Cereblon E3 ligase modulators (CELMoDs)
Cereblon modulators, such as the investigational drugs iberdomide and CC-92480, bind to cereblon with a higher affinity than lenalidomide or pomalidomide and degrade Ikaros (IKZF1) and Aiolos (IKZF3) in pomalidomide-refractory patients.[182]Matyskiela ME, Zhang W, Man HW, et al. A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos. J Med Chem. 2018 Jan 25;61(2):535-42.
http://www.ncbi.nlm.nih.gov/pubmed/28425720?tool=bestpractice.com
Iberdomide is being evaluated as monotherapy in patients with relapsed or refractory multiple myeloma (RRMM), and in combination with standard treatments in patients with newly diagnosed MM or RRMM.[183]ClinicalTrials.gov. A study to determine dose, safety, tolerability, drug levels, and efficacy of CC-220 monotherapy, and in combination with other treatments in participants with multiple myeloma. NCT02773030. Aug 2023 [internet publication].
https://www.clinicaltrials.gov/ct2/show/NCT02773030
[184]ClinicalTrials.gov. Open-label study comparing iberdomide, daratumumab and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (RRMM) (EXCALIBER-RRMM). NCT04975997. Jul 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04975997
Trials are also under way evaluating iberdomide as maintenance therapy in patients with MM post-transplant.[185]ClinicalTrials.gov. Iberdomide maintenance therapy in patients with multiple myeloma. NCT05177536. Jun 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT05177536
[186]ClinicalTrials.gov. Iberdomide (Cc220) maintenance after Asct in newly diagnosed MM patients. NCT04564703. Aug 2022 [internet publication].
https://www.clinicaltrials.gov/ct2/show/NCT04564703
CC-92480 is being evaluated in combination with dexamethasone in patients with RRMM, and in combination with standard treatments in patients with newly diagnosed MM or RRMM.[187]ClinicalTrials.gov. A safety, PK and efficacy study of CC-92480 monotherapy and in combination with dexamethasone in subjects with relapsed and refractory multiple myeloma (RRMM). NCT03374085. Aug 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03374085
[188]ClinicalTrials.gov. A study to determine the recommended dose and regimen and to evaluate the safety and preliminary efficacy of CC-92480 in combination with standard treatments in participants with relapsed or refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM). NCT03989414. Jun 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03989414
Ixazomib plus pomalidomide plus dexamethasone (for refractory MM)
In one phase 1/2 study of patients with lenalidomide- and proteasome inhibitor-refractory MM, an oral triplet regimen comprising ixazomib plus pomalidomide plus dexamethasone demonstrated an overall response rate of 51.7%.[189]Voorhees PM, Suman VJ, Tuchman SA, et al. A phase I/II study of ixazomib, pomalidomide, and dexamethasone for lenalidomide and proteasome inhibitor refractory multiple myeloma (Alliance A061202). Am J Hematol. 2021 Dec 1;96(12):1595-603.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713771
http://www.ncbi.nlm.nih.gov/pubmed/34559902?tool=bestpractice.com
Median duration of response was 16.8 months, median progression-free survival 4.4 months, and median overall survival 34.3 months.[189]Voorhees PM, Suman VJ, Tuchman SA, et al. A phase I/II study of ixazomib, pomalidomide, and dexamethasone for lenalidomide and proteasome inhibitor refractory multiple myeloma (Alliance A061202). Am J Hematol. 2021 Dec 1;96(12):1595-603.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713771
http://www.ncbi.nlm.nih.gov/pubmed/34559902?tool=bestpractice.com
Next-generation proteasome inhibitors
Investigational next-generation proteasome inhibitors include marizomib (an inhibitor of all three subunits of the 20S proteasome [beta5, beta1, and beta2]) and oprozomib.[190]Chauhan D, Catley L, Li G, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from bortezomib. Cancer Cell. 2005 Nov;8(5):407-19.
http://www.ncbi.nlm.nih.gov/pubmed/16286248?tool=bestpractice.com
[191]Kumar SK, Bensinger WI, Zimmerman TM, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014 Aug 14;124(7):1047-55.
