Quadruplet Regimens May Revolutionize Frontline Myeloma Treatment

Luciano J. Costa, MD, PhD

Proteasome inhibitors (PIs) plus immunomodulatory drugs (IMiDs) continue to serve as the backbone of frontline treatment in multiple myeloma, but the addition of CD38-targeted monoclonal antibodies, like daratumumab (Darzalex), has markedly improved depth of response in these patients, resulting in a revolution in care, according to Luciano J. Costa, MD, PhD.

“We are seeing a revolution in myeloma therapy. [Progress] tends to happen a lot faster in the relapsed/ refractory setting, where the need is [greater] and the standard [therapies] do not perform as well. The newly diagnosed setting is understandably a little bit slower. [Agents must prove to be] efficacious and safe before they can challenge the landscape,” Costa said. “It has become very clear that quadruplet therapy with a CD38-targeted monoclonal antibody plus a PI, an IMiD, and dexamethasone will be the standard going forward—at least for patients with newly diagnosed, transplant-eligible [disease].”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on multiple myeloma, Costa, an associate director of clinical research at O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, shared key updates regarding transplanteligible and -ineligible patients with multiple myeloma, novel triplet and quadruplet regimens that are shifting standards in the frontline setting, and other modalities under active exploration.

OncLive^®: What has been the most important update recently for transplant-ineligible patients with multiple myeloma?

Costa: At the 2020 ASH [American Society of Hematology] Annual Meeting and Exposition, we saw an update from the phase 3 MAIA study [NCT02252172], which had previously been published. MAIA built on the backbone of lenalidomide [Revlimid] and dexamethasone as a prior standard for these patients. [In] this trial, patients received either lenalidomide and dexamethasone or the CD38-targeted monoclonal antibody daratumumab plus lenalidomide and dexamethasone until progression or intolerance. This was a large study, with over 700 patients enrolled.

After 4 years or 48 months of follow-up, the [estimated progression-free survival (PFS)] rate [was] 60% in the experimental arm vs 38% in the control arm. That is really remarkable. In a population that has historically been affected by treatment nihilism because they are older and have comorbidities, the vast majority were alive without progression 4 years after [receiving] their diagnosis. [These data] have not been matched by any other study done in this setting thus far.

Shifting to the transplant-eligible setting, updated data from the phase 2 FORTE study (NCT02203643) were recently reported. Could you speak to the clinical significance of these findings?

FORTE is a large European study with [just under] 500 patients that sought to address whether the IMiD lenalidomide or the alkylator cyclophosphamide is the best partner for the [PI] carfilzomib [Kyprolis] as part of induction/consolidation therapy for patients with newly diagnosed myeloma.

[Investigators] also compared the approach of 4 cycles of induction with carfilzomib, lenalidomide, and dexamethasone [KRd] followed by transplant, followed by 4 cycles of consolidation, vs omission or deferral of transplant and just 12 cycles of KRd. Then there was a subsequent randomization between lenalidomide alone [and] lenalidomide plus carfilzomib, as maintenance. In this trial, we saw an update on the primary end point, which was PFS, from the first randomization, and we learned that omission or deferral of transplant is highly detrimental. The group that did the best consisted of those [who received] KRd, transplant, and KRd.

The other comparison was between KRd [plus] transplant vs carfilzomib, cyclophosphamide, and dexamethasone [plus] transplant. Here, the use of an alkylator instead of an IMiD almost doubled the risk of progression or death; the hazard ratio was 0.53. Therefore, there are 2 key messages: You cannot defer transplant without detrimental effect on PFS, and lenalidomide is, indeed, the best partner for a PI, [rather than] an alkylating agent.

We also [saw] the update for the second randomization, [which] was very intriguing. Patients who received carfilzomib and lenalidomide had better PFS than those who received lenalidomide alone, which has long been the standard here in the United States. That was quite surprising, [as it showed] that you can [strengthen] the impact of lenalidomide by adding a potent PI. However, it remains to be seen how much these data are going to affect clinical practice.

The phase 3 CASSIOPEIA (NCT02541383) and phase 2 GRIFFIN (NCT02874742) trials shed light on the value of adding a CD38-targeted monoclonal antibody into the mix for transplanteligible patients with newly diagnosed multiple myeloma. What were the lessons learned from this research?

CASSIOPEIA was the first large, randomized study to demonstrate that value in this population. The trial consists of daratumumab [plus bortezomib (Velcade), thalidomide, and dexamethasone (VTd)] induction followed by transplant, followed by daratumumab/VTd consolidation for 2 cycles, vs VTd induction, transplant, and VTd consolidation for 2 cycles. There was a subsequent randomization between observation [and] maintenance treatment with daratumumab monotherapy.

This trial enrolled over 1000 patients; it was very large. What [we] now know [is] that daratumumab/ VTd is superior to VTd alone in terms of the rate of stringent complete response [CR], which was the primary end point, and rate of minimal residual disease [MRD] negativity, which was a secondary end point, [as well as probability] of PFS rate at 18 months, which was 93% with daratumumab plus VTd vs 85% with VTd [alone]. Overall survival [OS] data are still not mature.

We also saw an update at ASH [from] the US equivalent of CASSIOPEIA, [the] much smaller phase 2 GRIFFIN study. Here, patients were randomized to what can be considered the standard of care, which is lenalidomide, bortezomib, and dexamethasone [RVd] induction, transplant, 2 cycles of RVd consolidation, and lenalidomide maintenance, vs the same regimen but with the addition of daratumumab to induction, consolidation, and maintenance. The primary end point was stringent CR.

At the meeting, we saw an update with 12 months of maintenance. Responses continued to deepen on both arms, but the [experimental arm] remains highly superior, with a rate of CR or better of 82% [after] 12 months of maintenance vs 61% [in] the control arm. It is not surprising that [this] is paralleled by the rate of MRD negativity, [which] was about 60% on the experimental arm vs about 24% [in] the control arm, in the intent-to-treat analysis. The PFS and OS [data] for this trial are not yet mature.

What modalities under active investigation are you excited to learn more about in the near future?

For [patients who are] transplant ineligible, [the future] probably looks like a monoclonal antibody in some kind of combination, whether [it is] a triplet or a quadruplet regimen. We saw several data sets confirming that transplant still has an important role for [select] patients.

There are many terrific future opportunities. One of them is to leverage the depth of response to modify therapy in this disease. As we saw with the updates of those large trials, we still study myeloma as if it [were] a single entity, when in reality it is not; it does not respond homogeneously to therapy. In the future, it is important that we [understand this] and are able to de-escalate therapy in patients who have terrific responses and, conversely, escalate therapy in patients who have inadequate responses, even to these very effective regimens.

Several [modalities] are being developed in the relapsed setting that have a great opportunity [for use] up front. Particularly, there is great enthusiasm for deploying CAR T cells in those very high-risk patients who are identified early. [However], perhaps more scalable and practical is the use of bispecific antibodies, [which] are off-the-shelf agents that have [yielded superior] response rates, even in [patients whose disease has been heavily pretreated]. [These agents] have the potential to be combined or sequenced with existing therapies in the newly diagnosed setting.

Other opportunities [exist] in certain subsets of patients. For example, venetoclax [Venclexta] may [be an option for] patients with t(11;14) given the very robust activity it has as a single agent or in combination with dexamethasone in those spaces in the relapsed setting. [We also have] the opportunity to develop selinexor [Xpovio] for use in combinations with PIs in [patients at high risk], [such as] those with extramedullary disease or those harboring deletion of chromosome 17p.