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.