https://ashpublications.org/blood/article/124/7/1047/33652/Phase-1-study-of-weekly-dosing-with-the
http://www.ncbi.nlm.nih.gov/pubmed/24904120?tool=bestpractice.com
[192]Richardson PG, Baz R, Wang M, et al. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46.
https://ashpublications.org/blood/article/124/7/1038/33629/Phase-1-study-of-twice-weekly-ixazomib-an-oral
http://www.ncbi.nlm.nih.gov/pubmed/24920586?tool=bestpractice.com
In one phase 1 dose escalation clinical trial, patients with RRMM responded to single-agent marizomib with minimal adverse effects.[193]Richardson PG, Zimmerman TM, Hofmeister CC, et al. Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 Part 1. Blood. 2016 Jun 2;127(22):2693-700.
https://ashpublications.org/blood/article/127/22/2693/35152/Phase-1-study-of-marizomib-in-relapsed-or-relapsed
http://www.ncbi.nlm.nih.gov/pubmed/27009059?tool=bestpractice.com
Marizomib has received Food and Drug Administration (FDA) orphan drug designation for MM.
B-cell maturation antigen (BCMA)-directed therapies
BCMA is a cell surface protein that is expressed on select B-cells and mature plasma cells. Binding of BCMA to its ligands APRIL and BAFF promotes B-cell proliferation and differentiation.[194]Tai YT, Anderson KC. Targeting B-cell maturation antigen in multiple myeloma. Immunotherapy. 2015;7(11):1187-99.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976846
http://www.ncbi.nlm.nih.gov/pubmed/26370838?tool=bestpractice.com
Investigational BCMA-directed bispecific antibodies/T-cell engagers (BITEs) include PF-06863135 and CC-93269. BCMA-directed antibody-drug conjugates include AMG-224 and SEA-BCMA.[195]Usmani SZ, Garfall AL, van de Donk NWCJ, et al. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021 Aug 21;398(10301):665-74.
http://www.ncbi.nlm.nih.gov/pubmed/34388396?tool=bestpractice.com
[196]ClinicalTrials.gov. PF-06863135 as single agent and in combination with immunomodulatory agents in relapse/refractory multiple myeloma. NCT03269136. Apr 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03269136
[197]ClinicalTrials.gov. Study of CC-93269, a BCMA x CD3 T cell engaging antibody, in participants with relapsed and refractory multiple myeloma. NCT03486067. Jul 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03486067
[198]Lee HC, Raje NS, Landgren O, et al. Phase 1 study of the anti-BCMA antibody-drug conjugate AMG 224 in patients with relapsed/refractory multiple myeloma. Leukemia. 2021 Jan;35(1):255-8.
http://www.ncbi.nlm.nih.gov/pubmed/32317775?tool=bestpractice.com
[199]ClinicalTrials.gov. A safety study of SEA-BCMA in patients with multiple myeloma. NCT03582033. Apr 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03582033
Myeloid cell leukemia-1 (MCL-1) inhibitors
Induced myeloid leukemia cell differentiation protein Mcl-1, encoded by the gene MCL-1, is a member of the B-cell lymphoma 2 (BCL-2) family of multidomain proteins that regulates apoptosis.[200]Adams JM, Cory S. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol. 2007 Oct;19(5):488-96.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754308
http://www.ncbi.nlm.nih.gov/pubmed/17629468?tool=bestpractice.com
MCL-1 promotes the survival of MM cells.[201]Peperzak V, Vikström I, Walker J, et al. Mcl-1 is essential for the survival of plasma cells. Nat Immunol. 2013 Mar;14(3):290-7.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041127
http://www.ncbi.nlm.nih.gov/pubmed/23377201?tool=bestpractice.com
Investigational MCL-1 inhibitors that are being evaluated in patients with MM include MIK665 (also referred as S64315), AMG 397, AZD5991, and AMG 176.
