Hari Reviews Recent Data in Relapsed/Refectory Multiple Myeloma

Parameswaran Hari, MD, MRCP

As new data for novel agents emerge in multiple myeloma, the question of whether new advances in immunotherapy will become the new standard of care and traditional approaches will continue to have a role in relapsed/refractory disease, according to Parameswaran Hari, MD, MRCP.

Hari highlighted key data presented at the 2020 European Hematology Association (EHA) Annual Congress and 2020 ASCO Virtual Scientific Program on this patient population and the drugs that are being used for treatment. While immunomodulatory (IMiD) drugs, proteasome inhibitors (PIs), and monoclonal antibodies have been traditionally standard treatments and can still outperform some newer drugs, novel agents, such as bispecific T-cell engagers (BiTEs), CAR T-cells, and other immunotherapy approaches are coming down the pipeline and challenging the established standard of care.

“The goal is to treat every [patient who] relapses with a very effective [regimen], usually a triplet or combination approach,” said Hari. 

In an interview with OncLive, 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 key data that has read out in relapsed/refractory multiple myeloma, exciting agents generating excitement, and the role of minimal residual disease (MRD).

OncLive: What does the current myeloma armamentarium look like?

Hari: A 3-drug, or sometimes a 4-drug, regimen is used as initial treatment, followed by transplant in eligible patients, followed by some form of maintenance therapy. In patients who are transplant ineligible, a 3-drug regimen would get pared-down after response to a maintenance regimen is achieved. Essentially, a long maintenance regimen would keep most patients in their first remission for a very long time, sometimes 3 to 4 years, but sometimes much longer. 

We have new agents coming through [the pipeline], such as immunotherapy. The traditional agents that we use include IMiDs, such as lenalidomide (Revlimid) and pomalidomide (Pomalyst); PIs, such as bortezomib (Velcade), ixazomib (Ninlaro), and carfilzomib (Kyprolis); and monoclonal antibodies, such as daratumumab (Darzalex) and isatuximab-irfc (Sarclisa).

Which studies were you most looking forward to this year?

One of the important studies is IKEMA; this is a large, open-label, phase 3 study [evaluating] isatuximab plus carfilzomib and dexamethasone (Kd) in [patients with] relapsed myeloma. That trial was presented by Philippe Moreau, MD, of University Hospital of Nantes, and that showed that the combination of isatuximab plus Kd was associated with a significantly better progression-free survival (PFS) compared with Kd alone. 

The combination of a monoclonal antibody with a PI has been shown to be effective in a couple of other studies; most notably, the daratumumab/bortezomib combination and the daratumumab/carfilzomib combination [have shown efficacy]. Isatuximab, the other approved monoclonal antibody, is also being [studied] in this setting. That's a very important [research effort] that opens up another option for patients with multiple myeloma.

Do you believe that the role of carfilzomib is firmly established in the relapsed/refractory setting?

The ENDURANCE study clearly showed that the carfilzomib, lenalidomide, and dexamethasone (KRd) combination was not superior to bortezomib, lenalidomide, and dexamethasone (VRd) [with regard to PFS]. This was notably a big group that did not undergo transplantation, so that's 1 niche where carfilzomib may still have a role. However, for patients who [will not] undergo an up-front transplant, carfilzomib is not necessary at this point.

In the CLARION study, carfilzomib in combination with melphalan flufenamide (Melflufen) and prednisone was not superior to bortezomib plus melphalan and prednisone [in transplant-ineligible patients]. In both of those settings, induction carfilzomib has been pushed out; therefore, we actually should be looking at carfilzomib as a strong PI that's effective and has been shown to be superior to bortezomib in head-to-head settings in patients who relapse. That's clearly where it has been going and the study essentially solidifies that.

What other studies within this space did you want to highlight?

The other study is the ixazomib maintenance study; this was a significant multicenter, international, phase 3 study known as the TOURMALINE-MM4 study. In this trial, investigators basically looked at oral ixazomib versus placebo as maintenance after induction treatment in patients with newly diagnosed myeloma who are transplant ineligible. 

In these kinds of studies, what we actually look at is the PFS, and this was significantly better with ixazomib. Ixazomib almost doubled the PFS, at 17.4 months versus 9.4 months with placebo; that's a significant finding. Ixazomib is an oral agent, [which makes] it relatively easy to take and it's only given once a week. That's also an important takeaway from this study.

