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Invited paper

Daratumumab for the treatment of multiple myeloma

Katrine Fladeland Iversen1, Torben Plesner1
  • Department of Hematology, Vejle Hospital, University of Southern Denmark, Vejle, Denmark

ABSTRACT

Daratumumab is the first approved monoclonal antibody that targets the CD38 protein on the surface of myeloma cells. Historically, a well-established anti-myeloma protocol included oral melphalan and prednisolone as the standard of care. Apart from this, in a bit longer than two decades the high dose of melphalan followed by autologous stem cell transplantation became the standard for young and fit myeloma patients. Simultaneously, the prophylactic treatment of frequent and devastating skeletal complications was improved using intravenous bisphosphonate. In the following years, there came an era of significant improvements in anti-myeloma treatment that had an impact on survival rate of elderly and/or frail myeloma patients. The treatment included immunomodulatory drug thalidomide followed by the development of a less toxic and more effective analogue lenalidomide. At the same time, bortezomib, a first-in-class proteasome inhibitor, was introduced in the therapeutic protocols. Despite these improvements in survival, the prognosis remained poor for patients relapsing after treatment with bortezomib and lenalidomide with a median overall survival of only 9 months.

After the initial dose escalation studies daratumumab resulted in a prolonged survival in the absence of significant killing of tumor cells through modulation of the immune system or the bone marrow microenvironment. The emerging picture showed that the addition of daratumumab alone or in combination improved the outcome in all myeloma patients without adding significantly to toxicity. Owing to this approach, myeloma patients live longer and have a better quality of life and there are further efforts to cure them which represents the main therapeutic goal.


In a matter of a little more than two decades, we have witnessed a tremendous change in the treatment of multiple myeloma. Building on the well-established regimen of oral melphalan and prednisolone the InterGroup Francophone du Myelome improved the outcomes of young and fit myeloma patients that could tolerate the toxicity of high-dose melphalan [1],[2]. At the same time, prophylactic treatment of frequent and devastating skeletal complications of multiple myeloma was improved by the use of intravenous bisphosphonate [3]. The next milestones of improvements of anti-myeloma treatment that would also have impact on the survival of elderly and/or frail myeloma patients (Figure 1) was heralded by the observation of anti-myeloma activity of thalidomide followed by the development of less toxic and more effective analog lenalidomide [4],[5]. Simultaneously bortezomib, a first-in-class proteasome inhibitor, showed promising activity in myeloma [6],[7].

p340

Figure 1. History and treatment of multiple myeloma from1844 to the present

Despite these improvements in survival, prognosis remained poor for patients relapsing after the treatment with bortezomib and lenalidomide with a median overall survival of only 9 months [8]. Myeloma doctors were dreaming of an antibody that could transform the outcomes for myeloma patients in a manner similar to what rituximab had accomplished for patients with malignant lymphomas. In 2006 Genmab, a small Danish-Dutch biotech company, came forward with a proposal to test a CD38 antibody (daratumumab) clinically in relapsed-refractory myeloma. The rationale was a strong expression of the CD38 target by myeloma cells and demonstration of the ability of the antibody to kill myeloma cells in vitro along with synergistic anti-myeloma activity when combined with lenalidomide or bortezomib [9],[10]. However, wide expression of the multifunctional CD38 molecule in the human body and a lack of suitable animal models for preclinical testing of potential toxicities caused worries. Furthermore, the situation was complicated by a recent disaster in a clinical trial of a CD28 antibody that alerted the authorities to the potential danger of using monoclonal antibodies for therapy [11]. It was clear that the initial testing of daratumumab in a clinical trial had to be planned with great care. A very low starting dose, one patient included at a time with a sufficient observation period to detect potential side effects, and small increments of the dose of antibody from each cohort of patients to the next was the strategy, when starting up in 2008. Since the field was entirely new, many adjustments of the first protocol GEN501 had to be made along the way coming up to a total of 14 amendments to the protocol. Slow progress was inevitable and at the same time, Genmab, like many small biotech companies, was fighting for its life due to financial constraints. In the first 4 years of the trial only 23 patients were enrolled.

Despite a common dream of having a “rituximab for myeloma” one day, skepticism prevailed, and when the first data from GEN501 were presented at ASH 2011 it received very little interest and zero citations. The following year, dosing of daratumumab passed 2 and 4 mg/kg of body weight and the first signs of a response started to appear. This changed the whole picture, and at ASH 2012 the results of GEN501 received considerable interest and 23 citations (Chart 1) (Genmab: Data on file). Consequently, enrolment of patients into the trial accelerated and a companion study (SIRIUS) in North America and combination studies with lenalidomide and bortezomib were launched.

p342 1

Chart 1. The first human clinical trial with daratumumab GEN501 started in March 2008. The recruitment was initially very slow with only 23 patients enrolled in 4 years. With the first sign of clinical activity at 2 and 4 mg/kg presented at ASH 2012 interest increased considerably, recruitment for the trial accelerated and a companion study (SIRIUS) was initiated in North America (Genmab: Data on file)

