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Uloga daratumumaba u lečenju multiplog mijelom

Katrine Fladeland Iversen1, Torben Plesner1
  • Univerzitet u Južnoj Danskoj, Bolnica Vejle, Odeljenje hemtologije, Vejle, Danska

SAŽETAK

Daratumumab je prvo odobreno monoklonsko antitelo koje se vezuje za CD38 protein na površini ćelija mijeloma. Istorijski gledano, standardni antimijelomski protokol bio je oralni melfalan uz prednizolon. Nešto više od dve decenije nakon toga počinje primena visokodoznog melfalana praćenog autolognom transplantacijom matičnih ćelija, što postaje standard lečenja mlađih pacijenata sa mijelomom. Istovremeno, sprovodi se profilaksa čestih i razornih skeletnih komplikacija intravenskom primenom bisfosfonata. U narednim godinama počela je nova era značajnih poboljšanja u terapiji mijeloma sa uticajem na preživljavanje starijih i/ ili “frail” pacijenata imunomodulatornim lekom talidomidom, što je nastavljeno primenom njegovog manje toksičnog i efikasnijeg analoga lenalidomida. Istovremeno je u terapijske protokole uveden bortezomib, prvi u klasi inhibitora proteazoma. Uprkos poboljšanju u preživljavanju, prognoza je ostala loša za pacijente sa relapsom nakon terapije bortezomibom i lenalidomidom sa srednjim ukupnim preživljavanjem od samo 9 meseci.

Zatim se nakon početnih dozno eskalacionih studija, utvrđuje da daratumumab dovodi do produženog preživljavanja u odsustvu značajnog “ubijanja” tumorskih ćelija kroz modulaciju imunskog sistema ili mikrookruženja koštane srži. Primena daratumumaba samog ili u kombinaciji poboljšala je ishod lečenja svih pacijenata sa mijelomom bez značajnog povećanja toksičnosti. Zahvaljujući ovakvom pristupu, pacijenti sa mijelomom žive duže i imaju bolji kvalitet života. uz dalje napore za njihovo izlečenje, što predstavlja glavni terapijski cilj.


Tokom nešto više od dve decenije svedočimo velikoj promeni u lečenju multiplog mijeloma. Naslanjajući se na dobro uspostavljen režim koji podrazumeva korišćenje melfalana i prednizolona, InterGroup Francophone du Myelome je poboljšala ishode kod mladih i fizički zdravih pacijenata sa mijelomom koji su dobro podnosili toksičnost velikih doza melfalana [1],[2]. Istovremeno, profilaktička terapija čestih i razarajućih koštanih komplikacija koje nastaju usled multioplog mijeloma unapređena je intravenskom upotrebom bisfosfonata [3]. Naredne prekretnice u unapređenju lečenja mijeloma koje bi imale uticaja na preživljavanje starijih i/ili slabih pacijenata koji boluju od mijeloma (Slika 1) najavljene su posmatranjem efekta koji je talidomid imao na lečenje mijeloma nakon čega je usledio razvoj njemu analognog lenalidomida koji je manje toksičan i efikasniji [4],[5]. Istovremeno je bortezomib, prvi proteazomni inhibitor, pokazao obećavajući učinak u lečenju mijeloma [6],[7].

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Slika 1. Istorijat i lečenje multiplog mijeloma od 1844. godine do danas

