe-Cys) (RGD) is conjugated to IONP (RGD-IONP/CAPE) to target the overexpressed αvβ3 integrin on MM cells for receptor-mediated internalization and intracellular delivery of CAPE. A stable loading of CAPE on IONP can be achieved with a loading efficiency of 48.7% ± 3.3% (wt%). The drug-release studies indicate RGD-IONP/CAPE is stable at physiological (pH 7.4) and basic pH (pH 9.5) and subject to release of CAPE at acidic pH (pH 5.5) mimicking the tumor and lysosomal condition. RGD-IONP/CAPE causes cytotoxicity specific to human MM RPMI8226, U266, and NCI-H929 cells, but not to normal peripheral blood mononuclear cells (PBMCs), with IC50s of 7.97 ± 1.39, 16.75 ± 1.62, and 24.38 ± 1.71 μM after 72-h treatment, respectively. Apoptosis assays indicate RGD-IONP/CAPE induces apoptosis of RPMI8226 cells through a caspase-9 mediated intrinsic pathway, the same as applying CAPE alone. The apoptogenic effect of RGD-IONP/CAPE was also confirmed on the RPMI8226 cells co-cultured with human bone marrow stromal cells HS-5 in a Transwell model to mimic the MM microenvironment in the bone marrow. In conclusion, we demonstrate that water-insoluble CAPE can be loaded to RGD-IONP to greatly improve the biocompatibility and significantly inhibit the growth of MM cells in vitro through the induction of apoptosis. This study paves the way for investigating the MRI-trackable delivery of CAPE for MM treatment in animal models in the future.

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Association of Minimal Residual Disease Negativity Rates With Progression Free Survival in Frontline Therapy Trials for Newly Diagnosed Multiple Myeloma: A Meta-analysis

Ficek

Yuan

Kalaitzaki

et al. 2023

Clinical Lymphoma Myeloma and Leukemia

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Response rates and minimal residual disease outcomes as potential surrogates for progression-free survival in newly diagnosed multiple myeloma

Cited by 10 publications

References 33 publications

Long-Term Follow-Up Defines the Population That Benefits from Early Interception in a High-Risk Smoldering Multiple Myeloma Clinical Trial Using the Combination of Ixazomib, Lenalidomide, and Dexamethasone

Long-Term Follow-Up Defines the Population That Benefits from Early Interception in a High-Risk Smoldering Multiple Myeloma Clinical Trial Using the Combination of Ixazomib, Lenalidomide, and Dexamethasone

Tumor integrin targeted theranostic iron oxide nanoparticles for delivery of caffeic acid phenethyl ester: preparation, characterization, and anti-myeloma activities

Association of Minimal Residual Disease Negativity Rates With Progression Free Survival in Frontline Therapy Trials for Newly Diagnosed Multiple Myeloma: A Meta-analysis

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