Quadruplet Regimens Seek to Raise the Bar in Frontline Multiple Myeloma

Although 3-drug combinations have served as a standard of care in the frontline setting in multiple myeloma, according to Derek C. Galligan, MD, ongoing research efforts are focused on evaluating the use of quadruplet regimens earlier on in the treatment journey.

“Bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induction therapy has been a standard of care in myeloma for about a decade now. Looking forward, it will be interesting to see the true progression-free survival (PFS) benefit achieved with the investigational quadruple regimens in the frontline setting,” said Galligan. “We also want to learn whether adding agents like [daratumumab (Darzalex)] in the beginning is truly helpful in terms of survival benefit versus adding it later at relapse. That’s still an open question.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Multiple Myeloma, Galligan, a medical oncology specialist at Oregon Health & Sciences University, discussed up-front approaches under exploration in multiple myeloma.

OncLive®: What is the significance of utilizing high-intensive therapy in the first-line setting?

Galligan: Many [patients with] multiple myeloma show up to their appointments doing fairly well and there's enough time to figure out the next steps; however, other patients show up in extreme distress from complications such as renal failure, hyperviscosity syndrome, and extensive bone disease. These patients cannot wait weeks for us to arrange outpatient therapy; they must be admitted and treated urgently.

The regimen we tend to favor is modified cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD), with or without proteasome inhibitors. This chemotherapy regimen, combined with good supportive care, has proven to help control and even reverse organ damage. The number of patients that have come in on dialysis and have left the hospital off of dialysis has been encouraging.

What role does transplant eligibility play in determining subsequent treatment decisions?

For most patients, standard therapy, which is comprised of the 3-drug induction regimen of lenalidomide, bortezomib, and dexamethasone (RVd), is a bit agnostic in terms of whether that patient is going to receive a transplant. That's often the regimen we'll start with, regardless of what path they go down. Even so, understanding if they’re candidates for transplant early on in the course of their disease is important, as this can impact the number of cycles of therapy they will receive. For example, the more lenalidomide that a patient receives, the harder it is to collect stem cells. We would like to figure this out early; however, it’s not critical to determine whether they will undergo transplant when they first walk through the door.

When it comes to determining transplant eligibility, have the algorithms stayed the same or have they evolved over the years?

There are validated scores that we can use; however, at the end of the day, every transplant center and doctor approaches these decisions differently. Age is just a number; the decision really comes down to functional status, along with the patient's goals.

What are some of the updates that have recently read out for in the transplant-ineligible setting?

Several interesting updates have read out over the past couple of years. Updated results from the MAIA study were presented during the 2019 ASH Annual Meeting. The 36-month follow-up showed impressive progression-free survival (PFS) benefit for these patients. We also saw a much deeper depth of response with minimal toxicity after adding daratumumab to standard lenalidomide (Revlimid) and dexamethasone induction therapy.

This is an approach that I started to use, especially in my older and frail patients. Notably, elderly patients were included on the study and most of them did very well. Clinically, we're finding this strategy to be effective and well tolerated.

We also saw an update from the ALCYONE study, which examined bortezomib, melphalan, and dexamethasone, with or without daratumumab; this is a regimen that is primarily used in Europe. Certainly, [this regimen is] FDA approved, and we can we can provide that here, too. Very importantly, results showed a true survival benefit [with this approach], which is something that we're not seeing a lot of in up-front multiple myeloma studies these days.

What did we learn from the CASSIOPEIA, ENDURANCE, and GRIFFIN trials in the transplant-eligible space?

Overall, adding the anti-CD38 monoclonal antibody, daratumumab, to standard induction regimens is proving to be highly effective. In the CASSIOPEIA trial, [investigators evaluated] bortezomib, thalidomide (Thalomid), and dexamethasone (VTd) plus or minus daratumumab induction, transplant, and consolidation. Results showed that they met their primary end point of stringent complete response (sCR) right after consolidation.

The GRIFFIN trial evaluated RVd with or without daratumumab; this is more similar to what's commonly used in the United States and met its primary end point of sCR rate after consolidation. That regimen is not yet FDA approved, although we have had some luck with insurances approving it from time to time; as such, it’s making its way into clinical practice. We need to wait for more mature PFS data, but what we have seen certainly suggests a benefit there, as well.

How could treatment be amended to suit the needs of elderly and high-risk populations?

[Adequately addressing] high-risk disease is a huge unmet need in the field. If you look at the subset breakdown for several of these studies, including GRIFFIN, it's not obvious whether high-risk or cytogenetic disease benefits from quadruplet therapy versus triplet therapy. We still don’t know which is the right treatment for high-risk patients when they're first diagnosed.

Certainly, single-arm studies are using triplet induction, transplant, and long-term dose-reduced triplet maintenance, both with VRd and carfilzomib (Kyprolis), lenalidomide, and dexamethasone, which are used at many centers, especially for young patients and those who are at high risk. We don’t have randomized data to suggest that this approach is better.

Open trials are actively recruiting high-risk patients with different regimens, one including elotuzumab (Empliciti). At the moment, we're not sure what's the best regimen for the very high-risk and young patients.

For the elderly, however, it’s important to remember that age is just a number and that “elderly” and “frail” are 2 very different things.

At our institution, doublet induction therapy with lenalidomide and dexamethasone is very common, especially for older patients. However, again, as shown in the MAIA data, the addition of daratumumab introduces very little toxicity and certainly deepens responses. For those who are triplet candidates, we use VRd lite quite often.

Do you believe minimal residual disease (MRD) negativity will be used to inform what treatment to recommend for patients?

As time goes on, we're finding that MRD negativity is a very interesting surrogate marker, especially in early-phase studies. This helps us understand what's likely to happen down the road and has certainly been associated with better clinical outcomes. We want to determine the utility of transplants in patients who achieve MRD negativity during induction therapy.

Some emerging data have shown that, if a patient is truly MRD negative using next-generation sequencing, then an autologous transplant may not offer a huge benefit. MRD can assist in the selection process of which induction regimen should be used and also help us understand who may benefit from transplant.