Frontline Advances Propel Progress in Multiple Myeloma

Parameswaran Hari, MD, MRCP

Recent advances in the frontline setting are leading to deep and durable remissions in patients with multiple myeloma, and researchers are hopeful for the future with promising investigational regimens, said Parameswaran Hari, MD, MRCP.

For example, in the phase II FORTE study, the triplet regimen of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) emerged as a potential new standard of care for newly diagnosed patients. Patients were treated with KRd, followed by autologous stem cell transplant (ASCT) and KRd consolidation versus 12 cycles of KRd alone versus carfilzomib plus cyclophosphamide and dexamethasone (KCd), followed by ASCT and KCd consolidation. Following treatment, patients were randomized to receive maintenance lenalidomide alone or with carfilzomib.

Updated data from the intent-to-treat analysis showed that rates of minimal residual disease (MRD) negativity and stringent complete response (sCR)/complete response (CR) were significantly higher in both KRd arms, with and without transplant, compared with KCd.¹ No statistically significant differences in MRD and best response were observed between the KRd arms.

In addition, the CD38-directed monoclonal antibody daratumumab (Darzalex) has also shown potential in the frontline setting. In the phase III MAIA study, the combination of daratumumab in combination with lenalidomide and dexamethasone (DRd) led to a 44% reduction in the risk of disease progression or death compared with Rd alone in transplant-ineligible patients with newly diagnosed multiple myeloma.²

In an interview at the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Hari, the Armand J. Quick/William F. Stapp Professor of Hematology, and the chief of the Division of Hematology/Oncology, Department of Medicine, at the Medical College of Wisconsin, discussed the rapidly evolving paradigm of myeloma with a focus on the latest updates in the frontline setting.

OncLive: How has the frontline treatment of patients with myeloma evolved in recent years?

Hari: The frontline treatment of patients with myeloma is changing. In the myeloma field, we have been very lucky to have several new classes of drugs [FDA] approved in the past 5 to 6 years. We now have immunomodulatory agents, proteasome inhibitors, steroids, alkylators, and antibodies. There is promise of more to come. It is coming to a point where frontline induction therapies are becoming so good that we are getting higher and higher percentages of patients into CR, stringent CR, and even MRD-negative disease.

The goal of frontline therapy is rapidly changing from getting some sort of disease control in myeloma, which used to be the case 1 decade ago, to getting a deep remission. If you’re doing a transplant, this then translates into a much more prolonged PFS. It even now raises the question of whether we will get to a point where transplant becomes optional. Thus far, studies have suggested that transplant remains the best way of getting a long PFS, but we may soon be making that a thing of the past. Trials are already ongoing.

What frontline regimens have shown the most promise?

The 2 exciting trials reported at the 2018 ASH Annual Meeting were the FORTE trial, which looked at KRd with or without transplant, and it also compared carfilzomib plus cyclophosphamide and dexamethasone in the same setting. This [trial] showed surprisingly good CR rates and MRD-negative rates [with KRd]. There is also the MAIA trial, which is a European trial that, again, showed the efficacy of daratumumab-based combinations without the use of transplant. This combination achieved a very long PFS in transplant-ineligible patients. These studies have not been published—they are still in abstract form—but they are very promising.

How do you see these agents impacting the field in terms of sequencing?

That's a big question to answer. Essentially, myeloma therapy is getting to a point where you add on drugs [to the frontline setting], then you [move to] some sort of maintenance [approach]. You may have a transplant in between. All that news upfront has consequences for the future because patients do eventually relapse. At that point, do you go back to the same drugs you used in the past? Luckily, so far, we haven’t had to answer that question because we have come up with new drugs each time.

Again, new immunotherapies are coming out, [such as] antibody-drug conjugates (ADCs), BCMA-directed antigens, bispecific antibodies, and CAR T cells. Those may be the [approaches] that will get pretty much everyone into an MRD-negative remission early on and then that they may change the way we think about myeloma completely.

Could these frontline regimens have an effect on the frontline approval of daratumumab plus VMP?

This regimen was presented a while ago and published already. VMP, the backbone of this regimen, was never very popular in the United States to begin with. In the United States, our regimen for even truly transplant-ineligible patients based on the SWOG S0777 study has always been RVd, or in some cases, we would modify that to “RVd-lite.” It was always a triplet that was recommended to patients. RVd-lite has served us well. In patients who are truly ineligible to receive a triplet, we would give a doublet.

Melphalan has pretty much gone away in the United States, at least from the frontline setting. Most of the melphalan news that we have is in the transplant world. I don't think daratumumab plus VMP will gain much traction here. Daratumumab plus lenalidomide will be much more actionable in the United States.

What regimens in the relapsed/refractory space have the most potential to move into the frontline setting?

I am most excited about the BCMA-targeting drugs, either as single agent or as combinations in the future. We already have data with CAR T cells, [showing that they] give us the best MRD-negative rates, even in the relapsed setting. Several trials of CAR T cells are ongoing, and several more are coming. We also have ADCs targeting BCMA, and we have a variety of bispecific antibodies both against BCMA and CD38. The most exciting aspect is that there is some signal or suggestion that these may be agnostic to the high-risk cytogenetics which basically renders some of our chemotherapies ineffective.

Could you expand on the role of MRD as a goal of induction?

MRD is increasingly measurable these days, either by flow cytometry or next-generation sequencing. It measures the level of minimal detectable disease or no disease detection, which we call “MRD-0.” There are data, especially with the frontline trials, that MRD is a powerful predictor of prognosis of OS and PFS. Getting to MRD negativity is a very effective surrogate goal if you want to help patients achieve a longer survival. If you can get more patients to MRD negativity in a clinical trial, for example, you know that arm is going to [do well] in the future.

More importantly, MRD might be the key to eventually curing myeloma. If you want to truly cure a disease, you need to have no trace of the disease and you should not have the disease ever come back. The only way we can measure this at the moment is through MRD.

Finally, some of the patients who are MRD negative now will live the rest of their lives without their disease relapsing. I am very excited about our ability to use MRD these days, as well as our ability to achieve MRD negativity in higher proportions of patients. On the other hand, we have patients who relapse despite being MRD negative. We need to find out who these patients are. Thus, there are some caveats when we talk about MRD.

What is your take-home message to your colleagues working in the space?

We should be hopeful for the future in terms of myeloma treatment. We need more trials, and we should encourage patients to join trials—especially in the relapsed/refractory setting. We have a variety of agents with multiple antigenic targets and targets being discovered all the time. We also have [ongoing] vaccine trials, which is another form of immunotherapy. It's all very exciting. No patient should die of myeloma without having met with a specialist or having thought about entering a clinical trial. We should not give up too easily.

References

1. Gay F, Cerrato C, Scalabrini DR, et al. Carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous transplant (ASCT)-Krd consolidation vs Krd 12 cycles vs carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-Kcd consolidation: analysis of the randomized Forte Trial in newly diagnosed multiple myeloma (NDMM). Blood. 2018;132(suppl 1):121. doi: 10.182/blood-2018-99-112093.
2. 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). Blood. 2018;132(suppl 1):LBA-2. doi: 10.182/blood-2018-120737.