COMMENTARY

Myeloma Takeaways From ASH 2015: New Drugs, Regimens

Saad Z. Usmani, MD

Disclosures

December 23, 2015

Editorial Collaboration

Medscape &

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There have been a lot of exciting data being presented at the American Society of Hematology (ASH) 2015 Annual Meeting. The key elements that I would like to highlight are the takeaways for community doctors, specifically in treating newly diagnosed and relapsed/refractory myeloma.

There have been several issues regarding the optimal induction regimens or the use of early vs delayed stem cell transplant. I think we have a good answer for some of these questions.

I would like to highlight the abstracts that answered the induction question. One compared 2 triplet regimens and another compared a triplet with a doublet regimen as induction treatment for newly diagnosed myeloma patients.

The SWOG S0777 trial[1] comparing the combination of bortezomib and lenalidomide/dexamethasone with lenalidomide/dexamethasone as the initial therapy for newly diagnosed myeloma patients was presented by Dr Brian Durie. This trial was a large randomized phase 3 study, with the endpoint of progression-free survival (PFS) having been met. The study reported a superior PFS as well as a response rate benefit in favor of the bortezomib and lenalidomide/dexamethasone combination. That is an important takeaway for community doctors.

Another important takeaway is comparing the proteasome inhibitor, immunomodulator, and dexamethasone drug combination with a proteasome inhibitor, alkylator, and dexamethasone combination.[2] It was a randomized trial. They presented the response rates and PFS benefits of VTD (bortezomib, thalidomide, dexamethasone) and CyBorD (cyclophosphamide, bortezomib, dexamethasone). The combination of VTD resulted in a superior depth of response, and a PFS benefit appears to be seen.

These are two important induction treatment trials, and the manuscripts should be coming forth fairly shortly.

To answer the question about early vs delayed transplant, the IFM/DFCI 2009 trial[3] was initiated about 6 years ago. The French myeloma group reported on their 700-patient cohort, with a median follow-up of 39 months. It appears that there is a definite 3-year PFS benefit in favor of early transplant vs delayed transplant.

Some interesting themes around the depth of response were also discussed as part of ancillary studies[4] of this trial. So we've thought of depth of response as stopping at stringent complete response (CR), but this trial included a flow-based minimal residual disease (MRD) assay. The patients within the CR group who did the best were the ones that were MRD-negative by flow post-transplantation.

So, the other theme that we are developing, which will be extremely important to community doctors, is that MRD may have a role to play in prognosticating PFS and overall survival for newly diagnosed myeloma patients. It may be heading toward becoming a clinical endpoint for clinical trials, and something that we will be utilizing in clinic fairly soon. I think those were the most important studies in the newly diagnosed setting.

For relapsed/refractory myeloma, it has been an exciting 2 weeks, with three drugs that were approved for relapsed/refractory patients—namely ixazomib, elotuzumab, and daratumumab. The first two drugs were approved in combination with lenalidomide and dexamethasone for patients with one prior line of therapy, whereas daratumumab was approved for patients who had double refractory or have had more than three lines of therapy. Both very important areas. They've spurred a debate about how best to utilize ixazomib and elotuzumab in that setting, now that we have a lot of [options]in that particular area. It will be important to tease out the subgroups that benefited from one therapy over the other.

There are certain mechanistic aspects to those drug approvals as well. The ixazomib and lenalidomide/dexamethasone combination relies on the proteasome inhibitor and immunomodulatory drug platform and appears to be convenient. The only side effect: You have less neuropathy, but some more gastrointestinal side effects with that combination. With elotuzumab, the infusion time and convenience appear to be the theme. But outside of those, in the elotuzumab ELOQUENT-2 trial,[5] there was a higher incidence of high-risk patients that could enroll, and they appeared to be benefiting the same as standard-risk patients. So, there might be some risk stratification that may be involved in choosing therapies between those two. Based on daratumumab's single-agent activity, it is also being brought into the early clinical setting.

So now you have three options in the one to three prior lines of treatment. You've already had data on carfilzomib being combined with lenalidomide/dexamethasone and now you have data with ixazomib and elotuzumab. Unfortunately for community colleagues, we don't have a clear answer on which setting to use these drugs in. Perhaps the carfilzomib and ixazomib combinations may be utilized for people who require fairly rapid cytoreduction, whereas elotuzumab may be an option that is suitable for slow biochemical relapses or folks who have other comorbidities because of elotuzumab's fairly decent safety profile.

Those are the key takeaways in the relapse setting from the community perspective. I would highlight that there are some other-platform drugs that are being developed. Checkpoint inhibitors like pembrolizumab are being combined with immunomodulatory drugs, such as lenalidomide and pomalidomide. Those early data were also shared.

Anti-CD30 monoclonal antibodies in combination with immunomodulatory drugs were also presented. The early-phase data look promising, and larger phase 3 studies are going to be coming in 2016.

It's very encouraging to see a lot of these drugs making their way into larger phase 3 trials, and we're very excited that we have more of these options coming for our myeloma patients.

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