A team of Dutch researchers has published results of a small study in­ves­ti­gat­ing the impact of Darzalex treat­ment on immuno­glob­u­lin levels in multiple myeloma patients.

In their study, the researchers focus in particular on how the levels of a patient’s un­in­volve­d immuno­glob­u­lins are affected by treat­ment with Darzalex.

Uninvolved immuno­glob­u­lins in myeloma patients are immuno­glob­u­lins that have a type dif­fer­en­t from any mono­clonal immuno­glob­u­lin made by a patient’s myeloma cells.

Someone with IgG multiple myeloma, for example, has myeloma plasma cells that produce mono­clonal immuno­glob­u­lin G (IgG). For this myeloma patient, the un­in­volve­d immuno­glob­u­lins are IgA, IgM, IgD, and IgE – that is, every type of immuno­glob­u­lin other than IgG, which is the patient’s in­volve­d immuno­glob­u­lin.

Similarly, for someone with IgA multiple myeloma, the un­in­volve­d immuno­glob­u­lins are IgG, IgM, IgD, and IgE, and IgA is the in­volve­d immuno­glob­u­lin.

Uninvolved immuno­glob­u­lins in myeloma patients are polyclonal as opposed to mono­clonal. They are basically the same as the immuno­glob­u­lins of the same type found in people without multiple myeloma.

The Dutch researchers found that Darzalex affects the levels of IgG, IgA, and IgM dif­fer­en­tly when they are a patient’s un­in­volve­d immuno­glob­u­lins.

The drug seems to have little effect on IgG when it is an un­in­volve­d immuno­glob­u­lin. On the other hand, when IgA is one of a patient’s un­in­volve­d immuno­glob­u­lins, its level drops quickly after the patient’s first Darzalex in­fusion, reaching levels that are well below nor­mal, and then con­tinues to remain low, even a year after the start of treat­ment.

When IgM is one of a patient’s un­in­volve­d immuno­glob­u­lins, on the other hand, its level drops after a patient’s first Darzalex in­fusion, but then recovers over the course of the next 6-9 months of treat­ment.

Significance Of The Study Findings

These Dutch research team’s findings are im­por­tant for at least two reasons.

First, the findings highlight the need for patients being treated with Darzalex to be vigilant about pro­tecting themselves against in­fec­tion due to the impact the drug can have on IgA levels. People with lower-than-normal levels of IgA do not automatically develop lung or gastro­in­tes­ti­nal in­fec­tions, but they tend to be more sus­cep­tible to them. Thus, patients being treated with Darzalex who develop lower-than-normal levels of IgA should discuss with their doctors what precautions they should take to pro­tect themselves against poten­tial in­fec­tions.

Second, the findings can help physicians and patients better under­stand the implications of immuno­glob­u­lin level results from regular blood tests. The study results sug­gest, for example, that patients with IgG multiple myeloma need not be alarmed if their IgA level drops drastically after starting treat­ment with Darzalex.

Similarly, patients with IgA multiple myeloma who ex­peri­ence sig­nif­i­cant changes in their IgG level – either up or down – during treat­ment with Darzalex may want to work with their doctors to better under­stand the implications of those results.

Study Design

The results the Dutch researchers published re­gard­ing Darzalex and its impact on the levels of un­in­volve­d immuno­glob­u­lins were part of a broader study investigating the link be­tween Darzalex treat­ment and the risk of in­fec­tion.

Other parts of the Dutch study looked at how Darzalex affects plasma cell frequency in the bone marrow of myeloma patients and how the drug affects the efficacy of flu vaccines.

For their research related to Darzalex and un­in­volve­d immuno­glob­u­lin levels, the study authors analyzed blood samples from 30 re­lapsed and re­frac­tory multiple myeloma patients who par­tic­i­pated in a Phase 1/2 trial in the Netherlands investigating Darzalex as a single agent and in com­bi­na­tion with all-trans retinoic acid in re­lapsed and re­frac­tory multiple myeloma.

Patients in the trial re­ceived 16 mg/kg of Darzalex weekly for 8 weeks, bi-weekly for 16 weeks, and monthly there­after. During the first part of the trial, which is the source of un­in­volve­d immuno­glob­u­lin level data the researchers analyzed, patients re­ceive only Darzalex as a single agent (that is, without all-trans retinoic acid or any other myeloma treat­ment).

Patients who par­tic­i­pated in the first part of the trial a median of five prior ther­a­pies, in­clud­ing Revlimid Revlimid (lena­lido­mide) (100 per­cent of patients), Velcade (bor­tez­o­mib) (97 per­cent), Pomylast (poma­lido­mide, Imnovid) (50 per­cent), and Kyprolis (car­filz­o­mib) (10 per­cent).

The majority of patients (70 per­cent) had IgG myeloma. Another 27 per­cent had light-chain myeloma, and 3 per­cent had IgA myeloma.

The median patient age was 70 years old.

The levels of patients’ un­in­volve­d immuno­glob­u­lin levels were assessed at the start of the trial, at the start of each Darzalex treat­ment cycle, and at the time of dis­ease pro­gres­sion. Blood samples were drawn directly before the start of Darzalex treat­ment.

Patients who re­ceived in­tra­venous immuno­glob­u­lins (IVIG) transfusions as prophylaxis against in­fec­tions were excluded from the analysis.

Study Results

The results of the Dutch researchers’ analysis show that patients on average had below-normal levels of un­in­volve­d immuno­glob­u­lins even before they started treat­ment with Darzalex.

After 4 weeks of treat­ment with Darzalex, the researchers observed a sig­nif­i­cant de­crease in un­in­volve­d IgA, IgM, and IgE levels. IgG levels, on the other hand, remained stable. This devel­op­ment occurred in all patients independent of treat­ment re­sponse­. Figure 1 below in­cludes graphs of the average levels of un­in­volve­d IgG (Panel 1), IgA (Panel 2), and IgM (Panel 3) measured by the Dutch researchers during their study.

Uninvolved IgG levels remained stable, albeit below the lower limit of nor­mal, with successive treat­ment. The researchers point out that un­in­volve­d IgG levels may have been slightly overestimated because Darzalex is an IgG kappa anti­body. However, un­in­volve­d IgG remained stable after they made ad­just­ments to reflect Darzalex’s poten­tial influence on un­in­volve­d IgG levels.

The levels of un­in­volve­d IgE and IgM levels returned to the same level as at the start of the trial after 24 and 36 weeks of treat­ment, re­spec­tive­ly.

Uninvolved IgA levels, on the other hand, did not recover sub­stan­tially with successive treat­ment.

A Potential Explanation For The Results

The authors of the Dutch study note that plasma cells that produce nor­mal (non-monoclonal) IgG are found mainly in the bone marrow, whereas other parts of the body, such as mucous linings, lymph nodes, and the spleen play im­por­tant roles in the pro­duc­tion of non-monoclonal IgA, IgM, and IgE.

The Dutch researchers speculate that the dif­fer­en­t locations of these healthy plasma cells in the body may ex­plain why levels of un­in­volve­d IgG, IgA, and IgM change in dif­fer­en­t ways when myeloma patients are treated with Darzalex.

For more in­for­ma­tion, please see the study by Frerichs, K. A. et al., “Effect of dara­tu­mu­mab on nor­mal plasma cells, polyclonal immuno­glob­u­lin levels, and vaccination re­sponse­s in extensively pre-treated multiple myeloma patients,” in Haematologica, Sep­tem­ber 26, 2019 (full-text).