Multiple myeloma highlights from ASH 2019

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Published: 10 Dec 2019
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Prof Heinz Ludwig - Wilhelmeninen Cancer Research Institute, Vienna, Austria

Prof Heinz Ludwig speaks to ecancer at the 2019 ASH meeting in Orlando about some of the multiple myeloma (MM) highlights from this year's conference.

One of the studies he mentions is about the use of bispecific T-cell engagers (BiTEs) in relapsed/refractory disease, which has shown high response rates and good tolerability in these patients.

Prof Ludwig also discusses advancements in CAR T-cell therapy including one study which used alpha secretase to enhance the expression of BCMA which achieved a 100 percent response rate.

He also outlines other significant studies that focused on the treatment of MM, particularly in the newly-diagnosed setting that were presented at this year's conference. 

This meeting brings many highlights in myeloma. What I think to be very interesting is the BiTE, so it’s a T-cell engager, which binds both to T-cells and BCMA. A new product which has been tested in patients with relapsed refractory disease seems to be very active, high response rate, quick responses and very well tolerated. The drug has to be given only once weekly so this is an advantage as compared to other BiTEs and some of those BiTEs have already been taken off from further studies. So this BiTE is of high interest.

Of course there is a lot of data on CAR T-cells. In my opinion one study stands out because they used a molecule to enhance the alpha secretase, to enhance the expression of BCMA. When they used CAR T-cells against BCMA they achieved a 100% response rate and curable responses. So because with BCMA and CAR T-cells it is well known that myeloma cells lose the BCMA expression, well you can say there is outgrowth of myeloma population, myeloma clones which don’t express enough BCMA but that was different in this study. So if you can manage to maintain a high expression of BCMA you possibly may be able to achieve long-lasting responses in your patients.

Another issue is, for instance, it was shown in the BELLINI study where venetoclax was used that what was known is that when you have (11;14) translocation you have high expression of BCL2 and these patients respond quite well to venetoclax. But what they did in addition, they looked at patients without (11;14) translocation but with high expression of BCL2, gene expression, protein expression, and this subset of patients shows also a high sensitivity to venetoclax.

So it’s another advance. So the window of opportunity is a little bit open by including those patients in venetoclax trials.
Something you might, of course, think about the Spanish group, the PETHEMA group, showed data looking at MRD status plus assessment of residual paraproteins by mass spectrometry. Mass spectrometry is extremely sensitive and what they found is they had twenty patients who were negative with MRD in a large number of patients, 350, but were positive on mass spectrometry. So that means that our MRD assessment is not good enough. Also MRD was assessed by next generation flow by the Spanish technique which is very sensitive, 10-6. So this tells us that if you really want to assess MRD negativity you need to use a modern MRD assessment technique, you need to use PET-CT and you should also use mass spectrometry in order to exclude the presence of very small paraproteins. So that is something which is important.

Of course the GRIFFIN study has been presented, daratumumab VRD versus VRD. Excellent response rates, the best that you can imagine and in all subgroups. A small study but very important. The GRIFFIN study will be followed by the PERSEUS study, a similar concept – daratumumab VRD four cycles, transplantation, daratumumab VRD four cycles consolidation and then randomisation to daratumumab, lenalidomide or lenalidomide only as compared to VRD only.

This study has not been presented but we are pleased to hear that enrolment has been completed. So that will confirm what has been shown in the GRIFFIN study.

Something else which is interesting to the myeloma community is whether clarithromycin adds anything to myeloma therapy. Clarithromycin is an antibiotic and it has single agent activity in some patients with low grade lymphoma and it has some single agent activity even in patients with myeloma. But there is no big study randomising a treatment protocol with clarithromycin and comparing it with the same treatment protocol without clarithromycin. So the treatment protocol was RD. So, in a sense, when you add clarithromycin to RD you get higher response rates but in the end the PFS is slightly better but OS is not better because there were more adverse events and infections in the elderly patients, so in patients above 75 years. So the illusion that adding clarithromycin would benefit the majority of patient is falsified but there may be a segment of younger patients, fit younger patients, who still may have a benefit but overall when you look at this big study you can’t say there is any great benefit for the entire patient cohort. So that is something which is interesting, yes.