18th International Myeloma Workshop

Melflufen and dexamethasone vs pomalidomide and dexamethasone in relapsed refractory multiple myeloma

Dr Fredrik Schjesvold - Oslo Myeloma Center, Oslo, Norway

It’s a randomised trial between melflufen dexamethasone and pomalidomide dexamethasone in patients who have received two to four prior lines of treatment and were refractory to lenalidomide.

What was the methodology that you used?

It’s a quite standard randomised trial with a randomisation 1:1 between the two arms. Contrary to most myeloma randomised studies this is a head-to-head study with two different drugs, so one is the standard and one is the novel drug melflufen. Most randomised studies in myeloma are add-on studies where you give the same treatment and you add on one drug in the intervention arm. So this is a head-to-head study which sometimes creates a different type of result because you will more often see subgroups benefitting from one or the other while in an add-on study usually most subgroups are benefitting from the new treatment since it’s both the old and new treatment at the same time.

Pomalidomide dexamethasone was given in approved standard dosing and melflufen was an intravenous drug given once every cycle for 28 days. The primary endpoint was PFS and normal secondary endpoints were overall survival and overall response rate and such.

What were the key findings?

The primary endpoint was positive with an increase in progression free survival from about 4.9 for pomalidomide and 6.3, about there, for melflufen dexamethasone. So it’s a positive study with a positive primary endpoint. However, we saw that even though it wasn’t statistically significant there was a slight numerical increase in mortality in the intervention arm. So that led to a partial clinical hold in ongoing studies for melflufen.

What we did see in the subgroups, especially the subgroup which is half of the patients in the study and this is the subgroup who had previously received a transplant or not, we saw that melflufen dexamethasone benefitted also in overall survival as well as in PFS the patients who had not received a previous transplant. But pomalidomide, especially for OS, benefitted the patients who had received a previous transplant. So this actually gives a result that you can use in picking patients who would benefit from one treatment versus the other.

Were there any adverse events?

Those events were in line with previous reports on the two drugs. Melflufen, the new drug, that’s mainly haematological. There is a large fraction of the patients who experience thrombocytopenia and neutropenia and anaemia, more than the pomalidomide arm. But these were mainly manageable and you saw that only 1%, if you’re discussing thrombocytopenia, only 1% of the patients had a severe bleeding. Regarding neutropenia we actually saw that there were more infections, all types of infections, in the pomalidomide arm. So it was not more infections than expected, maybe even less. Anaemia is not such a problematic thing to manage. Besides the haematological adverse events there wasn’t any signal of any other adverse event that happened in a fraction of the patients.

How can these results impact the future treatment of RRMM?

Now there’s a pending decision by the FDA with this partial clinical hold and they’re looking into the data. We have discussed now, and was shown at the conference now also, of course, even more data later than that. My belief is that they will approve the continuous development of melflufen in patients who have not received a previous transplant. They will probably say that patients who have received a previous transplant, especially within the last five years, should not be treated with pomalidomide. But in the patients without the transplant the results are better than for pomalidomide and would be a new standard of care for the patients who would otherwise have received pomalidomide.

This is an alkylator so it’s also interesting what happens to patients who are refractory to alkylators. In that setting we saw that both PFS and OS was much improved by melflufen versus pomalidomide dexamethasone in the patients who were alkylator refractory if they were not transplanted. So it’s the transplant that’s the problem, not the alkylator in itself. So it also confirms, or this strengthens, the argument that melflufen is not just another alkylator, it’s a better alkylator than the ones we have on the market as of today. As long as you’re not giving them to patients who are recently transplanted.