BCL-2 inhibitors
BCL-2 is a member of the BCL-2 family of pro-apoptotic and anti-apoptotic proteins that function to regulate apoptosis.[202]Tsujimoto Y. Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells. 1998 Nov;3(11):697-707.
https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2443.1998.00223.x
http://www.ncbi.nlm.nih.gov/pubmed/9990505?tool=bestpractice.com
Trials of venetoclax (an oral BCL-2 inhibitor) in patients with RRMM were temporarily suspended following reports of an increased risk of death among patients receiving venetoclax (combined with bortezomib and dexamethasone [VD]) compared with the control group.[203]Kumar SK, Harrison SJ, Cavo M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1630-42.
http://www.ncbi.nlm.nih.gov/pubmed/33129376?tool=bestpractice.com
Overall survival analysis of the trial indicated that patients who benefited most from venetoclax plus VD were those with either t(11;14) or tumor cells with high BCL-2 expression.[204]Kumar S, Harrison SJ, Cavo M, et al. Final overall survival results from BELLINI, a phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Paper presented at: 63rd ASH Annual Meeting. Dec 11-14, 2021. Atlanta, GA/online. 653: myeloma and plasma cell dyscrasias - clinical-prospective therapeutic trials. Oral abstracts. Blood. 2021 Nov 23;138(suppl 1):84.
https://ashpublications.org/blood/article/138/Supplement%201/84/477532/Final-Overall-Survival-Results-from-BELLINI-a
BRAF and MEK inhibitors
The use of combined therapy with a BRAF inhibitor (e.g., encorafenib, vemurafenib) and a MEK inhibitor (e.g., cobimetinib, binimetinib) has been reported in patients with BRAF V600 mutation-positive RRMM.[205]Otieno SB, Nasir S, Weir A, et al. Rapid response in a patient with relapsed/refractory multiple myeloma treated with BRAF/MEK inhibitors. Case Rep Hematol. 2020 Dec 11;2020:8821415.
https://www.hindawi.com/journals/crihem/2020/8821415
http://www.ncbi.nlm.nih.gov/pubmed/33381330?tool=bestpractice.com
[206]Mey UJM, Renner C, von Moos R. Vemurafenib in combination with cobimetinib in relapsed and refractory extramedullary multiple myeloma harboring the BRAF V600E mutation. Hematol Oncol. 2017 Dec;35(4):890-3.
http://www.ncbi.nlm.nih.gov/pubmed/27641727?tool=bestpractice.com
[207]Raab MS, Giesen N, Schneid C, et al. Safety and preliminary efficacy results from a phase II study evaluating combined BRAF and MEK inhibition in relapsed/refractory multiple myeloma (rrMM) patients with activating BRAF V600E mutations: the GMMG-Birma trial. Paper presented at: 62nd ASH Annual Meeting. Dec 5-8, 2020. Online. 653: myeloma/amyloidosis: therapy, excluding transplantation. Oral abstracts. Blood. 2020 Nov 5;136(suppl 1):44-5.
https://ashpublications.org/blood/article/136/Supplement%201/44/470151/Safety-and-Preliminary-Efficacy-Results-from-a
Research is ongoing.
Autologous stem cell transplantation followed by allogeneic transplantation
Autologous stem cell transplantation followed by nonmyeloablative allogeneic transplantation improved survival compared with double autologous transplantation during a median 45-month follow-up.[208]Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007 Mar 15;356(11):1110-20.
https://www.nejm.org/doi/full/10.1056/NEJMoa065464
http://www.ncbi.nlm.nih.gov/pubmed/17360989?tool=bestpractice.com
Nonmyeloablative regimens that preserve graft-versus-myeloma allogeneic immunity may help to reduce toxicity.[107]Lokhorst H, Einsele H, Vesole D, et al; International Myeloma Working Group. International Myeloma Working Group consensus statement regarding the current status of allogeneic stem-cell transplantation for multiple myeloma. J Clin Oncol. 2010 Oct 10;28(29):4521-30.
http://www.ncbi.nlm.nih.gov/pubmed/20697091?tool=bestpractice.com
[209]Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203.
http://www.ncbi.nlm.nih.gov/pubmed/21962393?tool=bestpractice.com
Allogeneic transplantation should only be conducted in the setting of specialized centers or clinical trials.
Melphalan flufenamide
In February 2024, the FDA announced its final decision to withdraw approval of melphalan flufenamide in the US due to the results of the confirmatory phase 3 study, and its safety and efficacy profile.[210]U.S. Food & Drug Administration. FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide). 2024 [internet publication]
https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-final-decision-withdraw-approval-pepaxto-melphalan-flufenamide
Melphalan flufenamide is approved in other countries (including Europe) for patients with RRMM (specific indications may differ).