Multiple myeloma is a disease that affects many different organ systems including the bones in 90% of patients and the kidneys in about 60% of myeloma patients over the course of a patient’s experience with the disease. Bone protective or bone directed therapy is a recommended part of all myeloma therapy. There is one small niche or unmet need and that is for patients who have renal dysfunction defined as a creatinine clearance less than 30 or patients on haemodialysis. The historic standard of care for treating bone disease had been zoledronic acid which you cannot safely administer in a creatinine clearance less than 30. Recently denosumab was approved for bone directed therapy in multiple myeloma. One of the advantages of denosumab is that it’s not renally cleared and safe for the kidneys.
So this study is the first, and a much needed study, that addresses that population of patients with multiple myeloma who have a creatinine clearance less than 30 who need bone directed therapy but have not yet received it.
What were your methods?
This is a single arm phase II study. For this study we presented an interim analysis of the first 20 of 40 patients. All patients in the study, which includes both newly diagnosed and relapsed refractory myeloma patients, will receive denosumab subcutaneously once monthly for twelve months or doses. We’ll be following the serum CTx level to look at the change in their bone turnover biomarker and also as a secondary endpoint we’re evaluating the safety and adverse events as a result of the drug administration.
What did you find?
So far we’ve enrolled 20 patients. At the time of this analysis 10 were on track to complete the study as predefined. It’s interesting looking at the first 20, their arms are balanced between men and women and there are six patients who were on haemodialysis, that’s about 30% of the study. The majority of these patients were high risk, so 75% had ISS stage 3 disease, the majority of the patients had light chain disease which goes along with the renal picture that we’re seeing. So in terms of the primary endpoint we saw a 75% reduction or percentage change in the CTx level but in terms of the practical use what are the toxicities? We worry about hypocalcaemia in the renally impaired receiving these types of agents. We did see hypocalcaemia in about 39% of patients. If you look at this in contrast to the phase III study comparing zoledronic acid and denosumab it’s a little bit higher than patients who did have normal renal function. Of the events of hypocalcaemia we saw that 22% were grade 3 or higher; there actually were no grade 4 or 5 events, so it’s just grade 3. If you broke it down a little bit further looking at who was getting hypocalcaemia, so we looked at patients who were getting dialysis versus those who just had a creatinine clearance less than 30, three out of the six patients on haemodialysis did have hypocalcaemia, four out of the twelve non-dialysis also had hypocalcaemia.
Then going a step further, because it’s one thing to have hypocalcaemia but also was this something that we did well, that we controlled, or was it a recurring problem, we did see when we looked at it that five out of the seven patients who had hypocalcaemia had multiple events. I think what this really underscores, we knew this going in and all patients are given prophylactic doses of calcium and vitamin D, they have to have a normal level of vitamin D and calcium going in. We allow for repletion prior to study initiation to ensure safety and efficacy of giving bone directed therapy. But it really underscores that this is a population that needs to be studied. Even though we know in theory that denosumab is safe in renal dysfunction we have to study it and we need to know how we’re giving it to these very vulnerable patients. So we have demonstrated that it can be done, that it’s efficacious but that you absolutely do have to pay attention to hypocalcaemia and treat accordingly.
What are the next steps for the study?
Finishing it. So we’re accruing it, we continue to recruit patients for this study and then our hope is that this indication for patients with creatinine clearance less than 30 will be added to the FDA label for this drug, for denosumab.