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Cancers Oct 2023Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma...
Efficacy and Safety of Daratumumab, Pomalidomide, and Dexamethasone (DPd) Compared to Daratumumab, Bortezomib, and Dexamethasone (DVd) in Daratumumab-Naïve Relapsed Multiple Myeloma.
Daratumumab-based combinations with pomalidomide/dexamethasone (DPd), or bortezomib/dexamethasone (DVd), have shown activity in relapsed/refractory multiple myeloma (RRMM) patients. However, no direct comparisons of safety or efficacy of the two regimens have been published to date. We conducted a retrospective study to compare the safety and efficacy of DPd and DVd in daratumumab-naïve RRMM patients. We included 140 daratumumab-naïve patients who had received DPd or DVd for RRMM. Overall, the DPd group had a greater number of patients who had high-risk disease characteristics. Although response was deeper in the DPd group, the median progression-free survival (PFS) and overall survival (OS) were similar between the two groups. The DPd group exhibited a higher incidence of hematologic toxicities, whereas the DVd group had a higher incidence of peripheral neuropathy. The study results showed that while DPd may provide a deeper response, there was no significant difference in PFS or OS compared to DVd. For the high proportion of difficult-to-treat patients, duration of treatment may have contributed to these results, indicating that patient and disease characteristics should be considered when selecting salvage treatments.
PubMed: 37835587
DOI: 10.3390/cancers15194894 -
British Journal of Haematology Jun 2023Lenalidomide maintenance in myeloma is well established. Nevertheless, pomalidomide could provide an alternative. Myeloma patients in first relapse, initially treated in...
Lenalidomide maintenance in myeloma is well established. Nevertheless, pomalidomide could provide an alternative. Myeloma patients in first relapse, initially treated in the Intergroupe Francophone du Myélome (IFM) 2009 trial, and subsequently in the IFM 2013-01 phase 2 trial, received four cycles of salvage therapy with pomalidomide plus cyclophosphamide plus dexamethasone (PCD) with transplantation plus 2 PCD consolidation or without transplantation but with 5 PCD and for all patients pomalidomide plus dexamethasone maintenance therapy. This consisted of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dexamethasone 20 mg weekly until progression. The primary endpoint was an improved response to treatment. A total of 75/100 patients reached therapy. The median follow-up time was 73 months. The median duration of treatment was 23.7 months. One third of patients improved their response from the initiation of treatment: 11%, 19% and 4% to a very good partial response, complete response or stringent complete response respectively. The median progression-free survival time was 33.2 months and the median overall survival time was not reached. Among the 75 patients, the reasons for pomalidomide discontinuation were progressive disease (54%), adverse events (AEs) (30%), investigator discretion (11%) and consent withdrawal (5%). Grade (G) 3/4 haematological AEs included neutropenia (51%) and lymphopenia (35%); G3/4 drug-related non-haematological AEs (>5%) comprised 13% infections. Long-term administration of pomalidomide and dexamethasone is feasible and one third of the patients improved their response.
Topics: Humans; Multiple Myeloma; Salvage Therapy; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone
PubMed: 36974007
DOI: 10.1111/bjh.18772 -
Annals of Hematology Jan 2020
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Lymphohistiocytosis, Hemophagocytic; Middle Aged; Multiple Myeloma; Thalidomide
PubMed: 31844932
DOI: 10.1007/s00277-019-03877-7 -
European Journal of Haematology Jun 2024We conducted a multicenter retrospective study to analyze the safety and efficacy of DPd versus DKd in daratumumab naïve RRMM patients treated in real-world practice.
OBJECTIVES AND METHODS
We conducted a multicenter retrospective study to analyze the safety and efficacy of DPd versus DKd in daratumumab naïve RRMM patients treated in real-world practice.
RESULTS
A total of 187 patients with RRMM were included in the analysis; 128 patients received DPd, and 59 patients received DKd. A vast majority (80%) of patients had lenalidomide refractory disease and nearly 50% had bortezomib refractory disease. The overall response and complete response rates were 76% and 34% in the DPd group versus 80% and 51% in the DKd group, respectively. With a median follow up of 36 months for the entire patient population, median PFS and OS in the DPd versus DKd groups were 12, 12, 37, and 35 months, respectively. The most common grade 3+ adverse events in the DPd versus DKd groups were neutropenia (32% vs. 7%), anemia (14% vs. 10%), thrombocytopenia (13% vs. 15%), and cardiovascular events (4% vs. 15%), respectively. Both DPd and DKd appeared to be a safe and effective treatment options for RRMM.
CONCLUSIONS
While there were more cytopenias associated with DPd and more cardiovascular side effects with DKd, there were no significant differences in the survival outcomes with these two regimens.