Uprkos napretku u preživljavanju, prognoza je ostala loša za pacijente kod kojih dolazi do relapsa nakon lečenja bortezomibom i lenalidomidom, pri čemu njihovo srednje preživljavanje iznosi svega 9 meseca [8]. Lekari koji su se bavili lečenjem mijeloma sanjali su o pronalaženju antitela koje bi u potpunosti promenilo ishod kod pacijenata koji boluju od mijeloma, slično onome što je rituksimab učinio za pacijente obolele od malignog limfoma. Jedna mala dansko-holandska biotehnološka kompanija, Genmab, 2006. godine je predložila kliničko testiranje antitela CD38 (daratumumaba) kod relapsirajućeg refraktornog mijeloma. To su obrazložili postojanjem jake ekspresije CD38 u ćelijama mijeloma i dokazane sposobnosti ovog antitela da in vitro ubije ćelije mijeloma uz postojanje sinergističkog anti-mijelomskog dejstva kada se kombinuje sa lanalidomidom ili bortezomibom [9],[10]. Međutim, visoka ekspresija muktifunkcionalnog molekula CD38 u ljudskom telu i nedostatak pogodnih životinjskih modela za prekliničko testiranje potencijalne toksičnosti izazvali su zabrinutost. Situaciju je dodatno zakomplikovala nedavna katastrofa koja se dogodila prilikom kliničkog ispitivanja antitela CD38 koja je vlastima skrenula pažnju na potencijalnu opasnost koju može da izazove korišćenje monoklonskih antitela u vidu terapije [11]. Bilo je jasno da početna testiranja daratumumaba u okviru kliničkog istraživanja moraju biti pažljivo isplanirana. Kada se počelo sa testiranjem 2008. godine primenjena je strategija koja je podrazumevala davanje veoma male početne doze jednom po jednom pacijentu, uz dovoljno dugačak period posmatranja kako bi se otkrili eventualni neželjeni efekti, i malo povećanje doze antitela svakoj narednoj grupi pacijenata. Pošto je polje istraživanja bilo potpuno novo, prvobitni protokol GEN501 je dosta prilagođavan, u hodu, a do kraja je uneto čak 14 izmena. Spor napredak je bio neizbežan, a Genmab se istovremeno, poput mnogih drugih malih biotehnoloških kompanija, borio da preživi usled finansijskih problema. Tokom prve četiri godine, u istraživanje je uključeno svega 23 pacijenta.

Uprkos postovanju zajedničkog sna o tome da će jednoga dana biti pronađen ,,rituksimab za mijelom”, prevladao je skepticizam i kada su predstavljeni prvi rezultati iz GEN501na ASH 2011 za njih je pokazano veoma malo interesovanje, a citiranost je bila na nuli. Naredne godine, doza daratumumaba je porasla na 2 i 4 mg/kg telesne težine i odgovor je počeo da se nazire. To je promenilo celokupnu sliku i na ASH 2012 rezultati iz GEN501 privukli su znatnu pažnju, a bilo je 23 citata (Grafikon 1) (Genmab: Podaci u dosijeu). Shodno tome, ubrzano je uključivanje pacijenata u istraživanje, a u Severnoj Americi započeto je prateće istraživanje (SIRIUS), kao i kombinovane studije sa lenalidomidom i bortezomibom.

p342 1

Grafikon 1. Prvo kliničko istraživanje upotrebe daratumumaba na ljudima GEN501 započelo je u martu 2008. godine. Regrutacija je u početku išla veoma sporo i samo 23 pacijenta uključeno je u projekat tokom prve četiri godine. Sa prvim znacima kliničke aktivnosti pri dozi od 2 i 4 mg/kg koja je predstavljena na ASH 2012 interesovanje je značajno poraslo, ubrzano je uključivanje novih pacijenata i prateće istraživanje (SIRIUS) pokrenuto je u Severnoj Americi (Genmab: Podaci u dosijeu).

