Association between response kinetics and outcomes in relapsed/refractory multiple myeloma: analysis from TOURMALINE-MM1.
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ABSTRACT:
SUBMITTER: Garderet L
PROVIDER: S-EPMC6127091 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
Publications
Association between response kinetics and outcomes in relapsed/refractory multiple myeloma: analysis from TOURMALINE-MM1.
Garderet Laurent L Laubach Jacob P JP Stoppa Anne-Marie AM Hari Parameswaran P Cavo Michele M Ludwig Heinz H Mateos María-Victoria MV Luptakova Katarina K Lin Jianchang J Yung Godwin G van de Velde Helgi H Berg Deborah D Moreau Philippe P Richardson Paul G PG
Leukemia 20180312 9
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Project description:Prior treatment exposure in patients with relapsed/refractory multiple myeloma may affect outcomes with subsequent therapies. We analyzed efficacy and safety according to prior treatment in the phase 3 TOURMALINE-MM1 study of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd. Patients with relapsed/refractory multiple myeloma received ixazomib-Rd or placebo-Rd. Efficacy and safety were evaluated in subgroups defined according to type (proteasome inhibitor [PI] and immunomodulatory drug) and number (1 vs. 2 or 3) of prior therapies received. Of 722 patients, 503 (70%) had received a prior PI, and 397 (55%) prior lenalidomide/thalidomide; 425 patients had received 1 prior therapy, and 297 received 2 or 3 prior therapies. At a median follow up of ~15 months, PFS was prolonged with ixazomib-Rd vs. placebo-Rd regardless of type of prior therapy received; HR 0.739 and 0.749 in PI-exposed and -naïve patients, HR 0.744 and 0.700 in immunomodulatory-drug-exposed and -naïve patients, respectively. PFS benefit with ixazomib-Rd vs. placebo-Rd appeared greater in patients with 2 or 3 prior therapies (HR 0.58) and in those with 1 prior therapy without prior transplant (HR 0.60) versus those with 1 prior therapy and transplant (HR 1.23). Across all subgroups, toxicity was consistent with that seen in the intent-to-treat population. In patients with relapsed/refractory multiple myeloma, ixazomib-Rd was associated with a consistent clinical benefit vs. placebo-Rd regardless of prior treatment with bortezomib or immunomodulatory drugs. Patients with 2 or 3 prior therapies, or 1 prior therapy without transplant seemed to have greater benefit than patients with 1 prior therapy and transplant. TOURMALINE-MM1 registered at clinicaltrials.gov identifier: 01564537.
| S-EPMC5622861 | biostudies-literature
Project description: Not available
| S-EPMC9617177 | biostudies-literature
Project description:Multiple myeloma (MM) represents an incurable hematologic malignancy. Despite significant advances over the past decade, with the advent of multiple new classes of anti-myeloma agents, including immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies, patients ultimately relapse. Selinexor is a first-in-class exportin-1 inhibitor with activity in these multiply relapsed and refractory patients. Although the current Food and Drug Administration (FDA) approval is for the doublet of Selinexor in combination with dexamethasone, ongoing clinical trials are evaluating a number of combination regimens. These triplet and quadruplet, selinexor-based, regimens are showing significant activity in "triple-class" refractory patients. With appropriate combination drug choice, drug dosing, and supportive measures, patients with previously no viable options for therapy, now have multiple potential regimens to control their disease.
| S-EPMC7285937 | biostudies-literature
Project description:BackgroundTeclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma.MethodsIn this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better).ResultsAmong 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).ConclusionsTeclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).
| S-EPMC10587778 | biostudies-literature
Project description:The therapeutic strategy for relapsed and refractory multiple myeloma (RRMM) integrates a holistic approach regarding patient, disease, and drug-related factors. Patient-related factors include age, frailty status, and underlying comorbidities, especially cardiovascular and renal diseases and peripheral neuropathies that affect tolerability to multiple drug combinations or transplantations. Disease-related factors encompass these multiple patient-related factors, particularly the aggressiveness of the disease and cytogenetics. Regarding drug-related factors, the approval of novel proteasome inhibitors (such as carfilzomib and ixazomib), immunomodulatory agents (such as pomalidomide), monoclonal antibodies (such as daratumumab and elotuzumab), and new classes of drugs increasingly makes the choice treatment more complex and necessitates a comprehensive summary and an update of the efficacy and toxicities of each antimyeloma drug and its combinations. Further, careful monitoring of the side effects and supportive care throughout the course of treatment are important to achieve better outcomes for patients with RRMM.
