Multiple myeloma – daratumumab

The monoclonal antibody daratumumab may offer a new treatment for the incurable blood cancer multiple myeloma

Multiple myeloma is one of the more common blood cancers, affecting the plasma cells that produce antibodies. These accumulate in the bone marrow, where they affect the production of normal blood cells. While it is currently incurable, a number of relatively effective treatments are available. However, relapse occurs and typically responses to successive alternative treatments get shorter and less effective. Eventually new treatment options run out.

Novel drugs to treat multiple myeloma are thus very much needed. One such treatment is the monoclonal antibody daratumumab, which is being developed by Genmab in collaboration with Janssen.1 It is a humanised antibody to CD38, and may have potential in other tumour types, too.

It is being investigated both as monotherapy and in combination with other agents. In the first part of a Phase I/II dose escalation study, 32 patients with relapsed or refractory multiple myeloma were given daratumumab according to a 3+3 dose escalation designed over a nine-week period, with two pre-doses and seven full doses.

The Phase II dose was established at 8mg/kg, and given every week for eight weeks, every other week for a further 16 weeks, and then every fourth week until disease progression or toxicity, for a maximum of two years. In the Phase I part of the study, of the 12 patients given at least 4mg/kg, five achieved partial responses and three minimal responses.2

In an expansion of this trial, patients who were resistant to or had relapsed after at least two prior lines of therapy were enrolled. Of these, 30 were given 8mg/kg either with or without a 10mg pre-dose for the first eight infusions, or 16mg/kg with no pre-dose with a three-week washout period after the first two doses, followed by a further seven weekly doses.

All patients were then given the drug every second week for 16 weeks, then every fourth week until disease progression, toxicity, or until two years had elapsed.3

Preliminary results indicated an overall response rate of 46% in the higher dose group, with three very good partial responses, three partial responses, a minimal response and three patients achieving stable disease, with three having disease progression. In the lower dosed group, there were two partial and five minimal responses and 16 patients with stable disease, and nine disease progressions. The overall safety profile was described as ‘manageable’.

It is also being investigated in combination with other agents. In one trial, its safety and efficacy when dosed with lenalidomide and dexamethasone was evaluated.4 Pre-treated patients with relapsed or refractory multiple myeloma were given 2–16mg/kg of daratumumab every week for eight weeks and then twice a month for 16 weeks, and then monthly until disease progression, unmanageable toxicity or two years had elapsed, alongside weekly 25mg lenalidomide and 40mg dexamethasone doses.

Initial results from 11 patients indicated that eight achieved a partial or very good partial response, and two a minimal response. The median time to response was four weeks. This trial is ongoing.

It is also being evaluated in a Phase Ib study in combination with a variety of other standard multiple myeloma treatment regimens, with other components including bortezomib, either alone or with thalidomide or melphalan, and pomalidomide, all in combination with dexamethasone.5

References

1. M. de Weers et al. J. Immunol. 2011, 186, 1840

2. H.M. Lokhorst et al. J. Clin. Oncol. 2013, 31 (suppl.), Abst. 8512

3. H.M. Lokhorst et al. J. Clin. Oncol. 2014, 32 (suppl.), Abst. 8513

4. T. Plesner et al. J. Clin. Oncol. 2014, 32 (suppl.), Abst. 8533

5. P. Moreau et al. 56th Amer. Soc. Hematol. Ann. Meet (San Francisco, December 2014), Abst. 176

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