MLN9708 in combination with lenalidomide and dexamethasone against multiple myeloma

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Published: 17 Dec 2012
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Dr Shaji Kumar - Mayo Clinic, Rochester, USA

Dr Shaji Kumar talks to ecancer at the 2012 ASH annual meeting in Atlanta, Georgia about the phase I study of MLN9708, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma.


The high response rates seen with the bortezomib, lenalidomide, and dexamethasone regimen highlights the possibility feasibility of combining a proteasome inhibitor with an immunomodulatory agent and a steroid in patients with previously untreated multiple myeloma.


MLN9708 is an investigational, oral, reversible proteasome inhibitor with promising anti-MM effects and favorable toxicity profile with low rates of peripheral neuropathy.

ASH 2012

MLN9708 in combination with lenalidomide and dexamethasone against multiple myeloma

Dr Shaji Kumar – Mayo Clinic, Rochester, USA


The results that we presented today are from a phase I/II clinical trial looking at a new combination of MLN9708 in combination with lenalidomide and dexamethasone. Now patients with myeloma are living a lot longer compared to ten years ago and that has been the result of several new drugs that have been introduced, including the proteasome inhibitors like Velcade and immunomodulatory drugs like Revlimid. Now, with patients living longer and longer with better quality of life I think it’s important for us to start turning our attention towards developing regimens which retain the efficacy but are more convenient and more tolerable with less toxicity. I think the MLN9708 represents that kind of paradigm shift in the treatment of myeloma. It is an orally bioavailable proteasome inhibitor, the first one that is in the clinic and is probably the most advanced at this point in terms of clinical trials. It is quite similar to bortezomib or Velcade but, at the same time, chemically quite distinct in that it is bioavailable orally so it can be taken as a pill. Now the combination of bortezomib, lenalidomide and dexamethasone is one of the most efficacious regimens that we have seen in this disease in terms of being able to control the disease so it seemed only logical that we try and develop a regimen that is similar but at the same time more convenient by introducing the oral medication into the combination. Also, probably less toxic because we have seen a lot less peripheral neuropathy with the MLN9708 in the phase I clinical trials compared to what we would have expected from the Velcade combination.

What was the trial design?

The study was designed as a phase I/II study; the phase I looked at increasing doses of the MLN9708 in combination with standard doses of lenalidomide and dexamethasone. That phase of the study enrolled a total of fifteen patients at different dose levels and we determined that 2.97mg/m2 is the best tolerated dose for the MLN9708. So we decided to go with one dose level lower for the phase II study because we wanted to continue to give this drug on a long term basis. Now the phase II portion of the study was designed to test how efficacious this combination is in terms of controlling multiple myeloma and also to see how safe and how tolerable this medication is in this patient group. So that portion of the trial enrolled fifty patients and overall we had 65 patients in the trial. What we saw in the phase II portion of the trial was that it is quite efficacious: over 90% of the patients did get what we call a partial response which included at least 50% of the patients who had a very good partial response and a quarter of the patients who had a complete response. Now, half of the patients are still staying on therapy and with increasing duration of therapy we anticipate those numbers will continue to improve.

The second thing we learned from the phase II study was how safe this combination is in this group of patients. In terms of safety, the main side effects that we observed with this combination are nausea, vomiting, diarrhoea, mostly they’re gastrointestinal disturbances, skin rash and fatigue. Most of the side effects that we saw with the combination was well managed with either decreasing the dose of one or more of the medications or giving them some symptomatic therapy for nausea and diarrhoea. So overall it appears that this combination is well tolerated and it appears to be quite efficacious in patients with newly diagnosed myeloma, forming the framework or the basis for future exploration of the same combination in phase III clinical trials.