Treatment for Newly Diagnosed Patients Shifts Across Myeloma Spectrum

Jesus Berdeja, MD

Jesus Berdeja, MD

There has been no shortage of data in the setting of newly diagnosed multiple myeloma, explained Jesus Berdeja, MD. Research has ranged from exploration of more intensive regimens in transplant-ineligible patients to that of quadruplet regimens in transplant-eligible patients.

Data from the phase III MAIA trial demonstrated a 44% reduction in the risk of disease progression or death with the combination of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in transplant-ineligible patients.¹ Moreover, an FDA supplemental biologics license application was initiated in January 2019 for this regimen.

“So many different treatments have been studied in the relapsed/refractory setting and are finally making their way to the newly diagnosed patient,” said Berdeja. “How to best use them and combine them is an ongoing process."

In the transplant-eligible population, quadruplet regimens are becoming more prominent, evidenced by the recent data with daratumumab plus bortezomib (Velcade), lenalidomide, and dexamethasone (VRd). According to findings from the run-in phase of an open-label study, the regimen induced a stringent complete response (sCR) or CR in 63% of patients by the end of consolidation therapy.²

Moreover, 2-year maintenance therapy with ixazomib (Ninlaro) was associated with a 39% improvement in progression-free survival (PFS) over placebo in patients who achieved a partial response to induction therapy with a proteasome inhibitor (PI) and/or an immunomodulatory agent, according to results from the phase III TOURMALINE-MM3 trial.³

OncLive^®: What are some emerging developments in the newly diagnosed setting of multiple myeloma?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Berdeja, the director of Multiple Myeloma Research at Sarah Cannon Research Institute, discussed emerging standards of care in transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma.Berdeja: When a patient is diagnosed with multiple myeloma, we have to decide whether or not they are a transplant candidate. There are some differences in opinion, but ultimately, we all have a way to decide who is transplant-eligible and who is transplant-ineligible.

In the past, the treatment paradigm for transplant-ineligible patients was relatively poor. Those patients were felt to be frail, and they were often treated less aggressively than they probably could have been treated. We're starting to see that there is a benefit to combination therapies [beyond] older doublet combinations. We're realizing that standard treatments like bortezomib, melphalan, and prednisone (VMP) and Rd are not the best options for patients.

The biggest advance has been the incorporation of the monoclonal antibodies—specifically daratumumab, which has significantly improved outcomes for these patients and added very little toxicity. We need to assess the long-term data, but [this approach] looks very promising.

In the transplant-eligible population, patients have always been treated relatively aggressively; I would argue that for the most part that [only applies to] induction. Often, we de-escalate therapy a lot more than we do with transplant-ineligible patients. We're starting to see more incorporation of quadruplets or perhaps consolidation later on. There's still an open question of whether 1 transplant is sufficient as compared with 2 transplants.

We're starting to see really strong combinations such as carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd), or even KRd plus daratumumab, and VRd plus daratumumab in this patient population. [We’re getting to the point where we can ask] whether we need transplant at all. [We think we figured it out that we don’t], and then all of a sudden [we realize that] adding high-dose melphalan is still important. At this point, it’s still the standard of care in those patients.

What are your thoughts regarding the FDA approval of daratumumab plus VMP?

Then, in both populations, there’s the open question of how to use minimal residual disease (MRD). MRD is a way to assess a much deeper depth of response. The question is whether [achieving MRD means that we can] back off on therapy or [indicates that] these patients are going to relapse. That question will take years to answer, but it's great that we're asking those questions at this stage of the game. The combination of daratumumab and VMP was proven to be superior to VMP; this was the first regimen to show that the addition of the anti-CD38 antibody to our backbone therapies makes a difference and can be done safely. If you used to use VMP, daratumumab plus VMP is a great option. In the United States, VMP has not been accepted as the standard therapy. We tend to lean more towards the non-alkylating—based therapies, such as Rd or VRd. The approval is unlikely to change treatment paradigms.

I wouldn't necessarily go from something like VRd to daratumumab plus VMP. The MAIA trial was presented at the 2018 ASH Annual Meeting on lenalidomide, daratumumab, and dexamethasone (RDd) versus Rd. That’s going to have more of an impact in United States because [the Rd backbone] is often used in practice.