| S-EPMC7386890 | biostudies-literature
Project description:Double relapsed and/or refractory multiple myeloma (DRMM), MM that is relapsed and/or refractory to bortezomib and lenalidomide, carries a poor prognosis. The healthcare costs of DRMM have not previously been reported. We analyzed detailed medical resource utilization (MRU) costs, drug costs and outcomes for 39 UK patients receiving standard DRMM therapy. Median OS in this cohort was 5.6 months. The mean cost of DRMM treatment plus MRU until death was £23,472 [range: £1,411-£90,262], split between drug costs £11,191 and other resource use costs £12,281. The cost per assumed quality-adjusted life year (QALY) during DRMM was £66,983. These data provide a standard of care comparison when evaluating the cost-effectiveness of new drugs in DRMM.
| S-EPMC4569348 | biostudies-literature
Project description:From a historic lens, treatment for patients with relapsed/refractory multiple myeloma (R/R MM) has advanced significantly since the advent of immunomodulatory agents (IMiDs) in the 1990s, proteasome inhibitors in the 2000s, monoclonal antibodies in the 2010s, and CAR-T treatments in the 2020s. However, the availability of multiple new therapies has also created significant ambiguity regarding therapy selection and sequencing, as consensus guidelines are limited, and cross-trial comparisons of the novel agents are challenging. In this focused review, we discuss the novel Food & Drug Administration (FDA)-approved medications for R/R MM, including the recently approved first-in-class BCMA-directed bispecific antibody teclistamab. We highlight the seminal clinical trials data and discuss optimal sequencing considerations based on the goal of treatment, with an emphasis on the two novel CAR-T cell products. We consider the limited tolerability of certain agents, prospects for our aging population, and financial aspects of these therapies. Finally, we spotlight ongoing trials involving promising agents making their way through the pharmacologic pipeline including the BCMA-directed bispecific antibody elranatamab and the GPRC5D-directed bispecific antibody talquetamab. We summarize our recommendations based on the best available evidence as we enter 2023.
| S-EPMC10888499 | biostudies-literature
Project description:Carfilzomib is the second proteasome inhibitor approved for relapsed multiple myeloma. Since its approval in 2012, carfilzomib has been an active and versatile drug, based on its efficacy as a single agent; superiority as a doublet with dexamethasone compared with bortezomib and dexamethasone; and as a partner in diverse three drug combinations such as with lenalidomide or daratumumab. While it has an established place in relapsed disease, clinicians should be aware of its cardiovascular and renal adverse event profile, which is manageable, in order to optimize outcomes. This review will provide a perspective on the current and future role of carfilzomib in relapsed/refractory multiple myeloma.
| S-EPMC8191071 | biostudies-literature
Project description:Despite the challenges imposed by the COVID-19 pandemic, exciting therapeutic progress continues to be made in MM. New drug approvals for relapsed/refractory (RR)MM in 2020/2021 include the second CD38 monoclonal antibody, isatuximab, the first BCMA-targeting therapy and first-in-class antibody-drug conjugate (ADC) belantamab mafodotin, the first BCMA-targeting CAR T cell product Idecabtagen-Vicleucel (bb2121, Ide-Cel), the first in-class XPO-1 inhibitor selinexor, as well as the first-in-class anti-tumor peptide-drug conjugate, melflufen. The present introductory article of the Special Issue on "Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond" summarizes the most recent registration trials and emerging immunotherapies in RRMM, gives an overview on latest insights on MM genomics and on tumor-induced changes within the MM microenvironment, and presents some of the most promising rationally derived future therapeutic strategies.
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Project description:Patients with relapsed and refractory multiple myeloma have a poor prognosis. The mitogen-activated protein kinase (MAPK) pathway has been implicated in the pathogenesis of multiple myeloma. Several mutations in this pathway can lead to its constitutive activation leading to oncogenesis. One such mutation is BRAFV600E which is a therapeutic target in the treatment of melanoma, lung cancer, colon cancer, thyroid cancer, and hairy cell leukemia. BRAFV600E-directed therapy currently does not have approval in multiple myeloma. It has been proposed that this mutation leads to proteasome inhibitor resistance. About 4-10% of multiple myeloma cases harbor the BRAFV600E mutation. Herein, we report a case of a patient with relapsed and refractory multiple myeloma who had a progression-free survival (PFS) of 8.5 months on BRAF-targeted therapy.
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