Showing papers by "Paul G. Richardson published in 2020"
Emory University1, University of Texas MD Anderson Cancer Center2, University of Maryland, Baltimore3, Princess Margaret Cancer Centre4, Icahn School of Medicine at Mount Sinai5, University of Kansas6, University of Wisconsin-Madison7, Memorial Sloan Kettering Cancer Center8, Huntsman Cancer Institute9, Indiana University10, University of Lyon11, University of Washington12, University of Navarra13, Medical College of Wisconsin14, St. Vincent's Health System15, GlaxoSmithKline16, Research Triangle Park17, University College London Hospitals NHS Foundation Trust18, UCL Institute of Ophthalmology19, Harvard University20
TL;DR: Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma.
Abstract: Summary Background Belantamab mafodotin (GSK2857916), an immunoconjugate targeting B-cell maturation antigen, showed single-agent activity in the phase 1 DREAMM-1 study in heavily pre-treated patients with relapsed or refractory multiple myeloma. We further investigated the safety and activity of belantamab mafodotin in the DREAMM-2 study. Methods DREAMM-2 is an open-label, two-arm, phase 2 study done at 58 multiple myeloma specialty centres in eight countries. Patients (aged ≥18 years) with relapsed or refractory multiple myeloma with disease progression after three or more lines of therapy and who were refractory to immunomodulatory drugs and proteasome inhibitors, and refractory or intolerant (or both) to an anti-CD38 monoclonal antibody with an Eastern Cooperative Oncology Group performance status of 0–2 were recruited, centrally randomly assigned (1:1) with permuted blocks (block size 4), and stratified by previous lines of therapy (≤4 vs >4) and cytogenetic features to receive 2·5 mg/kg or 3·4 mg/kg belantamab mafodotin via intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. The intention-to-treat population comprised all randomised patients, regardless of treatment administration. The safety population comprised all patients who received at least one dose of belantamab mafodotin. The primary outcome was the proportion of randomly assigned patients in the intention-to-treat population who achieved an overall response, as assessed by an independent review committee. This study is registered with ClinicalTrials.gov , NCT03525678 , and is ongoing. Findings Between June 18, 2018, and Jan 2, 2019, 293 patients were screened and 196 were included in the intention-to-treat population (97 in the 2·5 mg/kg cohort and 99 in the 3·4 mg/kg cohort). As of June 21, 2019 (the primary analysis data cutoff date), 30 (31%; 97·5% CI 20·8–42·6) of 97 patients in the 2·5 mg/kg cohort and 34 (34%; 23·9–46·0) of 99 patients in the 3·4 mg/kg cohort achieved an overall response. The most common grade 3–4 adverse events in the safety population were keratopathy (in 26 [27%] of 95 patients in the 2·5 mg/kg cohort and 21 [21%] of 99 patients in the 3·4 mg/kg cohort), thrombocytopenia (19 [20%] and 33 [33%]), and anaemia (19 [20%] and 25 [25%]); 38 (40%) of 95 patients in the 2·5 mg/kg cohort and 47 (47%) of 99 in the 3·4 mg/kg cohort reported serious adverse events. Two deaths were potentially treatment related (one case of sepsis in the 2·5 mg/kg cohort and one case of haemophagocytic lymphohistiocytosis in the 3·4 mg/kg cohort). Interpretation Single-agent belantamab mafodotin shows anti-myeloma activity with a manageable safety profile in patients with relapsed or refractory multiple myeloma. Funding GlaxoSmithKline.
458 citations
Emory University1, Harvard University2, Huntsman Cancer Institute3, University of North Carolina at Chapel Hill4, Wake Forest University5, Icahn School of Medicine at Mount Sinai6, Oregon Health & Science University7, University of Alabama at Birmingham8, University of Texas Southwestern Medical Center9, City of Hope National Medical Center10, University of California, San Francisco11, Ohio State University12, University of Nebraska Medical Center13, University of California, San Diego14, University of Chicago15, Washington University in St. Louis16, University of Texas MD Anderson Cancer Center17, University of South Florida18, University of Washington19, Janssen Pharmaceutica20
TL;DR: Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns.
