Daratumumab-Based 4-Drug Induction Regimens Improve Outcomes in Myeloma

Ajay K. Nooka, MD, MPH, FACP

Newer induction regimens containing daratumumab (Darzalex) are showing impressive depths of response without significant added toxicity in patients with multiple myeloma, regardless of transplant eligibility, according to Ajay K. Nooka, MD, MPH, FACP.

“In a setting where we need a completely different agent that would be a good complement [to an] induction regimen without causing overlapping toxicity, daratumumab fits the bill,” said Nooka. “In both transplant-eligible and -ineligible patients, daratumumab achieves a good depth of response and [does not produce] additional toxicities.”

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Nooka, an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, discussed the shift in induction regimens in multiple myeloma and the impact of daratumumab on the space.

OncLive^®: Could you speak to the evolution of induction regimens in multiple myeloma?

Nooka: Modern-day induction regimens have expanded over the past 2 decades, and we have evolved with these newer regimens. We went from doublets to triplets, and then triplets to quadruplets, with the main intent of gaining [a better] depth of response. Four-drug induction regimens have taken over in the past year or so, mostly because they’re able to [induce] the depth of response that we’re looking for. This has always been our dream: to find the ideal quadruplet regimen, gain a better depth of response, and prolong progression-free survival, which [we hope] could translate to an overall survival advantage.

What are some of the available options? Do the options vary depending on whether a patient is eligible versus ineligible for transplant?

That’s a great question. In the past, we [mostly] used a 3-drug regimen [comprising] bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd). In transplant-ineligible patients, we still use the 3-drug regimen, but we make dose modifications [based on] the patient’s frailty status and what they can tolerate. In transplant-ineligible patients especially, we want [to achieve] the best benefit and mediate the toxicity that [comes with these drugs].

The framework of how we treat transplant-eligible versus -ineligible patients is almost exactly the same. In transplant-eligible patients, we use transplant after a few cycles of induction treatment to gain depth of response and we use a maintenance treatment. In the transplant-ineligible patients, we use a prolonged induction regimen in place of transplant, and we use continuous treatment so that we can still gain similar benefits to what we achieve with transplant.

In this framework, we were using VRd, or VRd-lite, for the transplant-ineligible patients. We were using doublets in those who could not tolerate any other regimens; [the doublets] included bortezomib plus dexamethasone or lenalidomide plus dexamethasone. Both [regimens] have phase III data to support their use in the up-front setting for transplantineligible patients.

Now, we’re using newer induction regimens with daratumumab, and [we see] no overlap in toxicity [when we] add [the agent] to either the doublet or the triplet regimens in both the transplant-eligible and -ineligible settings. That’s what’s so new about these novel induction regimens: We’re combining a monoclonal antibody [with] induction regimens in both transplant-eligible and -ineligible patients.

Could you speak to some of the data that we have with daratumumab, specifically the pivotal phase III MAIA trial?

In myeloma, we have always built on the existing framework, which in this case is the use of [lenalidomide/dexamethasone as the induction therapy backbone in transplant-ineligible patients]. In the MAIA trial, [investigators added] daratumumab to lenalidomide and dexamethasone. The trial had 2 arms: lenalidomide/dexamethasone versus daratumumab plus lenalidomide/dexamethasone. The primary end point was progression-free survival (PFS).

Amazingly, the addition of the antibody was not found to be extremely toxic to these elderly patients; a separation of the curves was observed as early as the first 6 months of treatment and it continues to get better. The trial has favored the daratumumab arm significantly and [the data have] led to the approval of daratumumab plus lenalidomide/ dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma.

Additionally, all of the secondary end points and every subgroup that has been seen—with the exception of the highrisk subgroup—[are] in favor of the daratumumab combination compared with lenalidomide/dexamethasone alone. This is a great success story, because we have always believed in building upon what we already know works. The addition of daratumumab has helped us to achieve the next level of benefit in our transplant-ineligible patients.

Daratumumab was also approved for use in combination with bortezomib, thalidomide (Thalomid), and dexamethasone (VTd) in newly diagnosed transplant-eligible patients. What data led to that approval?

For the transplant-eligible patients, what we have seen over and over again is the combination of a proteasome inhibitor plus an immunomodulatory drug, namely bortezomib plus thalidomide—which is the most common immunomodulatory agent used in Europe—plus dexamethasone. VTd is a standard of care with [regard to] induction regimens. VTd versus daratumumab plus VTd was tested in the CASSIOPEIA trial. The primary end point of this trial was not PFS, but stringent complete response (sCR) after completing consolidation [treatment].

All of the patients in both arms received 4 cycles of VTd versus daratumumab/VTd; then they went for a transplant, followed by further cycles of VTd versus daratumumab/VTd. The primary results [with regard to] sCRs at the completion of consolidation significantly favored the daratumumab arm. Even more interestingly, the secondary end points, PFS and minimal residual disease negativity rates, were almost to 2 to 3 times higher than what we saw in the arm without daratumumab.

[Based on these data, we know that the daratumumab combination] is really beneficial in delivering higher depths of responses. Daratumumab has been shown to have a safety profile that is similar to VTd. With regard to daratumumab/ VTd versus VTd, the safety is almost equivalent. Daratumumab did not have any negative impact on [stem cell collection] or toxicity, and patients went on to receive transplant, as planned.

Unfortunately, we don’t use VTd in the United States as much; we mostly use the VRd regimen.