Clinical development

The first clinical trials with DARA monotherapy included patients who had relapsed or refractory disease after two or more prior lines of treatment [14, 15]. The overall response rate (ORR) was 31% and for responders the median overall survival (OS) was > 20 months in this heavily pre-treated cohort of patients who at that time were only expected to have an OS of nine months on standard treatment [16]. These studies led to the approval of DARA as treatment for relapsed refractory multiple myeloma (RRMM) [17]. Interestingly, a clear benefit in OS (18 months, a doubling of the expected OS) was also found in the group of patients who only achieved SD or MR according to IMWG criteria. Thus, although the reduction of the tumour load in these patients is minimal, they live significantly longer than the expected nine months. This can only be understood if other mechanisms than tumour cell killing are important. This point to a potential role of DARA for the immune system’s ability to control myeloma and/or to a possible importance of DARA’s ability to block the transfer of mitochondria through nanotubes and thereby inhibit MM cell proliferation and survival as described earlier.
Many clinical studies of DARA in combination with standard of care anti-myeloma drugs have been conducted or are under way. So far, all studies showed that the addition of DARA to standard of care anti-myeloma drugs increases the ORR, the progression free survival (PFS) and the number of patients where the disease is no longer traceable even with the most sensitive techniques such as next generation flow cytometry or next generation sequencing, so the patient has become minimal residual disease (MRD) negative. With the most recent developments of technologies, the detection level of residual tumour cells has come down to one cell in one million BM cells [18]. The high quality responses have also translated into very significantly improved survival [19]. Recently an OS benefit was also found by adding DARA to established anti-myeloma therapies of NDMM or RRMM [20, 21]. In addition, progression free survival on the subsequent line of therapy (PFS2) may be improved by the addition of DARA [21].

Mechanism of resistance to daratumumab

DARA has improved the treatment of MM significantly, and improved both PFS, ORR, MRD negativity rates and OS [20, 21]. Nevertheless, even though the clinical benefits of DARA are well documented, a recent evaluation of all Danish MM patients, who have received DARA before 2019, showed that the majority of patients eventually relapse on DARA and that the median OS after progression is only approximately 12 months [22]. These findings highlight a need to examine the reasons for failure of DARA therapy in order to improve the outcome.
Immediately following the first infusion with DARA, there is a pronounced reduction of the expression of CD38 on the remaining MM cells [23]. Whether this downregulation of the CD38 expression is good or bad for the response to DARA is not yet clarified. The reduction of CD38 results in impaired CDC, ADCC and ADCP activity by DARA. On the other hand, formation of immunosuppressive adenosine, potentially protective adhesion of myeloma cells to stromal cells and the formation of nanotubes transferring mitochondria from stromal cells to myeloma cells that boost myeloma cells is also reduced by DARA. A high expression of CD38 before initiation of treatment with DARA is associated with a better chance of response, but it does not result in a longer PFS [23].

The complement system

The complement system is a part of the humoral immunity. Activation of the complement system results in formation of the membrane attack complex (MAC) on the surface of the target cell (Figure 2). The MAC forms pores in the plasma membrane, which results in osmotic swelling and rupture of the target cell. The plasma level of the complement degradation and activation products, e.g. C3a, C3d, C5a, C5b-9, reflects the extent of complement activation [24-26]. Normal cells have several complement inhibitory proteins (CIPs) on the cell surface to protect them from the effects of complement. CD59 is an important CIP, which blocks the final formation of the MAC, and thereby inhibits the function of this element of the complement system. CD55 accelerates the decay of C3- and C5-convertases (Figure 2). Analysis of samples collected during monotherapy with DARA has shown an increased level of the CIPs CD55 and CD59 on the myeloma cells at the time of loss of response and disease progression [23]. Thus, inhibition of CDC may be a cause of development of resistance to DARA.