Strengths and Bias of the Different Therapeutic Strategies for the Treatment of Multiple Myeloma Patients Who Progress after Front-Line use of Lenalidomide: A Systematic Review of Available Clinical Trials

Giuseppe Mele; Nicola Sgherza; Domenico Pastore; Pellegrino Musto*

Giuseppe Mele, Nicola Sgherza, Domenico Pastore and Pellegrino Musto*

Volume5-Issue7
Dates: Received: 2024-07-08 | Accepted: 2024-07-23 | Published: 2024-07-24
Pages: 838-844

Abstract

Purpose: Patients with Multiple Myeloma (MM) who relapse after exposure to lenalidomide in the context of their first line therapeutic strategy are becoming a growing and clinically relevant population. We performed a systematic review of available clinical trials evaluating the efﬁcacy, in terms of Progression-Free Survival (PFS), of different therapeutic strategies for the treatment of MM patients at first relapse after front-line use of lenalidomide.

Methods: Publications of interest were searched on the PubMed database. The following search terms were employed: relapsed multiple myeloma, refractory multiple myeloma, first relapse, second line therapy, and lenalidomide-refractory, lenalidomide-exposed.

Results: Triplets including anti-CD38 antibodies, carfilzomib and dexamethasone obtained more significant PFS regardless of the number of prior therapies. Other trials also demonstrated a not negligible benefit with combinations containing pomalidomide, particularly in early lines of therapy. However, the variable amount of Len-Exp/Len-R patients enrolled in these studies and the limited number of those analyzed after progression following front-line lenalidomide, makes it difficult to select an “optimal” choice for the treatment of these MM patients at first relapse. Promising results have been more recently obtained by using combo therapies including belantamab-mafodotin and immunotherapies with CAR-T cells.

Conclusion: In absence of clear-cut data regarding specifically the effects of currently available regimens in MM patients refractory or relapsed after first-line therapies including lenalidomide, novel approaches based on immune-therapies and focused on this specific population of MM patients would warrant further specific investigation.

FullText HTML FullText PDF DOI: 10.37871/jbres1962

Certificate of Publication

Copyright

How to cite this article

Mele G, Sgherza N, Pastore D, Musto P. Strengths and Bias of the Different Therapeutic Strategies for the Treatment of Multiple Myeloma Patients Who Progress after Front-Line use of Lenalidomide: A Systematic Review of Available Clinical Trials. J Biomed Res Environ Sci. 2024 Jul 24; 5(7): 838-844. doi: 10.37871/jbres1962, Article ID: JBRES1962, Available at: https://www. jelsciences.com/articles/jbres1962.pdf

Subject area(s)