Monoterapija daratumumabom značajno je poboljšala preživljavanje. Ciljana populacija je imala srednje preživljavanje 20 meseci, ali još je zanimljivija činjenica da je daratumumab produžio ukupno preživljavanje 52% pacijenata kod kojih nije bilo formalnog odgovora prema kriterijumima koje je propisala IMWG (International Myeloma Working Group), već samo stabilizacije bolesti ili minimalnog odgovora, na 18.5 meseci [12],[13],[14] (Grafikon 2). Ovo je bilo dvotruko veće preživljavanje od očekivanog u to vreme za pacijente otporne na bortezomib i lenalidomid [8]. Razlog za ovo produženje preživljavanja uprkos činjenici da ćelije tumora nisu ubijene nije potpuno jasan, ali moguća objašnjenja mogu biti modulacija imunog sistema ili koštano mikrookruženje.

p342 2

Grafikon 2. Monoterapija daratumumabom poboljšala je ukupno preživljavanje i kod ispitanika i kod pacijenata kod kojih je odgovor bio minimalan (MR) ili je došlo do stabilizacije bolesti (SD) (52%)

Narednih godina bismo mogli biti svedoci veoma aktivnog razvoja programa za upotrebu daratumumaba zahvaljujući saradnji kompanija Genmab i Janssen. Daratumumab je korišćen u svim terapijskim linijama i u kombinaciji sa svim najvažnijim lekovima koji se koriste za lečenje mijeloma. Pokazalo se da je uvođenje daratumumaba u terapiju poboljšalo ishod lečenja u svim slučajevima bez značajnijeg povećanja toksičnosti. Utvrđeno je da je rizik od razvoja pojave neutropenije i infekcija u blagom porastu, ali stvari se mogu dovesti u ravnotežu uz pomoć adekvatne nege. Reakcije izazvane infuzijom bile su prisutne kod otprilike polovine pacijenata prilikom prve primene infuzije, ali nakon togsu se retko javljale, i bile su blage. Dostupnost subkutanog daratumumaba povoljno je uticala na reakcije usled primene infuzije i olakšala je primenu leka.

Kako trenutno postoji više opcija za lečenje pacijenata sa relapsnim refraktornim mijelomom sve je teže prikazati poboljšanje ukupnog preživljavanja u kliničkim istraživanjima, iako je nedavno otkriveno da postoji korist za preživljavanje kod pacijenata koji primaju daratumumab u istraživanjima ALCYONE, POLLUX, CASTOR i MAIA [15],[16],[17],[18].

Zabrinutost da bi sveukupna korist za preživljavanje ostvarena u jednoj liniji terapije mogla loše da se odrazi na ishod naredne linije terapije nije potvrđena u praksi. Naprotiv, korist za preživljavanje dobijena upotrebom daratumumaba preneta je u sledeću liniju terapije kao što je pokazano u PFS-2 u okviru istraživanja MAIA (Slika 3) [18]. Takođe se pokazalo da produženo lečenje daratumumabom dovodi do progresivnog produbljivanja remisije što se odražava negativnošću minimalne rezidualne bolesti (MRD) (Grafikon 3) [19].

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Grafikon 3. Stopa MRD negativnosti u rendomiziranom istraživanju MAIA

U okviru studije CASSIOPEIA pokazano je da se dodavanjem daratumumaba indukcionom tretmanu pre autologne transplantacije matičnih ćelija, kao i kasnije terapiji održavanja povećava preživljavanje bez progresije (PFS) i stopa negativnosti minimalne rezidualne bolesti (MRD) [20].

Pored potrebe za dugoročnim lečenjem, važno je primetiti da se tokom lečenja daratumumabom kvalitet života postepeno popravlja [21]. Pošto se daratumumab veoma dobro podnosi, i kao jedini lek i u kombinaciji sa drugim lekovima, i oslabljeni stariji pacijenti mogu imati koristi od lečenja.