359 citations
Medical University of Silesia1, Academy of Medical Sciences, United Kingdom2, Charles University in Prague3, National and Kapodistrian University of Athens4, Imperial College London5, French Institute of Health and Medical Research6, University of Calgary7, University of Ostrava8, King's College London9, Nil Ratan Sircar Medical College and Hospital10, Indira Gandhi Institute of Medical Sciences11, University of Alberta12, University Hospitals of Leicester NHS Trust13, Hebron University14, Jagiellonian University Medical College15, Medical University of Łódź16, Flinders Medical Centre17, University of Wolverhampton18, University of Perugia19, St. Vincent's Health System20, Medical University Plovdiv21, Icahn School of Medicine at Mount Sinai22, Baylor University Medical Center23, Queen Elizabeth II Health Sciences Centre24, Hebrew University of Jerusalem25, University of Bologna26, Princess Margaret Cancer Centre27, University of Texas Southwestern Medical Center28, Harvard University29
TL;DR: This phase 3, randomised, open-label trial aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortzomib and dex amethas one in patients with previously treated multiple myeloma.
167 citations
Mayo Clinic1, Harvard University2, University of Pennsylvania3, University of Wisconsin-Madison4, Yale University5, Kaiser Permanente6, Saint Francis University7, Gundersen Health System8, University of California, Davis9, Wayne State University10, Emory University11, University of Texas MD Anderson Cancer Center12, Wake Forest University13
TL;DR: This multicentre, open-label, phase 3, randomised controlled trial aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT).
Abstract: Summary Background Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT). Methods In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0–2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m2 of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1–8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1–14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m2 of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1–21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing. Findings Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5–23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8–37·8) in the KRd group and 34·4 months (30·1–not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83–1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3–4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [ Interpretation The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs. Funding US National Institutes of Health, National Cancer Institute, and Amgen.
126 citations
TL;DR: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM.
Abstract: PURPOSESmoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, t...
89 citations
TL;DR: The authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.
Abstract: Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003–2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p < 0.001) due to an increase in MM progression. Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.
85 citations
National and Kapodistrian University of Athens1, Emory University2, Queen Elizabeth II Health Sciences Centre3, University of Navarra4, Medical University of Silesia5, Charles University in Prague6, Medical University of Lublin7, Sheba Medical Center8, Spanish National Research Council9, University of Alberta10, Ankara University11, Monash University12, Barts Health NHS Trust13, University of Texas MD Anderson Cancer Center14, Kyoto Prefectural University of Medicine15, Harvard University16, Bristol-Myers Squibb17
TL;DR: Elotuzumab plus lenalidomide/dexamethasone (ERd) is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1–3 prior LoTs, and the magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2–3Prior LoTs.
Abstract: Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1–3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1–3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68–1.00]; P = 0.0408 [less than allotted α of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1–3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2–3 prior LoTs.
79 citations
University of California, Los Angeles1, Fred Hutchinson Cancer Research Center2, University of North Carolina at Chapel Hill3, National Institutes of Health4, Centre for the AIDS Programme of Research in South Africa5, George Washington University6, Chris Hani Baragwanath Hospital7, Johns Hopkins University8, ViiV Healthcare9, FHI 36010
TL;DR: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials.
75 citations
TL;DR: The combination of lenalidomide, bortezomib and dexamethasone with transplant was associated with significantly longer progression-free survival (PFS) (primary endpoint) compared to RVd alone and overall survival at 4 years was similar in both groups.
63 citations
TL;DR: Most real-world patients with RRMM were ineligible for the hallmark RCTs, underlining the flawed nature of cross-study comparisons without RCT validation.
Abstract: Background Concern has been increasing in oncology regarding randomized clinical trial (RCT) eligibility limiting the generalizability of the findings to real-world populations. Using a large US electronic health record database, we investigated the real-world generalizability of the findings from recent RCTs for relapsed and/or refractory multiple myeloma (RRMM). Patients and Methods Patients with RRMM initiating second-to fourth-line therapy with the control arm of the following RCTs were retrospectively identified and categorized as "RCT eligible" or "RCT ineligible" according to the eligibility criteria: (1) Rd (lenalidomide, dexamethasone)—ASPIRE, TOURMALINE-MM1, POLLUX, and ELOQUENT-2; and (2) Vd (bortezomib, dexamethasone)—CASTOR and ENDEAVOR. Predictors of RCT ineligibility and overall survival were analyzed using logistic regression and Cox regression analysis. Results Variations in the individual trial ineligibility rates were noted, with up to 72.3% (range, 47.9%-72.3%) of patients not meeting the eligibility criteria for 1 of the 6 hallmark RCTs (n = 788 for Rd; n = 477 for Vd). Other malignancies, cardiovascular disease, acute infection, and renal dysfunction were the common reasons for ineligibility. Advanced age, Charlson comorbidity score of ≥ 2, later therapy lines (3-4), and refractory status to the previous line were independently predictive of RCT ineligibility. RCT-ineligible versus RCT-eligible patients had a significantly greater mortality risk (hazard ratio, Rd, 1.46; Vd, 1.51). Conclusion Most real-world patients with RRMM were ineligible for the hallmark RCTs. The eligibility rates varied across the RCTs, underlining the flawed nature of cross-study comparisons without RCT validation. Overall survival was significantly affected by the inability to meet the criteria, highlighting the limited generalizability of the RCT results. Greater efforts are required to broaden the eligibility criteria to reflect real-world clinical characteristics and narrow the gap between RCT efficacy and the observed effectiveness in real-world patients with RRMM.