Hematology

Therapeutics

References

Dimopoulos MA, Moreau P, Terpos E, Mateos MV, Zweegman S, Cook G, Delforge M, Hájek R, Schjesvold F, Cavo M, Goldschmidt H, Facon T, Einsele H, Boccadoro M, San-Miguel J, Sonneveld P, Mey U. Multiple Myeloma: EHA-ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up. Hemasphere. 2021 Feb 3;5(2):e528. doi: 10.1097/HS9.0000000000000528. Erratum in: Hemasphere. 2021 Mar 31;5(4):e567. doi: 10.1097/HS9.0000000000000567. Erratum in: Hemasphere. 2021 Nov 29;5(12):e659. doi: 10.1097/HS9.0000000000000659. PMID: 33554050; PMCID: PMC7861652.
Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR Investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. doi: 10.1016/S1470-2045(15)00464-7. Epub 2015 Dec 5. PMID: 26671818.
Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. doi: 10.1056/NEJMoa1606038. PMID: 27557302.
Usmani SZ, Mateos MV, Lentzsch S, Quach H, Capra M, Ovilla R, Jo JC, Shin HJ, Sonneveld P, Qi M, Amin H, Wang J, Qin X, Okonkwo L, Ukropec J, Trivedi S, Suzuki K, Dimopoulos MA, Cavo M, Nooka A, Chari A, Facon T. Efficacy of daratumumab in combination with standard of care regimens in lenalidomide-exposed or refractory patients with Relapsed/Refractory Multiple Myeloma (RRMM): Analysis of the CASTOR, POLLUX and MMY1001 studies. Blood. 2018;132(S1):3288. doi: 10.1182/blood-2018-99-112669.
Moreau P, Joshua D, Chng WJ, Palumbo A, Goldschmidt H, Hájek R, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Aggarwal S, Feng S, Dimopoulos MA. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Leukemia. 2017 Jan;31(1):115-122. doi: 10.1038/leu.2016.186. Epub 2016 Jul 4. PMID: 27491641; PMCID: PMC5220137.
Weisel KC, Sonneveld P, Mateos MV, Hungria VTM, Spencer A, Estell J, Barreto WG, Corradini P, Min CK, Medvedova E, Krevvata M, Trivedi S, Qin X, Pei H, Ukropec J, Kobos R, Qi M, Nooka AK. Efficacy and safety of daratumumab, bortezomib and dexamethasone (D-Vd) versus bortezomib and dexamethasone (Vd) in first relapse patients with multiple myeloma: Four-year update of Castor. Blood. 2019;134(s1):3192. doi 10.1182/blood-2019-123527.
Moreau P, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Risse ML, Asset G, Macé S, Martin T; IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021 Jun 19;397(10292):2361-2371. doi: 10.1016/S0140-6736(21)00592-4. Epub 2021 Jun 4. PMID: 34097854.
Dimopoulos MA, Moreau P, Augustson B, Castro N, Pika T, Delimpasi S, De la Rubia J, Maiolino A, Reiman T, Martinez-Lopez J, Martin T, Mikhael J, Yong K, Risse ML, Asset G, Marion S, Hajek R. Isatuximab plus carfilzomib and dexamethasone in patients with relapsed multiple myeloma based on prior lines of treatment and refractory status: IKEMA subgroup analysis. Am J Hematol. 2023 Jan;98(1):E15-E19. doi: 10.1002/ajh.26602. Epub 2022 Jun 4. PMID: 35604280; PMCID: PMC10084376.
Martin T, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Casca F, Macé S, Risse ML, Moreau P. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Blood Cancer J. 2023 May 9;13(1):72. doi: 10.1038/s41408-023-00797-8. Erratum in: Blood Cancer J. 2023 Sep 27;13(1):152. doi: 10.1038/s41408-023-00923-6. PMID: 37156782; PMCID: PMC10166682.
Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Yang H, Klippel Z, Zahlten-Kumeli A, Usmani SZ. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020 Jul 18;396(10245):186-197. doi: 10.1016/S0140-6736(20)30734-0. Erratum in: Lancet. 2020 Aug 15;396(10249):466. doi: 10.1016/S0140-6736(20)31669-X. PMID: 32682484.
Usmani SZ, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Gavriatopoulou M, Oriol A, Rabin N, Nooka A, Qi M, Beksac M, Jakubowiak A, Ding B, Zahlten-Kumeli A, Yusuf A, Dimopoulos M. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022 Jan;23(1):65-76. doi: 10.1016/S1470-2045(21)00579-9. Epub 2021 Dec 3. PMID: 34871550.
Usmani SZ, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Shu X, Li C, Dimopoulos M. Final analysis of carfilzomib, dexamethasone, and daratumumab vs carfilzomib and dexamethasone in the CANDOR study. Blood Adv. 2023 Jul 25;7(14):3739-3748. doi: 10.1182/bloodadvances.2023010026. PMID: 37163358; PMCID: PMC10368773.
Richardson PG, Oriol A, Beksac M, Liberati AM, Galli M, Schjesvold F, Lindsay J, Weisel K, White D, Facon T, San Miguel J, Sunami K, O'Gorman P, Sonneveld P, Robak P, Semochkin S, Schey S, Yu X, Doerr T, Bensmaine A, Biyukov T, Peluso T, Zaki M, Anderson K, Dimopoulos M; OPTIMISMM trial investigators. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jun;20(6):781-794. doi: 10.1016/S1470-2045(19)30152-4. Epub 2019 May 13. PMID: 31097405.
Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, Moreau P, Baldini L, Symeonidis A, Bila J, Oriol A, Mateos MV, Einsele H, Orfanidis I, Ahmadi T, Ukropec J, Kampfenkel T, Schecter JM, Qiu Y, Amin H, Vermeulen J, Carson R, Sonneveld P; APOLLO Trial Investigators. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Jun;22(6):801-812. doi: 10.1016/S1470-2045(21)00128-5. PMID: 34087126.
Bahlis NJ, Siegel DS, Schiller GJ, Samaras C, Sebag M, Berdeja J, Ganguly S, Matous J, Song K, Seet CS, Acosta-Rivera M, Bar M, Quick D, Anz B, Fonseca G, Chung W, Lee K, Mouro J, Agarwal A, Reece D. Pomalidomide, dexamethasone, and daratumumab immediately after lenalidomide-based treatment in patients with multiple myeloma: updated efficacy, safety, and health-related quality of life results from the phase 2 MM-014 trial. Leuk Lymphoma. 2022 Jun;63(6):1407-1417. doi: 10.1080/10428194.2022.2030477. Epub 2022 Feb 8. PMID: 35133221.
Mian H, Eisfeld C, Venner CP, Masih-Khan E, Kardjadj M, Jimenez-Zepeda VH, Khandanpour C, Lenz G, McCurdy A, Sebag M, Song K, LeBlanc R, White D, Stakiw J, Reiman A, Louzada M, Aslam M, Kotb R, Gul E, Reece D. Efficacy of Daratumumab-Containing Regimens Among Patients With Multiple Myeloma Progressing on Lenalidomide Maintenance: Retrospective Analysis. Front Oncol. 2022 Feb 18;12:826342. doi: 10.3389/fonc.2022.826342. PMID: 35251992; PMCID: PMC8894582.
Weisel K, Dimopoulos MA, Beksac M, Leleu X, Richter J, Heeg B, Patel S, Majer I, McFadden I, Mikhael J. Carfilzomib, daratumumab, and dexamethasone (KdD) vs. lenalidomide-sparing pomalidomide-containing triplet regimens for relapsed/refractory multiple myeloma: an indirect treatment comparison. Leuk Lymphoma. 2024 Apr;65(4):481-492. doi: 10.1080/10428194.2023.2300051. Epub 2024 Feb 12. PMID: 38345269.
Grosicki S, Simonova M, Spicka I, Pour L, Kriachok I, Gavriatopoulou M, Pylypenko H, Auner HW, Leleu X, Doronin V, Usenko G, Bahlis NJ, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Gironella M, Jurczyszyn A, Robak P, Galli M, Wallington-Beddoe C, Radinoff A, Salogub G, Stevens DA, Basu S, Liberati AM, Quach H, Goranova-Marinova VS, Bila J, Katodritou E, Oliynyk H, Korenkova S, Kumar J, Jagannath S, Moreau P, Levy M, White D, Gatt ME, Facon T, Mateos MV, Cavo M, Reece D, Anderson LD Jr, Saint-Martin JR, Jeha J, Joshi AA, Chai Y, Li L, Peddagali V, Arazy M, Shah J, Shacham S, Kauffman MG, Dimopoulos MA, Richardson PG, Delimpasi S. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020 Nov 14;396(10262):1563-1573. doi: 10.1016/S0140-6736(20)32292-3. PMID: 33189178.
Mateos MV, Engelhardt M, Leleu X, Gironella Mesa M, Auner HW, Cavo M, Dimopoulos MA, Bianco M, Marino Merlo G, la Porte C, Moreau P. P886: EFFICACY, SURVIVAL AND SAFETY OF SELINEXOR, BORTEZOMIB AND DEXAMETHASONE (SVD) IN PATIENTS WITH LENALIDOMIDE-REFRACTORY MULTIPLE MYELOMA: SUBGROUP DATA FROM THE BOSTON TRIAL. Hemasphere. 2023 Aug 8;7(Suppl ):e1470834. doi: 10.1097/01.HS9.0000970448.14708.34. PMCID: PMC10431164.
Hungria V, Robak P, Hus M. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma. 2024. doi: 10.1056/NEJMoa2405090.
Dimopoulos MA, Beksac M, Pour L. Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma. 2024. doi: 10.1056/NEJMoa2403407
Mateos MV, Robak P, Hus M, Fu C, Zherebtsova V, Ward C, Ho PJ, de Almeida AC, Hajek R, Kim K, Dimopoulos MA, Cerchione C, Pirooz N, McKeown A, Kazeem G, Baig H, Eccersley L. Ghanta SR, Opalinska J, Hungria V. DREAMM-7 update: Subgroup analyses from a phase 3 trial of belantamab mafodotin + bortezomib and dexamethasone vs daratumumab, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma. Presented at ASCO annual meeting. 2024. doi: 10.1200/JCO.2024.42.16_suppl.7503.
San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, Fernández de Larrea C, Martínez-López J, Moreau P, Touzeau C, Leleu X, Avivi I, Cavo M, Ishida T, Kim SJ, Roeloffzen W, van de Donk NWCJ, Dytfeld D, Sidana S, Costa LJ, Oriol A, Popat R, Khan AM, Cohen YC, Ho PJ, Griffin J, Lendvai N, Lonardi C, Slaughter A, Schecter JM, Jackson CC, Connors K, Li K, Zudaire E, Chen D, Gilbert J, Yeh TM, Nagle S, Florendo E, Pacaud L, Patel N, Harrison SJ, Einsele H. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med. 2023 Jul 27;389(4):335-347. doi: 10.1056/NEJMoa2303379. Epub 2023 Jun 5. PMID: 37272512.
Einsele H, Yong K, Harrison S, Mateos MV, Moreau P, van de Donk NWCJ, Sidana S, Popat R, Lendvai N, Lonardi C, Slaughter A, Schecter J, LI K, Zudaire E, Chen D, Gilbert J, Yeh TM, Pacaud L, Patel N, Dhakal B, San Miguel J. S100: FIRST PHASE 3 RESULTS FROM CARTITUDE-4: CILTA-CEL VERSUS STANDARD OF CARE (PVD OR DPD) IN LENALIDOMIDE-REFRACTORY MULTIPLE MYELOMA. Hemasphere. 2023 Aug 8;7(Suppl ):e471416f. doi: 10.1097/01.HS9.0000967308.47141.6f. PMCID: PMC10428371.