Frontline Quadruplet Regimens Advance Treatment in Myeloma

Nina Shah, MD

The introduction of 4-drug regimens has led to a myriad of therapeutic options in the frontline setting of multiple myeloma, said Nina Shah, MD. 

"The landscape is evolving quickly,” said Shah. “About 3 years ago, we would have all said [the combination of] lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) was the standard of care. Since then, more options [have emerged]."

Furthermore, quadruplet regimens with daratumumab (Darzalex) have garnered FDA approvals in the frontline setting for both transplant-eligible and -ineligible patients with myeloma.&#8239;At the 2019 ASH Annual Meeting, updated safety and efficacy results from the randomized phase III ALCYONE study showed a 48% reduction in the risk of disease progression or death with daratumumab plus bortezomib, melphalan, and prednisone (VMP) compared with VMP alone (HR, 0.42; 95% CI, 0.34-0.51; P <.0001) in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant.¹ The daratumumab regimen was approved in this setting in May 2018, based on initial ALCYONE results.

Daratumumab in combination has also demonstrated activity in the newly diagnosed transplant-eligible space. The combination of daratumumab with bortezomib, thalidomide (Thalomid), and dexamethasone (D-VTd) was approved by the FDA in September 2019 in this setting.

Moreover, the phase II GRIFFIN study evaluated daratumumab plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients with newly diagnosed, transplant-eligible multiple myeloma. Updated results demonstrated a 62.6% stringent complete response (sCR) rate with daratumumab plus RVd (D-RVd) versus&#8239;45.4% with RVd alone at a median follow-up of 22.1 months.²

In an interview during the 2019 OncLive^®&#8239; State of the Science Summit™ on Hematologic Malignancies, Shah, an associate professor of medicine and hematologist/oncologist at the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, discussed newer treatment options in the frontline and maintenance settings in multiple myeloma.&#8239;

OncLive:&#8239; What is the current state of frontline treatment for patients with myeloma?

Shah:&#8239;Certainly, a carfilzomib (Kyprolis)-based therapy, such as carfilzomib/lenalidomide/dexamethasone (KRd), is of particular interest. Although the trial data are still pending, that [regimen] has been [widely adopted in practice].&#8239;

More importantly, daratumumab has run to the frontline setting [as a result] of 4 trials. The ALCYONE trial showed that D-VMP is better than VMP alone in transplant-ineligible patients. That trial is less relevant for us in the United States, because melphalan is not [widely used].&#8239;

However, the MAIA trial showed that daratumumab plus lenalidomide/dexamethasone is better than lenalidomide/dexamethasone for transplant-ineligible patients. Certainly, this led to the approval of daratumumab in this setting.&#8239;

Most recently, the CASSIOPEIA trial showed a progression-free survival (PFS) improvement with D-VTd versus VTd alone for transplant-eligible patients after induction therapy and transplant. As a result, daratumumab was approved in the frontline setting for transplant-eligible patients, which is more relevant to our practice.&#8239;

However, the United States does not frequently use thalidomide. The GRIFFIN study looked at D-RVd versus RVd alone. We know that the data showed a deeper response [with the quadruplet]. More patients achieved an sCR and minimal residual disease (MRD)-negative disease with daratumumab; however, the PFS data are immature.&#8239;

There are enough data such that physicians are beginning to adopt D-RVd in the frontline setting. What about daratumumab plus KRd? That is a package of new drugs, but perhaps it should be brought to the frontline setting to give patients the best shot at the beginning of treatment and improve MRD-negativity rates.&#8239;

Two trials were presented at the 2019 ASH Annual Meeting that looked at this combination and showed very promising results with novel trial designs. Perhaps [this quadruplet will allow patients] to stop treatment after D-KRd based on MRD negativity.&#8239;

What criteria determine a patient's transplant eligibility?

In short, it comes down to a Gestalt assessment between the physician and the patient. Certainly, age is no longer a factor. It is more about comorbidities and frailty, but even that [is not a definitive answer as to whether a patient can undergo transplant].&#8239;

A frailty index helps to determine if a patient's score means they are unlikely to tolerate transplant. Ultimately, there are ways to modify transplant to make it more tolerable, such as decreasing the melphalan dose and adding aggressive supportive care measures.&#8239;

There are absolute criteria, such as ejection fraction, lung capacity, and current infections [that have defined cutoff points to undergo transplant]. Typically, these are not insurmountable, and I rarely have a patient who does not qualify for transplant based on these factors.&#8239;As we get more data with newer drugs, we will better understand the need for transplant.&#8239;

What options are available in the maintenance setting?

Maintenance therapy is also evolving, but less quickly than the frontline space. Lenalidomide is approved for maintenance therapy in myeloma, because it demonstrated a PFS and overall survival benefit over placebo. That is good, but not all patients can tolerate lenalidomide.&#8239;

The TOURMALINE-MM3 trial showed us that the oral proteasome inhibitor ixazomib (Ninlaro) is also an option for maintenance, as it too improves PFS.&#8239;

This year, the Multiple Myeloma Research Consortium and Washington University School of Medicine looked at ixazomib/lenalidomide/dexamethasone consolidation after transplant followed by randomized lenalidomide or ixazomib. This was among the first—potentially one of the only—clinical trials comparing ixazomib with lenalidomide. Interim results could not show noninferiority of ixazomib versus lenalidomide. As such, the trial randomization was halted.&#8239;

In short, it looked like patients who received lenalidomide progressed less frequently; however, patients had more difficulty tolerating lenalidomide. We did not have enough equipoise [to continue].&#8239;

After that analysis, patients have been given the choice [between lenalidomide and ixazomib maintenance], but physicians generally recommend lenalidomide because it has a known survival advantage. That being said, ixazomib [provides a reasonable alternative] for patients who cannot tolerate lenalidomide.

What trials are looking to move daratumumab into the maintenance setting?

The [AURIGA] trial examined the use of daratumumab/lenalidomide versus lenalidomide alone.&#8239;

We are starting a clinical trial at UCSF in which patients who are in complete response (CR) or very good partial response, but are MRD positive by next-generation sequencing, will be randomized to receive maintenance daratumumab/lenalidomide versus lenalidomide alone after transplant. The MRD negativity end point is 12 months. We are trying to get answers more quickly because we get a little impatient waiting for PFS results in multiple myeloma.&#8239;

What role does MRD play in frontline multiple myeloma treatment?

Many physicians are interested in understanding what MRD means in frontline multiple myeloma; it is unclear. We've used it as an end point in the GRIFFIN trial and we also used it in the MASTER study, which looked at serial MRD to decide if patients can stop D-KRd treatment.&#8239;

I do not make decisions based on MRD, because all of the trials we have seen that have led to FDA approvals were not based on MRD. I want to be fair to my patients and do what is right, based on the data we have. That being said, I still [test] for MRD because I want to get a better sense of where my patients are with so many of them achieving a CR now.&#8239;

References

1. Mateos M, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomized, open-label, phase 3 trial.&#8239;Lancet Oncol.&#8239;2020;395(10218):132-141. doi:10.1016/S0140-6736(19)32956-3.
2. Voorhees PM, Kaufman JL, Laubach, JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update. Blood. 2019;134(suppl 1):691. doi: 10.1182/blood-2019-123465.