62 citations
TL;DR: This study showed that blockade of the CXCR4–CXCL12 axis by ulocuplumab is safe with acceptable AEs and leads to a high response rate in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma, making CX CR4 inhibitors a promising class of antimyeloma drugs that should be further explored in clinical trials.
Abstract: Purpose: Ulocuplumab (BMS-936564) is a first-in-class fully human IgG4 monoclonal anti-CXCR4 antibody that inhibits the binding of CXCR4 to CXCL12. Patients and Methods: This phase Ib/II study aimed to determine the safety and tolerability of ulocuplumab alone and in combination with lenalidomide and dexamethasone (Arm A), or bortezomib and dexamethasone (Arm B), in patients with relapsed/refractory multiple myeloma. Results: Forty-six patients were evaluated (median age, 60 years; range, 53–67). The median number of prior therapies was 3 (range, 1–11), with 70% of subjects having received ≥3. This trial had a dose-escalation and a dose-expansion part. Using a 3+3 design on both arms of the trial, ulocuplumab9s dose was escalated to a maximum of 10 mg/kg without reaching MTD. The most common treatment-related adverse events (AE) were neutropenia (13 patients, 43.3%) in Arm A and thrombocytopenia (6 patients, 37.5%) in Arm B. No deaths related to study drugs occurred. The combination of ulocuplumab with lenalidomide and dexamethasone showed a high response rate (PR or better) of 55.2% and a clinical benefit rate of 72.4%, even in patients who had been previously treated with immunomodulatory agents (IMiD). Conclusions: This study showed that blockade of the CXCR4–CXCL12 axis by ulocuplumab is safe with acceptable AEs and leads to a high response rate in combination with lenalidomide and dexamethasone in patients with relapsed/refractory myeloma, making CXCR4 inhibitors a promising class of antimyeloma drugs that should be further explored in clinical trials.
TL;DR: In this analysis, daratumumab 16 mg/kg monotherapy showed durable responses and there were no new safety concerns with longer follow-up of these two studies.
TL;DR: A phase 1-2 study of melflufen and dexamethasone in patients with relapsed and refractory multiple myeloma to determine the maximum tolerated dose and to investigate its safety and efficacy is completed.
University of Paris1, Instituto Português de Oncologia Francisco Gentil2, University of Zurich3, King Saud bin Abdulaziz University for Health Sciences4, Goethe University Frankfurt5, University of Liège6, Medical University of Warsaw7, American University of Beirut8, Aix-Marseille University9, Vita-Salute San Raffaele University10, University of Regensburg11, Paris Diderot University12, University Medical Center Utrecht13, Hôpital Maisonneuve-Rosemont14, Case Western Reserve University15, Semmelweis University16, Claude Bernard University Lyon 117, Sheba Medical Center18, Trinity College, Dublin19, Keio University20, University of Cambridge21, LDS Hospital22, Mayo Clinic23, University of Helsinki24, Center for International Blood and Marrow Transplant Research25, Vanderbilt University Medical Center26, Harvard University27, Sahlgrenska University Hospital28, Lille University of Science and Technology29
TL;DR: An international consensus guideline for the treatment and prevention of SOS/VOD in adult patients is proposed on behalf of an international expert group.
Abstract: Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). While SOS/VOD may resolve within a few weeks in the majority of patients with mild-to-moderate disease, the most severe forms result in multiorgan dysfunction and are associated with a high mortality rate (>80%). Therefore, careful surveillance may allow early detection of SOS/VOD, particularly as the licensed available drug is proven to be effective and reduce mortality. The aim of this work is to propose an international consensus guideline for the treatment and prevention of SOS/VOD in adult patients, on behalf of an international expert group.
TL;DR: This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma.
Abstract: This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570’s formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit.