Are there other data with DRd that you would like to highlight?

What is the role for upfront maintenance therapy, specifically with ixazomib?

My expectation is that [DRd] will be FDA approved and will challenge the current standard [of care]. There's no head-to-head comparison between DRd and VRd, but the toxicity profile is likely to be better [with DRd]. If the numbers stand, the PFS and overall survival (OS) numbers should be similar or perhaps better. That’s what is going to drive a potential change in the standard of care in the United States. The data look great, but it's still a short follow-up. We're not going to see major survival changes yet. However, there did not seem to be much benefit in the patients with high-risk cytogenetics. It will be interesting to see whether or not that continues. That may potentially help us decide which patients we should potentially use a VRd-type combination for versus a DRd regimen. Of course, that is only until a quadruplet, such as VRd plus daratumumab or another PI, comes through that may challenge that.For the most part, maintenance therapy with lenalidomide is standard of care in patients who are transplant-eligible. There are data showing that bortezomib can be used in patients and also offers an advantage. However, in the study, the patients who received bortezomib maintenance also received bortezomib at induction, whereas the other arm never received a PI. The question is whether maintenance bortezomib or just the use of the PI at some point in therapy [provided benefit].

The study with ixazomib maintenance is important because it's the first time we're able to ask whether a PI as maintenance can improve PFS and OS. The follow-up data from the trial are short, but it looks like PFS is better compared with placebo. The question is whether it is better than lenalidomide, which is the current standard.

[Cross comparison] in all comers shows that the PFS in the ixazomib arm appears to be inferior to the PFS in the lenalidomide arm. The question is going to be whether there are subsets of patients who may benefit from one or the other. That's something that we haven't quite seen.

What is the financial feasibility of giving a quadruplet regimen?

There are some ongoing randomized studies that may help us answer the question better. There is a Myeloma Research Consortium study led by Ravi Vij, MD, MBA, of Washington University Medical School, in which patients undergo transplant and receive 4 cycles of consolidation with ixazomib, lenalidomide, and dexamethasone. Then, they're randomized to receive maintenance ixazomib or maintenance lenalidomide. That trial is going to help us because everyone in the trial will have received a PI prior to maintenance.We all struggle with this question. These drugs are expensive, especially in myeloma where the paradigm is one of continuous therapy. Putting them together is getting more expensive. Then, there are the newer immunotherapies coming down the pike that are also very expensive. I don't have a “magic ball” to sort out what the issue is, but it is important to start thinking about how we are going to use these therapies. What degree of benefit is sufficient to say that from an economic and world perspective that this is truly feasible?

There are many clinical trials out there that are looking at how we sequence and incorporate all of these drugs, which is a plus of having so many unanswered questions. I would urge patients to consider going on clinical trials for many reasons, and this is one of them.

What could be accomplished in this setting by the end of 2019?

Eventually, we're going to have to push to get randomized head-to-head studies to make a decision about which combinations seem to be the most helpful. Also, [we have to pursue] the MRD data, so that we can learn when to potentially stop therapy. However, that is many years down the road. By the end of 2019, we will have some preliminary data on randomized studies like GRIFFIN, and, also, an Italian trial looking at incorporating daratumumab with VRd in transplant-eligible patients. Additionally, there are studies looking at incorporating carfilzomib instead of bortezomib in transplant-eligible patients.

We won't have the final analysis, but we'll have an initial assessment of the degree of benefit. The other thing that's very intriguing in the frontline setting, that I'm hoping we'll start seeing more of, are trials looking at specific populations, such as venetoclax (Venclexta) in patients with t(11;14).

It's nice to start seeing targeted therapies for myeloma. This is the first drug that is really going after a subset of patients. There will be some frontline trials in both transplant-eligible and -ineligible patients that will be looking at the addition of venetoclax to some of these backbone therapies as well.

References

1. Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract LBA. ash.confex.com/ash/2018/webprogram/Paper120737.html.
2. Voorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab (dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; dara‐vrd) vs. vrd in patients (pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT). In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 151. ash.confex.com/ash/2018/webprogram/Paper113122.html.
3. Dimopoulos MA, Gay F, Schjesvold FH, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 TOURMALINE-MM3 trial. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 301. ash.confex.com/ash/2018/webprogram/Paper112079.html.