Daratumumab deluje na više različitih načina, ali nije poznato koji načini su najvažniji, dok su razlozi za izostanak odgovora na lečenje daratumumabom ili nestanak početnog odgovora nejasni. Neki od načina delovanja daratumumaba (citotoksičnost zavisna od komplementa (CDC), ćelijska citotoksičnost zavisna od antitela (ADCC) i ćelijska fagocitoza zavisna od antitela (ADCP)) zavise od jačine ekspresije CD38. Slaba ekspresija CD38 može negativno da utiče na ove načine delovanja, a do nje može doći vremenom s obzirom na to da primena leka daratumumab smanjuje ekspresiju CD38 u ćelijama mijeloma [22],[23]. S druge strane, smanjen nivo CD38 može imati i pozitivan efekat. Stvaranje imunosupresivnog adenozina je ometeno u mikrookruženju koštane srži [24]. Oslabljeno je potencijalno zaštitno pričvršćivanje ćelije mijeloma za stromu [25]. Osim toga, blokirno je stvaranje nanotuba koje povezuju stromalne ćelije sa ćelijama mijeloma i prenose mitohondrije koje daju energiju ćelijama mijeloma (Slika 2) [26].

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Slika 2. Mitohondrije se prenose od stromalnih ćelija do ćelija mijeloma putem međusobno povezanih nanotuba koje obezbeđuju energiju i jačaju maligni fenotip ćelija mijeloma. Stvaranje nanotuba zavisi od CD38 i može biti blokirano od strane CD38 antitela (prilagođeno i preuzeto iz Oncoscience 4, 173, 2017).

U kliničkoj praksi, brz početni odgovor na daratumumab je često praćen dugim periodom sporog ali postojanog opadanja M-proteina. U teoriji, za brz početni odgovor na daratumumab mogu biti zaslužni CDC, ADCC i ADCP koje najbolje funkcionišu kada je ekspresija CD38 visoka. Nakon toga može uslediti dug period u kojem značajniju ulogu imaju reprogramiranje imunog sistema i modulacija mikrookruženja do kojih dolazi zahvaljujući smanjenom stvaranju adenozina, slabijem pričvršćivanju ćelija mijeloma za stromu, ometanju stvaranja nanotuba i eleminaciji regulatornih T, B i M ćelija [27].

Uvođenje daratumumaba u protokol lečenja pacijenata sa mijelomom predstavlja retku kombinaciju efikasnog načina lečenja i lečenja koje se dobro podnosi. Zajedno sa imunomodulatornim lekovima i proteazomnim inhibitorima, daratumumab predstavlja prvi veliki korak dalje od staromodne terapije zasnovane na alkilatorima ka novom dobu u kome je imuni sistem podešen tako da može da se bori protiv mijeloma. Kao rezultat toga, pacijenti oboleli od mijeloma živeće duže i bolje kako se budemo sistematski kretali ka svom cilju izlečenja mijeloma.

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Informacije

Volumen 4 Broj 4

Decembar 2023

Strane 339-348

  • Ključne reči:
    daratumumab, multipli mijelom, terapija, prognoza
  • Primljen:
    10 Novembar 2023
  • Revidiran:
    20 Novembar 2023
  • Prihvaćen:
    20 Novembar 2023
  • Objavljen online:
    25 Decembar 2023
  • DOI:
  • Kako citirati ovaj članak:
    Iversen KF, Plesner T. Daratumumab for the treatment of multiple myeloma. Serbian Journal of the Medical Chamber. 2023;4(4):339-46. doi: 10.5937/smclk4-47645
Autor za korespodenciju

Torben Plesner
Department of Hematology, Vejle Hospital, University of Southern Denmark
4, Beriderbakken Street, 7100 Vejle, Denmark
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LITERATURA

1. Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, et al. Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA. 1969 Jun 2;208(9):1680-5. doi: 10.1001/jama.208.9.1680. [CROSSREF]

2. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996 Jul 11;335(2):91-7. doi: 10.1056/NEJM199607113350204. [CROSSREF]

3. Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med. 1996 Feb 22;334(8):488-93. doi: 10.1056/NEJM199602223340802. [CROSSREF]

4. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. doi: 10.1056/NEJM199911183412102. [CROSSREF]

5. Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002 Nov 1;100(9):3063-7. doi: 10.1182/blood-2002-03-0996. [CROSSREF]

6. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002 Nov 15;20(22):4420-7. doi: 10.1200/JCO.2002.01.133. [CROSSREF]

7. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. doi: 10.1056/NEJMoa030288. [CROSSREF]

8. Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al; International Myeloma Working Group. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012 Jan;26(1):149-57. doi: 10.1038/leu.2011.196. [CROSSREF]

9. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004 Apr;121(4):482-8. doi: 10.1309/74R4-TB90-BUWH-27JX. [CROSSREF]

10. Nijhof IS, Groen RW, Noort WA, van Kessel B, de Jong-Korlaar R, Bakker J, et al. Preclinical evidence for the therapeutic potential of CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to lenalidomide and bortezomib. Clin Cancer Res. 2015 Jun 15;21(12):2802-10. doi: 10.1158/1078-0432.CCR-14-1813. [CROSSREF]

11. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006 Sep 7;355(10):1018-28. doi: 10.1056/ NEJMoa063842. [CROSSREF]

12. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348. [CROSSREF]

13. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. doi: 10.1016/S0140-6736(15)01120-4. [CROSSREF]

14. Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. doi: 10.1182/blood-2016-03-705210. [CROSSREF]

15. Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020 Jan 11;395(10218):132-41. doi: 10.1016/S0140-6736(19)32956-3. [CROSSREF]

16. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): A randomized, open-label, phase III trial. J Clin Oncol. 2023 Mar 10;41(8):1590-9. doi: 10.1200/ JCO.22.00940. [CROSSREF]

17. Sonneveld P, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): A randomized, open-label, phase III trial. J Clin Oncol. 2023 Mar 10;41(8):1600-9. doi: 10.1200/ JCO.21.02734. [CROSSREF]

18. Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1582-96. doi: 10.1016/S1470-2045(21)00466-6. [CROSSREF]

19. Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-15. doi: 10.1056/ NEJMoa1817249. [CROSSREF]

20. Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019 Jul 6;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1. [CROSSREF]

21. Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, et al. Health-related quality of life in transplant-ineligible patients with newly diagnosed multiple myeloma: findings from the phase III MAIA trial. J Clin Oncol. 2021 Jan 20;39(3):227-37. doi: 10.1200/JCO.20.01370. [CROSSREF]

22. Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K, et al. CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood. 2016 Aug 18;128(7):959-70. doi: 10.1182/blood-2016-03-703439. [CROSSREF]

23. Overdijk MB, Verploegen S, Bögels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311-21. doi: 10.1080/19420862.2015.1007813. [CROSSREF]

24. Horenstein AL, Bracci C, Morandi F, Malavasi F. CD38 in adenosinergic pathways and metabolic re-programming in human multiple myeloma cells: in-tandem insights from basic science to therapy. Front Immunol. 2019 Apr 24;10:760. doi: 10.3389/fimmu.2019.00760. [CROSSREF]

25. Ghose J, Viola D, Terrazas C, Caserta E, Troadec E, Khalife J, et al. Daratumumab induces CD38 internalization and impairs myeloma cell adhesion. Oncoimmunology. 2018 Jul 23;7(10):e1486948. doi: 10.1080/2162402X.2018.1486948. [CROSSREF]

26. Marlein CR, Piddock RE, Mistry JJ, Zaitseva L, Hellmich C, Horton RH, et al. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res. 2019 May 1;79(9):2285-97. doi: 10.1158/0008- 5472.CAN-18-0773. [CROSSREF]

27. Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016 Jul 21;128(3):384- 94. doi: 10.1182/blood-2015-12-687749. [CROSSREF]

1. Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, et al. Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA. 1969 Jun 2;208(9):1680-5. doi: 10.1001/jama.208.9.1680. [CROSSREF]

2. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996 Jul 11;335(2):91-7. doi: 10.1056/NEJM199607113350204. [CROSSREF]

3. Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA, Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med. 1996 Feb 22;334(8):488-93. doi: 10.1056/NEJM199602223340802. [CROSSREF]

4. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. doi: 10.1056/NEJM199911183412102. [CROSSREF]

5. Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002 Nov 1;100(9):3063-7. doi: 10.1182/blood-2002-03-0996. [CROSSREF]

6. Orlowski RZ, Stinchcombe TE, Mitchell BS, Shea TC, Baldwin AS, Stahl S, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol. 2002 Nov 15;20(22):4420-7. doi: 10.1200/JCO.2002.01.133. [CROSSREF]

7. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. doi: 10.1056/NEJMoa030288. [CROSSREF]

8. Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al; International Myeloma Working Group. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012 Jan;26(1):149-57. doi: 10.1038/leu.2011.196. [CROSSREF]

9. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004 Apr;121(4):482-8. doi: 10.1309/74R4-TB90-BUWH-27JX. [CROSSREF]

10. Nijhof IS, Groen RW, Noort WA, van Kessel B, de Jong-Korlaar R, Bakker J, et al. Preclinical evidence for the therapeutic potential of CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to lenalidomide and bortezomib. Clin Cancer Res. 2015 Jun 15;21(12):2802-10. doi: 10.1158/1078-0432.CCR-14-1813. [CROSSREF]

11. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006 Sep 7;355(10):1018-28. doi: 10.1056/ NEJMoa063842. [CROSSREF]

12. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348. [CROSSREF]

13. Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. doi: 10.1016/S0140-6736(15)01120-4. [CROSSREF]

14. Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. doi: 10.1182/blood-2016-03-705210. [CROSSREF]

15. Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020 Jan 11;395(10218):132-41. doi: 10.1016/S0140-6736(19)32956-3. [CROSSREF]

16. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): A randomized, open-label, phase III trial. J Clin Oncol. 2023 Mar 10;41(8):1590-9. doi: 10.1200/ JCO.22.00940. [CROSSREF]

17. Sonneveld P, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): A randomized, open-label, phase III trial. J Clin Oncol. 2023 Mar 10;41(8):1600-9. doi: 10.1200/ JCO.21.02734. [CROSSREF]

18. Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1582-96. doi: 10.1016/S1470-2045(21)00466-6. [CROSSREF]

19. Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-15. doi: 10.1056/ NEJMoa1817249. [CROSSREF]

20. Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019 Jul 6;394(10192):29-38. doi: 10.1016/S0140-6736(19)31240-1. [CROSSREF]

21. Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, et al. Health-related quality of life in transplant-ineligible patients with newly diagnosed multiple myeloma: findings from the phase III MAIA trial. J Clin Oncol. 2021 Jan 20;39(3):227-37. doi: 10.1200/JCO.20.01370. [CROSSREF]

22. Nijhof IS, Casneuf T, van Velzen J, van Kessel B, Axel AE, Syed K, et al. CD38 expression and complement inhibitors affect response and resistance to daratumumab therapy in myeloma. Blood. 2016 Aug 18;128(7):959-70. doi: 10.1182/blood-2016-03-703439. [CROSSREF]

23. Overdijk MB, Verploegen S, Bögels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311-21. doi: 10.1080/19420862.2015.1007813. [CROSSREF]

24. Horenstein AL, Bracci C, Morandi F, Malavasi F. CD38 in adenosinergic pathways and metabolic re-programming in human multiple myeloma cells: in-tandem insights from basic science to therapy. Front Immunol. 2019 Apr 24;10:760. doi: 10.3389/fimmu.2019.00760. [CROSSREF]

25. Ghose J, Viola D, Terrazas C, Caserta E, Troadec E, Khalife J, et al. Daratumumab induces CD38 internalization and impairs myeloma cell adhesion. Oncoimmunology. 2018 Jul 23;7(10):e1486948. doi: 10.1080/2162402X.2018.1486948. [CROSSREF]

26. Marlein CR, Piddock RE, Mistry JJ, Zaitseva L, Hellmich C, Horton RH, et al. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res. 2019 May 1;79(9):2285-97. doi: 10.1158/0008- 5472.CAN-18-0773. [CROSSREF]

27. Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016 Jul 21;128(3):384- 94. doi: 10.1182/blood-2015-12-687749. [CROSSREF]

CURRICULUM VITAE

Katrine Fladeland Iversen, MD, PhD

Katrine Fladeland IversenEducation

2008-2015: MD / Cand. Med., University of Southern Denmark, Odense, Denmark 2020-2023: PhD, University of Southern Denmark, Odense, Denmark

Clinical experience

2022 – present: Resident in Hematology, Vejle Hospital, Department of Internal Medicine, Section of Haematology 2018-2022: MD at the Hematologic Research Unit, Vejle Hospital
2017-2018: Registrar, Vejle Hospital, Department of Internal Medicine, Section of Haematology
2015-2017: Internship, General Medicine, Bredsten Lægehus and Lægerne Sct. Maria, Vejle

2015: Internship, Vejle Hospital, Department of Orthopaedics

Clinical research

Principal investigator: GCT3014-01, ANV419

Sub-investigator: GMI-1271-230, M15-654, GCT3013-01, GCT3013-02, GCT3013-03, GCT3013-05, M20-621, M20- 638, CC-92480-MM002, CLL-17, POLAR BEAR, GCT3009-01

GCP training

April2018:GCPcourse(InvestigatorinitiatedclinicaltrialsandGCPrules),twodays Feb. 2018, Feb. 2020 and June 2022: GCP training (e-learning)

Publications

Fladeland Iversen K. et al.

Kieran Brennan-Katrine F Iversen, Alfonso Blanco-Fernández, Thomas Lund, Torben Plesner and Margaret M Mc Gee. Extracellular Vesicles Isolated from Plasma of Multi- ple Myeloma Patients Treated with Daratumumab Express CD38, PD-L1, and the Complement Inhibitory Proteins CD55 and CD59. Cells. 2022, 11, 3365.

Katrine Fladeland Iversen, Line Nederby, Thomas Lund, and Torben Plesner. High expression of the costimulatory checkpoint factor DNAM-1 by CD4+ T-cells from multiple myeloma patients refractory to daratumumab containing regimens. Clin Hematol Int. 2022 Sep;4(3):107-116.

Szabo AG, Thorsen J, Iversen KF, Levring MB, Preiss B, Helleberg C, Breinholt MF, Hermansen E, Gjerdum LMR, Bønløkke ST, Nielsen K, Kjeldsen E, Teodorescu EM, Dokhi M, Kurt E, Strandholdt CN, Andersen MK, Vangsted AJ. The clinical course and life expectancy of patients with multiple myeloma who discontinue their first daratumumab- containing line of therapy. Am J Hematol. 2021;1-4.

Szabo AG, Klausen TW, Levring MB, Preiss B, Helleberg C, Breinholt MF, Gjerdrum LMR, Bønløkke ST, Nielsen K, Kjeldsen E, Iversen KF, Teodorescu EM, Dokhi M, Kurt E, Strandholdt C, Andersen MK, Vangsted AJ. The real-world outcomes of multiple myeloma patients treated with daratumumab. PLOS ONE. 16, 10, 11 p., e0258487.

Højholt KL, Gregersen H, Szabo AG, Klausen TW, Levring MB, Preiss B, Helleberg C, Breinholt MF, Hermansen E, Gjerdrum LMR, Bønløkke ST, Nielsen K, Kjeldsen E, Iversen KF, Teodorescu M, Kurt E, Strandholdt C, Andersen MK, Vangsted A. Outcome of treatment with carfilzomib before and after treatment with daratumumab in relapsed or refractory multiple myeloma patients. Hematological Oncology. 2021;39:521-528.

Szabo AG, Thorsen J, Iversen KF, Hansen CT, Teodurescu E, Pedersen SB, Flæng SB, Strandholt C, Frederiksen M, Vase M, Frølund U, Krustrup D, Plesner T, Vangsted A. Clin- ically suspected cast nephropathy: a retrospective, national, real-world study. Am J Hematol. 2020 Nov;95(11):1352-1360.

