Quadruplet Regimens Show Promising Activity in Multiple Myeloma

Ajai Chari, MD

With the approval of several new agents in multiple myeloma, triplet regimens are now the standard of care, yet quadruplets are on the horizon, explained Ajai Chari, MD.

“The SWOG S0777 study showed that triplet therapy was better than doublet [therapy], though that was for patients without the intent to transplant,” said Chari, an associate professor in hematology and medical oncology at Mount Sinai Hospital. “Now, the question is, ‘Can we do better than that?’ We know from several studies that the best partner for proteasome inhibitors (PIs) is probably lenalidomide (Revlimid) as opposed to cyclophosphamide.”

One study that supports the use of quadruplet regimens is the CASSIOPEIA study, which examined the addition of daratumumab (Darzalex) to bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone. At day 100 after transplantation, the stringent complete response (sCR) rate was 28.9% in those who received bortezomib/thalidomide/dexamethasone plus daratumumab versus 20.3% in patients who received bortezomib/thalidomide/dexamethasone alone.

Moreover, selinexor (Xpovio), which was recently approved by the FDA, will likely soon enter trials in an effort to determine what combination regimens make the drug most effective, Chari said. The agency approved the XPO1 inhibitor in July 2019 for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 PIs , ≥2 immunomodulatory (IMiD) agents, and a CD38-targeted monoclonal antibody.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Multiple Myeloma, Chari discussed current and emerging research in patients with transplant-eligible and -ineligible multiple myeloma as well as updates in smoldering multiple myeloma.

OncLive: Could you discuss the use of daratumumab in the frontline setting for transplant-eligible patients with multiple myeloma?

Chari: Our approach to transplant-eligible patients historically has been triplet therapy with bortezomib, lenalidomide [or] thalidomide, and dexamethasone. The new question coming up is, “Are four drugs better than three?” We have two versions of this question being answered.

The CASSIOPEIA study showed the primary endpoint of a sCR increased from 20% in the control arm to 29% with the addition of daratumumab to bortezomib, thalidomide, and dexamethasone. With a relatively short follow-up of 18 months, there was a significant improvement in progression-free survival (PFS) with the addition of daratumumab. Daratumumab improves efficacy with minimal additional toxicity. There was a slight decrease in stem cell yield, but overall, the PFS and the sCR results are very compelling.

The other study that was also recently released is the GRIFFIN study, in which patients in the United States were randomized to lenalidomide, bortezomib, and dexamethasone plus or minus daratumumab. In this study, we saw again that the sCR and minimal residual disease (MRD)—negativity rates were improved, and all supported supporting the addition of frontline daratumumab. This shows that the future might be quadruplet therapy in terms of consolidation with transplant. The IFM 2009 study still speaks for itself, with a higher PFS relative to non-transplant.

The StaMINA study, however, didn't show benefit with consolidation therapy while the [CASSIOPEIA] study did. The reason might be that [in the CASSIOPEIA study, patients] only received cyclophosphamide, bortezomib, and dexamethasone for 3 to 4 cycles, so there is some benefit to consolidation therapy and second-transplant in high-risk patients. However, we didn't see those benefits in the StaMINA study.

Could you discuss new research for transplant-ineligible patients with multiple myeloma?

Finally, lenalidomide maintenance has recently been reported to not only improve PFS with a hazard ratio of 0.5, but an OS improvement, as well. The newer data that we have from recent publications and presentations is the role of ixazomib (Ninlaro). The TOURMALINE-MM3 trial did show improved PFS [with ixazomib], but not as much as we would have liked. It only had a hazard ratio of 0.7. In the study design, ixazomib was continued at 2 years; it wasn't stopped until progression. There was no risk of secondary malignancy. There were a lot of new, compelling data for the transplant-eligible population.

What is the biggest study looking forward to hearing the results of?

We are eagerly waiting to hear the details of the GRIFFIN study, including the high-level data as well as the true responses, toxicity profiles, and stem cell collection.

The other study that we're also eagerly awaiting is the American version of the IFM/DFCI 2009 trial. The big difference here is that lenalidomide was used through progression as opposed to the French version, which was a fixed duration of lenalidomide. That's going to be important in understanding the role of transplant in 2019. If you use efficacious induction and effective maintenance therapy, what is the role of transplant? Those are [going to be] very important data.

What are your thoughts on the recent FDA approval of selinexor?

When we talk about selinexor, the most important thing to recognize is who the patients are that led to the FDA approval. These patients were [refractory to] PIs, IMiD drugs, and a CD38-targeted monoclonal antibody. Historically, there has been no FDA-approved therapy for this [patient population] and the eligibility criteria were very permissive. The response rate was about 26%, with a [median] PFS of 3.5 months. While those numbers might be modest, it's important to remember that every drug that has been approved in myeloma—including pomalidomide(Pomalyst), carfilzomib (Kyprolis), and daratumumab—all had similar profiles of a response rate around 20% and a median PFS of 3 to 3.5 months when used as a single agent. Now, it's getting harder to hit those benchmarks.

We've exhausted all the prior drugs. The fact that we saw this response is really great for patients. Additionally, at Mount Sinai Hospital, the adverse events due to toxicities was quite manageable. We've been very aggressive with supportive care. Our efficacy results [with selinexor] are better than the overall [study] population and we're working on a manuscript where our ORR was over 50%, and the median PFS was over 5 months. It is the importance of supportive care in this population.

Selinexor is approved at 80 mg twice weekly, but this is an accelerated approval; accelerated approvals and initial approvals aren't necessarily how the drug is going to be used. Often, we use drugs in combination in the relapsed/refractory setting because no single drug by itself is enough. Therefore, while accelerated approval is an important first step, the combination studies of selinexor with other agents is going to be how people will use this drug in the future.

Could you discuss the data regarding the use of lenalidomide in smoldering myeloma?

The management of smoldering multiple myeloma is challenging. There's a lot of interest in treating patients earlier. It's a two-part question: what is the right group of patients to treat? In other words, do we have a reproducible risk stratification system? The second question is, “What is the best treatment?”

At the 2019 ASCO Annual Meeting, the results of the phase III E3A06 study where presented where patients were randomized to either lenalidomide or observation. In this study, we saw a significant reduction in the risk of progression with lenalidomide. The 3-year PFS rate was 91% for lenalidomide versus 60% with the observation arm. There was a very impressive hazard ratio, as well. This suggests lenalidomide is favorable.

However, there are some limitations because, first, this study included all types of smoldering myeloma, including some low-risk and intermediate-risk patients. Those didn't seem to benefit as much because their natural history is better. The challenge is when we look at the truly high-risk component, it was a relatively small number.

We don't know a lot of details about the endpoints. For example, how many patients had symptoms in the observation arm that were minimized by the use of lenalidomide maintenance? We don't yet have PFS or overall survival data. There was concern about some toxicity with higher rates of secondary malignancy. Also, 50% of patients in the lenalidomide treatment arm discontinued due to toxicity. This study tells us that we are on the right track with asking these questions regarding treating smoldering myeloma.

Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results. J Clin Oncol. 2019;37(suppl; abstr 8003). doi: 10.1200/JCO.2019.37.15_suppl.8003