University of Texas MD Anderson Cancer Center1, Nationwide Children's Hospital2, Children's Hospital Los Angeles3, Harvard University4, University of Minnesota5, Morgan Stanley Children's Hospital6, Baylor College of Medicine7, St. Jude Children's Research Hospital8, University of Missouri–Kansas City9, University of Michigan10, Albert Einstein College of Medicine11, Duke University12
TL;DR: An international panel of multidisciplinary experts including physicians with expertise in HSCT, paediatric intensive care, nephrology, hepatology, radiology, pathology, and transfusion medicine provide consensus recommendations for the international implementation of guidelines for the diagnosis, severity grading, and treatment of sinusoidal obstructive syndrome.
TL;DR: This phase 2 multicenter study evaluated incorporation of autologous stem cell transplant (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma and met the primary endpoint, with an sCR rate of 60% after 8 cycles.
TL;DR: P palladium-catalyzed C(sp3)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs.
Abstract: DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C-H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp3)-H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp3)-H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C-H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp3) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.
Harvard University1, University of Oxford2, Princess Margaret Cancer Centre3, Complutense University of Madrid4, Chartered Institute of Management Accountants5, Emory University6, University College London Hospitals NHS Foundation Trust7, City of Hope National Medical Center8, University of Texas MD Anderson Cancer Center9, Bristol-Myers Squibb10, University of Calgary11
TL;DR: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos that has enhanced antiproliferative and tumoric properties in vitro.
Abstract: 8500Background: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoric...
TL;DR: A suite of on-DNA chemistries are demonstrated to incorporate medicinally relevant and C-S, C-P and N-S linkages into DELs, which are underrepresented in the canonical methods.
Abstract: DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C-S, C-P and N-S linkages into DELs, which are underrepresented in the canonical methods.
TL;DR: A genomically defined MM subgroup is identified with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort.
Abstract: PURPOSEMultiple myeloma (MM) is accompanied by heterogeneous somatic alterations. The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing ...
VU University Amsterdam1, University College London Hospitals NHS Foundation Trust2, Mayo Clinic3, Utrecht University4, Mount Sinai Hospital5, Harvard University6, University of Navarra7, University of Maryland Medical Center8, University of Pennsylvania9, University of Turin10, University of Michigan11, Hackensack University Medical Center12, Academy for Urban School Leadership13, Hebron University14, Erasmus University Rotterdam15, Bristol-Myers Squibb16, Emory University17
TL;DR: D dose escalations of IBER with different treatment combinations in independent cohorts, in patients (pts) with RRMM showed a favorable safety profile with promising efficacy and a selected IBER RP2D of 1.6 mg 21/28 days (D).
TL;DR: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients, and ongoing studies investigate its therapeutic potential also in earlier lines of therapy.
Abstract: Introduction: Despite unprecedented advances in the treatment of multiple myeloma (MM), almost all patients develop a disease that is resistant to the five most commonly used and active anti-MM agents. The prognosis for this patient population is particularly poor resulting in an unmet need for additional therapeutic options. Exportin-1 (XPO-1) is a major nuclear export protein of macromolecular cargo frequently overexpressed in MM. Selinexor is a first-in-class, oral Selective-Inhibitor-of-Nuclear-Export (SINE) compound that impedes XPO-1. Based on results of the STORM-trial, selinexor in combination with dexamethasone was granted accelerated FDA approval for patients with penta-refractory MM in July 2019.Areas covered: This article summarizes our up-to-date knowledge on the pathophysiologic role of XPO-1 in MM. Furthermore, it reviews the most recent clinical data on selinexor in combination with dexamethasone and other anti-MM agents; and discusses its safety profile, management strategies; and potential future developments.Expert opinion: Selinexor represents a next-generation-novel agent with an innovative mechanism of action that marks a significant advance in the treatment of heavily pretreated MM patients. Ongoing studies investigate its therapeutic potential also in earlier lines of therapy. Additional data is needed to confirm that selinexor and other SINE compounds are a valuable addition to our current therapeutic armamentarium.
TL;DR: Single-agent belamaf in a lyophilised presentation showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.
Abstract: DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.
TL;DR: Melflufen, with its novel mechanism of action, has the potential to provide clinically meaningful benefits to patients with relapsed/refractory multiple myeloma, including those with high unmet needs.