Szabo AG, Iversen KF, Möller S, Rosenvinge FS, Plesner T. The incidence and timing of blood culture days in multiple myeloma – results from a retrospective, single center, real-world study. Clin Hem Intl. 2020 Aug 10;2(4):168-172.

Szabo AG, Iversen KF, Möller S, Plesner T. The clinical course of multiple myeloma in the era of novel agents: A retrospective, single-center, real-world study. Clin Hem Intl. 2019;1(4):220-228.

Iversen KF, Holdgaard PC, Preiss B, Nyvold CG, Plesner T: Daratumumab for treatment of blastic plasmacytoid dendritic cell neoplasm. A single case report. Haematologica. 2019 Sep;104(9):e432-e433.

Iversen KF, Frostberg E. Borrelia-lymfocytom hos en to-årig pige. Ugeskr Laeger. 2018 Sep 24;180(39).

Stauffer Larsen T, Iversen KF, Hansen E et al: Long term molecular response in a cohort of Danish patients with essential thrombocythemia, polycythemia vera and myelo- fibrosis treated with recombinant interferon alpha. Leukemia Research. 2013 Sep;37(9):1041-5.

 

 

Torben Plesner, M.D., Doc. Med. Sci., Professor of Hematology

Torben PlesnerLifeline:

Born on 28. February 1947.
Medical Degree: University of Copenhagen, Copenhagen, Denmark. First part: 1968. Second part: 1972.

Doctor of Medical Sciences at the University of Copenhagen 1981. Thesis title: "Immunochemical Studies of Human β2-Microglobulin. A Review of Recent Methodological Progress and Clinical Applications".

Certified as clinical chemistry (MD) Specialist in Denmark, 1981. Certified as internal medicine Specialist in Denmark, 1989.

Certified as hematology Specialist in Denmark, 1990.

1. March 1993 - 30. September 2000: Consultant of Hematology, Herlev Hospital, University Hospital, Copenhagen.

From 1. October 2000: Consultant of Hematology, Section of Internal Medicine, Vejle Hospital, and from 1. March 2009 Professor of He- matology,

University of Southern Denmark, Institute of Regional Health Science.

 

Scientific profile:

I have published 152 scientific articles that are indexed in PubMed.
ISI Web of Science has 134 hits for scientific articles with 8574 citations giving an average of 58 citations per item and an “H-index” of 44. See also: https://scholar.google.com/citations?user=ShMcuGEAAAAJ.
Thesis accepted by University of Copenhagen July 1981 in fulfillment of Doctor of Medical Sciences degree.
Thesis title: "Immunochemical Studies of Human β2-Microglobulin. A Review of Recent Methodological Progress and Clinical Applications".

Lines of research, GCP training and experience from Clinical Trials

  • Immunochemical Studies of Human β2-Microglobulin with development of the first radioimmunoassay of β2-Microglobulin.
  • Development of monoclonal antibodies to human leukocyte antigens and participation in the Clusters of Differentiation (CD) Workshops and development program.
  • Development of a diagnostic test for Paroxysmal Nocturnal Hemoglobinuria (PNH) by flow cytometry and studies of the Urokinase-type Plasminogen Activator Receptor (UPAR) in PNH.
  • Development of new therapies in multiple clinical trials with a focus on immunotherapy of multiple myeloma. Dosed the first myeloma patient with Daratumumab in March 2008.
  • GCP training 15 MAR 2023.

Contactdetails:

Torben Plesner, M.D. Professor of Hematology
University of Southern Denmark, Institute of Regional Health Science & Department of Hematology, Vejle Hospital, Beriderbakken 4
DK-7100 Vejle, Denmark
Tel. + (45) 79406313 / + (45) 20887692
E-mail: Ova adresa e-pošte je zaštićena od spambotova. Omogućite JavaScript u vašem brauzeru da biste je videli.


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