Topics: Humans; Multiple Myeloma; Male; Female; Antineoplastic Combined Chemotherapy Protocols; Aged; Middle Aged; Dexamethasone; Antibodies, Monoclonal; Thalidomide; Retrospective Studies; Oligopeptides; Treatment Outcome; Aged, 80 and over; Adult; Recurrence; Retreatment
PubMed: 38382632
DOI: 10.1111/ejh.14193 -
Panminerva Medica Dec 2020Over the last two decades, the outcomes of patients with multiple myeloma (MM), a malignant plasma cells dyscrasia, have dramatically improved. The development and the... (Review)
Review
INTRODUCTION
Over the last two decades, the outcomes of patients with multiple myeloma (MM), a malignant plasma cells dyscrasia, have dramatically improved. The development and the introduction of the immunomodulatory drugs (IMiDs) which include thalidomide, lenalidomide, and pomalidomide, have contributed significantly to these improvements.
EVIDENCE ACQUISITION
The IMiDs have been shown a multitude of mechanisms of action, including antiangiogenic, cytotoxic and immunomodulatory. The more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3, have provided new insight about their activities.
EVIDENCE SYNTHESIS
The IMIDs are widely used in the treatment of the different setting of MM patients and particularly lenalidomide represents the backbone in the therapy of newly diagnosed transplant eligible and transplant ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting.
CONCLUSIONS
Here the mechanisms of action, the clinical efficacy and the management of side effects are reviewed as well as the new classes of cereblon E3 ligase modulator (CELMoD) and their promising clinical data are described.
Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Humans; Immunologic Factors; Immunotherapy; Multiple Myeloma; Treatment Outcome; Ubiquitin-Protein Ligases
PubMed: 32955182
DOI: 10.23736/S0031-0808.20.04125-7 -
Clinical Lymphoma, Myeloma & Leukemia Mar 2024A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use...
INTRODUCTION
A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment.
METHODS
Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed.
RESULTS
Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without.
CONCLUSION
Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty.
Topics: Humans; Multiple Myeloma; Bortezomib; Lenalidomide; Frailty; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Thalidomide
PubMed: 38072743
DOI: 10.1016/j.clml.2023.10.009 -
Japanese Journal of Clinical Oncology Aug 2019The prognosis of multiple myeloma was quite poor in the last century, but it has significantly improved with the incorporation of novel agents, immunomodulatory drugs... (Review)
Review
The prognosis of multiple myeloma was quite poor in the last century, but it has significantly improved with the incorporation of novel agents, immunomodulatory drugs (IMiDs) and proteasome inhibitors. Thalidomide was first developed as a sedative in 1950s, but it was withdrawn from the market because of teratogenicity. In 1990s, however, thalidomide received attention due to the discovery of its anticancer potential derived from antiangiogenic and immunomodulatory activities, and its therapeutic effect on myeloma. In 2006, the U.S. Food and Drug Administration approved the use of thalidomide under strict control for the treatment of multiple myeloma. After that, two new IMiDs, lenalidomide and pomalidomide, were developed for the sake of more antitumor activity and less adverse events than thalidomide. The molecular mechanism of action of IMiDs remained unclear for a long time until 2010 when the protein cereblon (CRBN) was identified as a primary direct target. IMiDs binds to CRBN and alters the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in breakdown of intrinsic downstream proteins such as IKZF1 (Ikaros) and IKZF3 (Aiolos). There are many clinical trials of multiple myeloma using IMiDs under various conditions, and most of them show the efficacy of IMiDs. Nowadays lenalidomide plays a central role in both newly diagnosed and relapsed/refractory settings, mainly in combination with other novel agents such as proteasome inhibitors and monoclonal antibodies. This review presents an overview of recent advances in immunomodulatory drugs in the treatment of multiple myeloma.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Immunologic Factors; Multiple Myeloma; Proteasome Inhibitors; Randomized Controlled Trials as Topic; Stem Cell Transplantation
PubMed: 31187860
DOI: 10.1093/jjco/hyz083 -
Expert Review of Anticancer Therapy Jan 2021Immunotherapy has emerged as a major class in the therapeutic arsenal of multiple myeloma. Cell-based immunotherapy (CAR T-cells) and monoclonal antibody-based... (Review)
Review
INTRODUCTION
Immunotherapy has emerged as a major class in the therapeutic arsenal of multiple myeloma. Cell-based immunotherapy (CAR T-cells) and monoclonal antibody-based immunotherapy (naked monoclonal antibodies, antibody-drug conjugates, and bispecific T-cell engagers) are the two cornerstones of this novel approach for myeloma patients. Among numerous targets evaluated in the previous decade; CD38, SLAMF7, and, more recently, BCMA stand as the most promising.
