Monoclonal antibody in the treatment of multiple myeloma

iStock_000025815091_Full (1)Multiple myeloma (MM) is considered to be an incurable disease. However, with the release of Daratumumab by the US FDA in November 2015 there is a real hope for patients suffering from this chronic disease. The drug was registered for patients with MM in whom the use of elementary line treatment, with the proteasome inhibitor (PI) and an immunomodulating agent, was ineffective.

Multiple myeloma (MM) is a malignant haematological cancer of unknown etiology in which there is a clonal proliferation of plasmatic cells. The cancer is the most common in bone marrow where myeloma cells usually produce monoclonal protein – protein M. The disease is relatively common. It accounts for about 10% of cancers stemming from hematopoietic cells, what makes it the second most common cancer after lymphoma. Also, it represents 1% of all cancers. About 1.3 thousand of new cases are reported annually in Poland. The risk increases with age, peaking in the seventh decade of life. In Europe, the annual incidence is about 40: 1 000 000. The first symptoms of the disease are usually bone pains. Renal failure, anemia, reduced resistance to infection and blood hyperviscosity syndrome appear with progression. Despite significant progress in medicine it is still considered as an incurable disease. Eventually, there is a relapse and the disease develops resistance against available drugs. Indicator of 5 year survival is approximately 47%.

Daratumumab (DARA) is fully human monoclonal antibody anti-CD38. In the body, the molecule CD38 functions as a surface receptor present on most malignant plasma cells what has become an attractive pharmacological point of the offensive. It allows myeloma cells for adhesion, migration and colonization of the organ of origin. Recent clinical studies (GEN501 and SIRIUS) demonstrated that DARA alone showed a significant clinical activity and was well tolerated in severely ill patients with relapsed and refractory MM inducing death of myeloma cells by several mechanisms: antibody dependent cellular cytotoxicity antibody, phagocytosis dependent cell and antibody dependent cytotoxicity of complement.

In GEN501 and SIRIUS studies patients who did not respond to more than two basic lines of therapy were given the drug at a dose of 16 mg/kg within a specific period of time. In both studies the following indicators of response to treatment were assessed: overall response rate (ORR), partial response (PR), very good partial response (VGPR) and complete remission (CR).

Results of these studies showed that overall response rate was 36% in GEN501 and 29% in SIRIUS. Total remission (CR) was reported in 2.8% of patients, very good partial response (VGPR) was reported in 9.4% of patients, and partial response (PR) was observed in 17% of patients. In total analysis, the median duration of response in patients with a remission was 7.6 month. 46% of those patients remained free from progression for over 1 year.

Dr. Sagar Lonial from the Department of Hematology and Oncology at Emory Universit, who is an author of the SIRIUS, believes that Daratumumab can have an important role as monotherapy for patients in advanced stages of multiple myeloma.

Recent years have led to a great leap in possibilities of MM therapy. Nevertheless, it remains an incurable disease. Targeted therapy with the use of Daratumumabu and other monoclonal antibodies gives hope for a durable remission and may become a standard treatment of MM in the future. We believe that broadening of knowledge and performing further research on the mAb is the direction which should be taken by oncology.

Written by: Jaromir Ziomek, Erwin Ciechański, Szymon Stec

1. Saad Z. Usmani, MD; Brendan M. Weiss, MD Clinical Efficacy of Daratumumab Monotherapy in Patients With Heavily Pretreated Relapsed or Refractory Multiple Myeloma 2015
2. Lokhorst HM, Plesner T, Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. doi: 10.1056/NEJMoa1506348.
3. van de Donk NW, Lokhorst HM,  New developments in the management and treatment of newly diagnosed and relapsed/refractory multiple myeloma patients.Expert Opin Pharmacother 2013;14(12):1569-1573
4. Raje N, Longo DL , Monoclonal Antibodies in Multiple Myeloma Come of Age. N Engl J Med 2015;373(13):1264-1266

Would you like to know more? Watch on Multiple myeloma – Histopathology – Bone

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