As monotherapy, daratumumab improved survival considerably. The intention to treat population had a median overall survival of 20 months, but perhaps most interestingly, daratumumab also prolonged the overall survival of the 52% of patients that did not obtain a formal response according to IMWG criteria, but only stable disease or a minor response, to 18.5 months [12- 14] (Chart 2). This was a doubling of the survival that could be expected at that time for patients refractory to bortezomib and lenalidomide [8]. The reason for this extension of survival in the absence of significant killing of tumor cells is not well understood, but modulation of the immune system or the bone marrow microenvironment are likely explanations.

p342 2

Chart 2. Daratumumab monotherapy improved overall survival both for responders (31%) and for patients obtaining only MR or SD (52%)

In the following years, we could witness a very active development program for daratumumab owing to collaboration between Genmab and Janssen. Daratumumab was used in all lines of therapy and in combination with all most important drugs used for the treatment of myeloma. The emerging picture showed that the addition of daratumumab improved the outcome in all cases without adding significant toxicity. A slight increase in the risk of neutropenia and infections has been found, but this can be counterbalanced by appropriate supportive care. Infusion-related reactions were seen in about half of the patients during the first infusion but rarely thereafter and were mild in nature. The infusion -related reactions and the ease of administration have been improved by the availability of a subcutaneous formulation of daratumumab.

In the present scenario of multiple treatment options for patients with relapsed refractory myeloma it is increasingly difficult to demonstrate improved overall survival in clinical trials, but recently an overall survival benefit was found for patients receiving daratumumab both in the ALCYONE, the POLLUX, the CASTOR, and the MAIA trial [15],[16],[17],[18].

Worries that an overall survival benefit in one line of therapy might translate into a poorer outcome of the subsequent line of therapy were not supported. On the contrary, the survival benefit from daratumumab was carried forward into the subsequent line of therapy as shown by the PFS-2 of the MAIA trial (Figure 2) [18]. It has also been shown that prolonged treatment with daratumumab will result in progressive deepening of remission as reflected by MRD negativity (Figure 3) [19].

p343

Chart 3. Rate of MRD negativity (10-5) in the intention to treat population of the MAIA trial.

The CASSIOPEIA study has revealed that adding DARA to the induction treatment before autologous stem-cell treatment and to the consolidation treatment afterwards increases the PFS and the rate of MRD negativity [20].

Along with a need for a long-term treatment it is important to notice that the quality of life is improving over time during treatment with Daratumumab [21]. Since daratumumab is so well tolerated both as a single agent and combined, frail elderly patients obtain benefits from the treatment as well.

Daratumumab has multiple modes of action but it is unknown which are the most important and the reason for failure to respond to treatment with daratumumab or loss of response are obscure. Some of daratumumab´s modes of action (complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP)) depend on the level of CD38 expression. These modes of action may be impaired by a low level of expression of CD38, which may occur with time as treatment with daratumumab reduces the expression of CD38 by myeloma cells [22],[23]. On the other hand, the reduced level of CD38 may also be beneficial. The formation of immunosuppressive adenosine is inhibited in the bone marrow microenvironment [24]. Potentially protective adhesion of myeloma cells to stroma is impaired [25]. Apart from this, the formation of nanotubes connecting stromal cells with myeloma cells and transferring energizing mitochondria to the myeloma cells is blocked (Figure 2) [26].

p344

Figure 2. Mitochondria are transferred from stromal cells to myeloma cells trough interconnecting nanotubes providing energy and boosting the malignant phenotype of the myeloma cell. The formation of nanotubes is dependent on CD38 and may be blocked by CD38 antibody (modified and reprinted from Oncoscience 4, 173, 2017)

In clinical practice, a rapid initial response to daratumumab is often followed by a long period with a slow but steady decline of the M-protein over time. In theory, the rapid initial response to daratumumab could be due to CDC, ADCC and ADCP that work best when CD38 expression is high. This may be followed by a long period where reprogramming of the immune system and modulation of the microenvironment by reduced formation of adenosine, impaired adhesion of myeloma cells to stroma, inhibition of formation of nanotubes and elimination of regulatory cells of the T, B and M cell systems become more important [27].

The introduction of daratumumab in the treatment of patients with myeloma offers a rare combination of a very efficient and well-tolerated new treatment modality. Together with the immunomodulatory drugs and proteasome inhibitors, it represents the first major step away from old-fashioned alkylator based therapy towards a new era where the immune system is tuned to cope with myeloma. As a result, myeloma patients will survive longer and live better lives as we systematically move forward towards the goal of curing myeloma.

  • Conflict of interest:
    None declared.

Informations

Volume 4 No 4

December 2023

Pages 339-348
  • Keywords:
    daratumumab, multiple myeloma, therapy, prognosis
  • Received:
    10 November 2023
  • Revised:
    20 November 2023
  • Accepted:
    20 November 2023
  • Online first:
    25 December 2023
  • DOI:
  • Cite this article:
    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
Corresponding author

Torben Plesner
Department of Hematology, Vejle Hospital, University of Southern Denmark
4, Beriderbakken Street, 7100 Vejle, Denmark
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


  • 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]


REFERENCES

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]

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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: This email address is being protected from spambots. You need JavaScript enabled to view it.


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