Choosing the Optimal Treatment for Patients With Newly Diagnosed Multiple Myeloma

At the 2023 Great Debates & Updates in Hematologic Malignancies Meeting in New York, New York, Peter M. Voorhees, MD, Atrium Health/Wake Forest School of Medicine, Charlotte, North Carolina shared his insights into strategies for selecting the best frontline therapy for patients with multiple myeloma (MM). 

Transcript:

My name is Peter Voorhees. I'm a myeloma specialist at Levine Cancer Institute in Charlotte, North Carolina. Today I talked about optimal therapy for newly-diagnosed multiple myeloma patients. I think that there are 3 takeaway points that are important.

The first is for those patients that are fit, an autologous stem cell transplant still remains an important option for their care. We have numerous randomized trials now, including the most recent one, the DETERMINATION trial, that have shown this improvement in progression-free survival with the use of upfront transplant for patients with newly-diagnosed multiple myeloma. 

Now, that being said, no overall survival advantage to that upfront transplant has emerged with fairly long follow-up, so a transplant is not necessarily the right thing for every single patient. But for that patient who wants to improve their odds of the longest remission the first time around, it remains a very important consideration, particularly in those patients who have high-risk cytogenetics, where the difference in progression-free survival with the use of upfront transplant was even more striking and a signal towards better survival outcomes in that group of patients as well.

The second point is that with regards to induction therapy for transplan- eligible patients, at least now in the United States we're moving more towards 4 drug-based combinations for induction therapy prior to autologous stem cell transplant. That's largely been driven by 2 randomized studies, CASSIOPEIA, which was a phase 3 study that looked at incorporating daratumumab with the bortezomib, thalidomide and dexamethasone (VTD) backbone for transplant-eligible myeloma patients. Then the GRIFFIN trial, which I led, which was a randomized phase 2 study looking at the addition of daratumumab into the lenalidomide, bortezomib, and dexamethasone (RVD) backbone.

What we've shown in both of those studies is that the addition of the CD38 antibody in with the proteasome inhibitor, IMiD-dex triplet, improves depth of response as measured by stringent complete response or minimal residual disease negativity, and that improvement in depth of response translates into improved progression-free survival. And importantly, the addition of the CD38 antibody to the RVD or VTD triplet is safe. You're seeing a trend now where we're starting to use quadruplets in that transplant-eligible patient population.

There is another important study, the GMMG-HD7 trial, which is a randomized study out of Germany that's looking at incorporating the CD38 antibody, isatuximab, with the RVD backbone for transplant-eligible patients. Not surprisingly, they too have shown that when you add isatuximab to the RVD backbone, that you're improving [minimal residual disease] MRD negativity rates. It'll be very interesting to see the progression-free survival data from that trial in the future.

Then the third point is that for the transplant-ineligible patient, I think we're starting to see a gravitation in the US towards the use of the daratumumab-lenalidomide-dexamethasone triplet, although the lenalidomide-bortezomib-dexamethasone triplet remains a very important and highly effective option as well. This is based on, again, randomized phase 3 data.

With regards to RVD, we've got the SWOG S0777 trial where the addition of bortezomib to the lenalidomide-dexamethasone backbone in this patient population not only improved depth of response, but improved progression-free and overall survival. Similarly, the MAIA trial looked at daratumumab with lenalidomide and dexamethasone and again showed improvement in depth of response, whether you measure that by complete response rates or minimal residual disease negativity. That improvement in depth of response translated into not only a prolongation of progression-free survival, but an improvement in overall survival as well.

What's interesting when you look at the SWOG study and you look at MAIA, there was probably more patients in the SWOG study that were truly transplant-eligible, but elected to defer their transplant. There is a fairly sizable number of patients that were under the age of 65, whereas in the MAIA trial, virtually everybody except for 1% were 65 years of age and older.

When you looked at survival outcomes in the SWOG study, that survival advantage was really restricted to those less than 65 years of age, whereas those that were 65 and older, the survival signal with the additional bortezomib wasn't clearly there. Whereas in the MAIA trial, you see the overall survival signal in a group of patients that is almost universally 65 years of age and older.

I think with that information in hand, the lack of neuropathy with daratumumab relative to bortezomib, again, you're starting to see the paradigm shift in the transplant ineligible, newly-diagnosed myeloma patient population towards the CD38 antibody lenalidomide-dexamethasone triplets. 

I will just lastly mention that there are very important studies that are ongoing looking at the possibility of using quadruplet therapy in the transplant-ineligible or transplant-deferred [multiple myeloma] patient population as well.

Source:

Voorhees P. Optimal Frontline Therapy of Myeloma. Presented at the Great Debates & Updates in Hematologic Malignancies Meeting; April 13-15, 2023; New York, NY.