AREAS COVERED
This review presents and discusses the currently available data regarding monoclonal antibodies in the treatment of multiple myeloma.
EXPERT OPINION
Anti-CD38-naked monoclonal antibodies have become a standard-of-care in multiple myeloma, greatly improving the depth and duration of response when combined with conventional therapy. Elotuzumab is approved in the relapse setting in combination with pomalidomide and maybe an interesting option in patients whose disease became refractory to anti-CD38 monoclonal antibodies. Anti-BCMA drug conjugates and bispecific T-cell engager antibodies are promising new molecules in the multiple myeloma armamentarium.
Topics: ADP-ribosyl Cyclase 1; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Humans; Immunotherapy; Immunotherapy, Adoptive; Membrane Glycoproteins; Multiple Myeloma; Receptors, Chimeric Antigen
PubMed: 33052750
DOI: 10.1080/14737140.2021.1837627 -
Biomarker Research Jun 2021Immunomodulatory drugs (IMiDs) include thalidomide, lenalidomide, and pomalidomide, which have shown significant efficacy in the treatment of multiple myeloma (MM),... (Review)
Review
Immunomodulatory drugs (IMiDs) include thalidomide, lenalidomide, and pomalidomide, which have shown significant efficacy in the treatment of multiple myeloma (MM), myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) and other hematological malignancies. IMiDs hijack the CRL4 ubiquitin ligase to target cellular proteins for ubiquitination and degradation, which is responsible for their clinical activity in MM and MDS with del(5q). However, intrinsic and acquired resistance frequently limit the efficacy of IMiDs. Recently, many efforts have been made to explore key regulators of IMiD sensitivity, resulting in great advances in the understanding of the regulatory networks related to this class of drugs. In this review, we describe the mechanism of IMiDs in cancer treatment and summarize the key regulators of IMiD sensitivity. Furthermore, we introduce genome-wide CRISPR-Cas9 screenings, through which the regulatory networks of IMiD sensitivity could be identified.
PubMed: 34090534
DOI: 10.1186/s40364-021-00297-6 -
Bioorganic & Medicinal Chemistry Nov 2023Proteolysis-targeting chimera (PROTAC) technology is a disruptive innovation in the drug development community, and over 20 PROTAC molecules are currently under clinical...
Proteolysis-targeting chimera (PROTAC) technology is a disruptive innovation in the drug development community, and over 20 PROTAC molecules are currently under clinical evaluation. These PROTAC molecules contain small-molecule warheads that bind to target proteins. Recently, oligonucleotide-warheaded PROTACs have emerged as a promising new tool to degrade DNA-binding proteins such as transcription factors. In this study, we applied an oligonucleotide-warheaded PROTAC technology to induce the degradation of signal transducer and activator of transcription 3 (STAT3), which is a hard-to-target protein. A double-stranded decoy oligonucleotide specific to STAT3 was conjugated to E3 binders (pomalidomide, VH032, and LCL161) to generate PROTAC molecules that recruited different E3 ubiquitin ligases cereblon (CRBN), von Hippel-Lindau (VHL), and inhibitor of apoptosis protein (IAP), respectively. One of the resulting PROTAC molecules, POM-STAT3, which recruits CRBN, potently induces STAT3 degradation. STAT3 degradation by POM-STAT3 was abolished by scrambling the oligonucleotide sequences of POM-STAT3 and by adding a double-stranded decoy oligonucleotide against STAT3 in a competitive manner, suggesting the significance of oligonucleotide sequences in STAT3 degradation. Moreover, POM-STAT3-induced STAT3 degradation was suppressed by the CRBN binder thalidomide, proteasome inhibitor bortezomib, E1 inhibitor MLN7243, and siRNA-mediated depletion of CRBN, indicating that STAT3 degradation is mediated by the ubiquitin-proteasome system, which involves CRBN as the responsible E3 ubiquitin ligase. Consistent with STAT3 degradation, NCI-H2087 cell viability was severely reduced following POM-STAT3 treatment. Thus, POM-STAT3 is a STAT3 degrader that potentially has cytocidal activity against cancer cells that are highly dependent on STAT3 signaling, which implies that inducing protein degradation by decoy oligonucleotide-warheaded PROTAC molecules could be harnessed to be therapeutic against oncogenic transcription factors.
Topics: STAT3 Transcription Factor; Ubiquitin-Protein Ligases; Proteolysis; Proteasome Endopeptidase Complex; Ubiquitins
PubMed: 37922656
DOI: 10.1016/j.bmc.2023.117507