Abstract: Despite the availability of new therapies that have led to improved outcomes for patients with multiple myeloma, most patients will eventually relapse. With triplet and even quadruplet combination therapies becoming standard in the first and second line, many patients will have few treatment options after second-line treatment. Melflufen (melphalan flufenamide) is a first-in-class peptide–drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents into tumor cells. Once inside the tumor cells, melflufen is hydrolyzed by peptidases to release alkylator molecules, which become entrapped. Melflufen showed anti-myeloma activity in myeloma cells that were resistant to bortezomib and the alkylator melphalan. In early phase studies (O-12-M1 and HORIZON [OP-106]), melflufen plus dexamethasone has demonstrated encouraging clinical activity and a manageable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma, including those with triple-class refractory disease and extramedullary disease. The Phase III OCEAN study (OP-104) is further evaluating melflufen plus dexamethasone in patients with relapsed/refractory multiple myeloma. The safety profile of melflufen is characterized primarily by clinically manageable hematologic adverse events. Melflufen, with its novel mechanism of action, has the potential to provide clinically meaningful benefits to patients with relapsed/refractory multiple myeloma, including those with high unmet needs.
Mayo Clinic1, Harvard University2, University of Pennsylvania3, University of Wisconsin-Madison4, Yale University5, Kaiser Permanente6, Saint Francis University7, Gundersen Health System8, University of California, Davis9, Wayne State University10, Emory University11, University of Texas MD Anderson Cancer Center12, Wake Forest University13
TL;DR: In this randomized phase 3 trial, KRd did not improve PFS compared with VRd in NDMM and VRd remains the standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations.
Abstract: LBA3Background: Bortezomib (btz) combined with lenalidomide (len) and dexamethasone (dex) (VRd) is a standard initial therapy for NDMM. Carfilzomib (cfz), a next-generation proteasome inhibitor, in...
TL;DR: A trial-efficacy/real-world-effectiveness gap is suggested in RRMM patients initiating IRd, KRd, or VRd in line of therapy ≥2, underlining the limited generalizability of trial results where >50% of patients are excluded.
Abstract: Lack of head-to-head trials highlights a need for comparative real-world evidence of proteasome inhibitors plus Rd.Methods: In this retrospective, US population-representative EHR study of RRMM pat...
TL;DR: This consensus article was designed to assist providers in the practical administration of this anti-myeloma agent in clinical practice and consists of physicians and nurse practitioners who participated in the clinical trials with selinexor.
Abstract: Multiple myeloma patients have seen an unprecedented improved survival in the last decade, primarily due to the introduction of three novel classes of anti-myeloma drugs (proteasome inhibitors, immunomodulatory agents and monoclonal antibodies) and the appropriate use of autologous stem cell transplant. Despite these advances, myeloma remains an incurable disease that behaves more aggressively with each subsequent relapse, and in majority of patients at some point in their disease course are left with exhaustion of all the existing options. Selinexor is an oral and first-in-class nuclear export inhibitor approved by the United States Food and Drug Administration (FDA) in July 2019 for patients with relapsed and refractory myeloma that have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody. The FDA approval of selinexor was based on the Phase 2b STORM (Selinexor Treatment of Refractory Myeloma) study with single agent activity with a 25.3% overall response rate (ORR) in heavily pretreated patients. As an oral agent, selinexor carries significant but predictable toxicity profile that can be appropriately managed with adequate supportive care, primarily anorexia, nausea and cytopenias. As a result, in the STORM trial 58% of patients required dose adjustments and 27% discontinued treatment due to adverse events. This consensus article was designed to assist providers in the practical administration of this anti-myeloma agent in clinical practice. The expert panel consists of physicians and nurse practitioners who participated in the clinical trials with selinexor.
TL;DR: Marizomib is a novel drug that displays strong inhibitory properties on all enzymatic subunits of the proteasome and crosses the blood-brain barrier, making it a potentially very active novel agent against intrinsic brain tumors.
Abstract: Glioblastoma is a primary brain tumor with a poor prognosis despite multimodal therapy including surgery, radiotherapy and alkylating chemotherapy. Novel therapeutic options are therefore urgently ...
TL;DR: Biophysical and biochemical data as well as cocrystal structures were obtained for both compounds and these data were used to rationalize the binding affinity differences observed between the two compounds and a MLGP peptide-containing substrate and confirm the Naa50 binding of 4a.
Abstract: Two novel compounds were identified as Naa50 binders/inhibitors using DNA-encoded technology screening. Biophysical and biochemical data as well as cocrystal structures were obtained for both compounds (3a and 4a) to understand their mechanism of action. These data were also used to rationalize the binding affinity differences observed between the two compounds and a MLGP peptide-containing substrate. Cellular target engagement experiments further confirm the Naa50 binding of 4a and demonstrate its selectivity toward related enzymes (Naa10 and Naa60). Additional analogs of inhibitor 4a were also evaluated to study the binding mode observed in the cocrystal structures.