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ASH 2021 | Optimizing treatment sequencing in multiple myeloma: daratumumab upfront versus subsequent lines

Rafael Fonseca, MD, Mayo Clinic, Phoenix, AZ, discusses the findings of a study investigating optimal treatment sequencing in multiple myeloma. With the available options for treatment expanding rapidly, determining the best strategies for upfront treatment and subsequent lines of therapy is of critical importance. In this analysis, the clinical value of daratumumab (DARA) first line compared to later lines was examined in patients with newly diagnosed transplant-ineligible multiple myeloma, since it is unclear where it performs optimally. It was shown that using DARA, lenalidomide, and dexamethasone (D-Rd) first line substantially improved overall survival compared with delaying DARA-based treatment until second line. Due to higher attrition rates in second line and beyond, the results demonstrate that achieving the longest possible progression-free survival in first line is key to optimize overall survival outcomes and therefore, saving DARA to later lines is a suboptimal approach. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.

Transcript (edited for clarity)

I would like to tell you about a study that we presented at this meeting that evaluates the worth of using daratumumab upfront combination with lenalidomide and dexamethasone, as opposed to VRd in patients who are transplant ineligible.

Now, it should be said, both regimens have been accepted by the major guidelines recommending treatments for patients who are transplant ineligible in the United States, mSMART and CCN...

I would like to tell you about a study that we presented at this meeting that evaluates the worth of using daratumumab upfront combination with lenalidomide and dexamethasone, as opposed to VRd in patients who are transplant ineligible.

Now, it should be said, both regimens have been accepted by the major guidelines recommending treatments for patients who are transplant ineligible in the United States, mSMART and CCN. But we wanted to know what might be a better choice and we did a simulation, which goes as follows:

First of all, we look at the MAIA study and we look at the data from MAIA study, that has shown significant improvements in progression-free survival and overall survival and that has been published. Then, we looked at the SWOG study and the SWOG study has been a reference study, that compared again, the triplet VRd versus Rd, which shows its superiority of the triplet, with improvement in overall survival, in the intention to treat population.

However, as one looks at patients who are over the age of 65, there appears to be no difference. Now, when you think about the choices, we have a conundrum because we have great data for the treatment of that first relapse with regimens like POLLUX. POLLUX is daratumumab and lenalidomide and dexamethasone versus Rd. What happens is you can’t extrapolate from POLLUX because patients in POLLUX are younger by about a decade of what you see in MAIA, and they’re also enriched for more fit patients. In fact, 60% of them had a prior stem cell transplant. So, we wanted to do the simulation in the following way. So, we took the data from frontline therapy, from MAIA, for DRd and Rd. We look at the Flatiron health database for RBd. Although, we did this as well, too, with the SWOG study and the results are exactly the same.

Then, we introduce a step that is critically important, and that is that of attrition. Our group has published, and others have published, that with every line of treatment, there’s a percent of patients that just cannot move on, cannot complete the subsequent line of treatment. And we took a whole range of an upper boundary and a lower boundary. The upper boundary is the current one for MAIA, which is on the high side. The lower boundary is 27.2, which excludes the sensor patients. Now 27.2 attrition is actually low. In our publication, it was up to 50% per line of therapy. So, let’s go with 27. And what we did is then we looked at the use of regimen that could rescue any one of this initial therapy. So, if you start with daratumumab, then your first line for rescue or first relapse, would be either carfilzomib or pomalidomide.

And if you start with RVd or Rd, then we said, you should look at daratumumab. So, we look at again, real world data sets from Flatiron and with that, then we could create some calculations. And the bottom line is what we found is that if you start with our Rd and then follow with carfilzomib and pomalidomide, using this real-world data, you have a median overall survival of about 9.1 years, for the transplant ineligible, which is in itself remarkable. But importantly, two and a half years longer than with RVd and about three and a half years longer than with Rd. And once more, again, we ran all the range of the various attritions, the results did not change. So, what I present in this paper, and what we conclude, is that using our Rd, seems to be the best choice for patients with frontline therapy.

And I say, parenthetically, which I don’t really address in the analysis, but you’re looking at the regimen that has no peripheral neuropathy. And with a simulation like this, we say, I think the choice is clear. The question could come up. What about those patients with high risk disease? And there’s a couple of answers there. Number one is high risk is less common in the elderly. It’s more like 10 to 15% as opposed to 25, 30% in the younger. And then there’s emerging data that drugs like daratumumab and others like selinexor, isatuximab, others might be able to overcome some of those high risk markers. So, I don’t think that’s a major consideration. So, in my opinion, this really sets the stage for this being the preferred regimen. Again, this starting from the point that both have been accepted by old guidelines.

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