Frontline Approaches Focus on Depth of Response in Newly Diagnosed Myeloma

Giada Bianchi, MD

Though transplant continues to play an important role for eligible patients with newly diagnosed multiple myeloma, the abundance of novel therapies in both transplant eligible and ineligible patient populations is enabling the field to move toward attaining deeper responses—–a known correlative of lasting responses and improved survival, said Giada Bianchi, MD.

“In the current era of myeloma treatment, it's really crucial to try to get our patients into as deep of a response as possible with upfront therapy by incorporating proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and possibly daratumumab pending an FDA approval,” said Bianchi.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Bianchi, physician, Instructor in Medicine, Harvard Medical School, Dana-Farber Cancer Institute, discussed the scope of frontline therapy and subsequent maintenance strategies among patients with transplant eligible and ineligible newly diagnosed multiple myeloma.

OncLive: Can you discuss some of the recent frontline advances we’re seeing in newly diagnosed multiple myeloma?

Bianchi: Over the past several years, we have seen a lot of advances in the field of myeloma. The standard of care and the role of autologous stem cell transplant has really evolved over the past 2 to 3 years. Randomized trials have shown that it's safe to defer transplant in newly diagnosed patients. We're in a lucky position where we can now counsel our patients and defer transplant safely. We understand that a salvage transplant is going to have about the same effect as a transplant in first-line remission.

We're also incorporating immunotherapy into our frontline regimens. The first randomized trials comparing the CD38 antibody daratumumab (Darzalex) in combination with PIs and IMiDs are currently accruing. This is a very exciting era in which we’re really trying to potentiate our armamentarium to put our patients into a deep and lasting remission. Much of this is predicated on the minimal residual disease (MRD) work that has been done in the past few years.

What are some of the options for patients who are transplant eligible?

The most exciting one is really the incorporation of daratumumab in the frontline setting in combination with either bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (RVd), or carfilzomib (Kyprolis), lenalidomide, and dexamethasone. The early data from the GRIFFIN study which is comparing daratumumab/RVd with RVd in the frontline setting is showing high potency with deep and frequent responses that are achieved fairly early. Moreover, we’re seeing profound [rates] of MRD negativity very early on in treatment.

The field is really moving toward understanding how to incorporate transplant for patients who achieve such deep remissions with chemotherapy alone. That has been a major breakthrough in myeloma.

Then, there are data coming from the FORTE study. This multicenter study is comparing 12 cycles of continuous therapy of carfilzomib, lenalidomide, and dexamethasone (KRd) with KRd/transplant with carfilzomib, cyclophosphamide, and dexamethasone. This trial is showing very interesting data. Both arms that contain the IMiDs, both the transplant arm and nontransplant arm of KRd, are superior to the cyclophosphamide arm; that we could have predicted. Interestingly, continuous therapy with KRd is performing the same as KRd and transplant. There’s no statistically significant difference in the overall response rate, depth of response, or MRD negativity in this trial. Again, this raises the question of whether patients in first remission need a transplant if they’ve received highly active frontline therapy. Perhaps we can reserve transplant for patients in second remission.

What about available options for transplant-ineligible patients?

The field has also come to realize that maximizing chemotherapy in an effort to really achieve deep remissions, even in transplant-ineligible patients, is truly key. Originally, doublets were the standard of care, and specifically lenalidomide and dexamethasone. However, emerging data with triplets and even quadruplets show that these regimens are safe to administer even in our more elderly patient population. Certainly, in patients with comorbidities. These patients can achieve very deep and lasting responses.

The Mayo Clinic presented data on daratumumab with ixazomib (Ninlaro), lenalidomide, and dexamethasone in the frontline setting. In patients not receiving transplant, this quadruplet therapy has been very potent. Moreover, 3 out of 4 drugs are oral; that’s a major breakthrough.

Then, there’s the dose-adjusted RVd, known as the “RVd-lite” regimen where bortezomib is administered once weekly rather than twice weekly and lenalidomide is dosed at 15mg rather than 25mg. This has been shown to be safe and induce deep responses and progression-free survival (PFS) in patients who are not transplant eligible.

It’s important to remember that patients who are transplant ineligible and over the age of 75 may still achieve very deep responses if they're treated with dose-adjusted combination therapy. I would not shy away from giving this opportunity to our elderly patients. With careful management, we can get these patients into a deep and lasting remission with triplets and even quadruplets. This will provide them with the best PFS and OS benefit as well as quality of life.

What maintenance strategies have been explored?

Right now, lenalidomide is approved as a maintenance strategy post-transplant. The first trial that really put lenalidomide on the road map used lenalidomide continuously. So lenalidomide is used as maintenance therapy, even in our transplant ineligible patients. This is a highly potent and active agent, but some patients cannot tolerate it. So, we asked whether we had an oral proteasome inhibitor that we could administer in place of lenalidomide as maintenance therapy.

Earlier this year, the TOURMALINE-MM3 trial was published which assessed the use of ixazomib as a maintenance strategy in newly diagnosed patients after their autologous stem cell transplant. The data from the trial show that there is about a 5-month improvement in PFS in patients maintained with ixazomib, in comparison to patients who received placebo. The trial may have suffered from the fact that the majority of patients enrolled on the study did not receive an IMiD as part of induction chemotherapy, which is the standard of care in the United States. The reduced PFS with ixazomib compared to what we saw in the study comparing lenalidomide and placebo may have reflected the fact that these patients were never exposed to lenalidomide or a similar agent. We now know that’s crucial in providing a deep response. However, that's an exciting alternative strategy that we can use in patients who are intolerant to lenalidomide or who have other constraints for lenalidomide.

We often use bortezomib in combination with lenalidomide as maintenance, especially in our high-risk patients now. It will be nice to have an all oral PI and IMiD combination to use as maintenance therapy in high-risk patients. There are data coming from the TOURMALINE-MM1 study of continuous therapy with ixazomib, lenalidomide, and dexamethasone. [Preliminary data] suggests the regimen is effective in improving the prognosis of patients with high-risk features, including deletion 17p. That's an exciting project to look forward to.

What challenges still need to be addressed to move the field forward?

One of the challenges is access to therapy. In the TOURMALINE-MM3 study, more than 60% of patients did not receive an IMiD as part of their induction chemotherapy. It's really crucial that the most effective therapies are made available to patients worldwide. The same goes for financial accessibility.

I'm very interested to see what the future of therapy will look like in myeloma, and whether our definitive treatments now will continue to be part of our frontline regimens. Moreover, how are we going to use transplant and stratify our patients in terms of when they should receive it.

Many of the trials that are currently accruing are going to provide us with more answers in those regards. There’s also exciting data with CAR T-cell therapy. There are many questions about where we're going to fit CAR T-cell therapy in. It’s going to be very interesting to see how we're going to fit these in with all the chemotherapy agents that we now have available.