Is there still a debate on the utility of ixazomib as maintenance therapy?

The problem with any maintenance therapy is that the gold standard has been established as lenalidomide. Unless there is a head-to-head comparison to settle the debate, we actually don't know the value of ixazomib versus lenalidomide. It's not good to do cross-trial comparisons, and lenalidomide is the established gold standard. None of these studies give us a signal that ixazomib is actually going to be superior to lenalidomide, but there may be a niche population, such as patients who cannot tolerate lenalidomide, who have progressed on lenalidomide, or for whom lenalidomide is unaffordable. All of these settings are where ixazomib could be used.

Also, again, ixazomib is an oral agent and it could be [used as] combination maintenance in patients with especially high-risk myeloma who may be susceptible to proteasome inhibition. It actually is more proof of principle that ixazomib actually is a sustainable maintenance therapy. Then it's up to the community of myeloma doctors and patients [to determine] how to [best] use it.

Could you speak to the use of bortezomib in combination with lenalidomide and dexamethasone (RVd) with elotuzumab (Empliciti)?

Another study examined the use of RVd with elotuzumab (ELO-RVd) in the United States; this study was [performed] by the SWOG group and presented by Saad ​Z. Usmani, MD, of Levine Cancer Institute. Results did not show any superiority over the standard of RVd. This was a trial that was confined to patients with high-risk myeloma.

At EHA, the German-Speaking Myeloma Multicenter Group (GMMG) presented their trial HD6; this was an interesting study that used the 4-drug combination of RVd plus elotuzumab followed by transplant. Investigators presented the initial results with regard to overall response rate (ORR). The ORRs and the very good partial response (VGPR) rates were pretty much similar in the RVd and the ELO-RVd groups. However, again, the difference in this study compared with the study presented from the United States was that these patients are transplant eligible. We still have to wait to see if the addition of transplant [impacts anything].

There was a signal for the number of patients who died during the study; although statistically not different, 4 deaths were reported in the RVd group and 9 deaths were reported in the ELO-RVd group. This basically finishes off elotuzumab as an agent, specifically for high-risk myeloma. That question has been settled because in both of these studies, patients did not show a significant advantage, and the United States study was enriched for a high-risk population. However, it remains to be seen whether the German study will show us any further differences with regard to [the regimen] in combination with transplant and following maintenance.

What is some of the exciting work that is being done with BiTEs?

Two of the most interesting studies for the future of patients with myeloma are the 2 BiTE antibody studies. One study examined teclistamab (JNJ-64007957), which is a BCMA CD3-specific antibody that redirects T cells that can kill BCMA-expressing myeloma cells. One end of the antibody binds to BCMA, and the other end of the antibody binds to CD3 cells or T cells. A phase 1 study [focused on] patients who had multi-refractory myeloma who had this as their only option at that time. This went up in serial dosing and, essentially, investigators showed that there was significant T-cell redistribution and cytokine release syndrome. Out of the 65 patients evaluable for response, 38% had achieved a response, which is actually a pretty good number in this population. However, if you look at the highest doses in which patients had more responses, 67% of the patients responded. Essentially, these were very good data and of the patients who achieved MRD negativity, their treatment was ongoing for more than 1 year, which suggests that these responses are durable, too. This is a major game-changer for patients with myeloma.

Similarly, Luciano J. Costa, MD, of the University of Alabama's Birmingham School of Medicine, also presented data from a bispecific agent similar to that of teclistamab called CC-93269. With this agent, a dose of 10 mg, which was the top dose, induced a response rate of 88.9%, of which 16.7% or 5 out of 30 patients achieved MRD negativity. Both of these studies are very promising for patients, which tells us that immunotherapy is here to stay in myeloma.

What are your thoughts on these treatment-adapted clinical trial designs incorporating MRD negativity? Could they curb the uptick in the quantity of treatments that we're seeing?

I don't think anyone has a great answer to that question. Clearly, it is good for patients and caregivers that most agents in myeloma in the induction [phase] now produce an almost 100% response rate. If you compare 3-drug versus 4-drug versus 5-drug [regimens], the marginal benefit that you can go up to in terms of response rates is very, very limited. 

Number 2, the PFS is so good for patients with myeloma now that in order to show a difference, a large number of patients and longer-term follow-up are needed. From both of those aspects, MRD becomes a surrogate that we can utilize; however, when you use a surrogate endpoint, we always have a caveat. There can be situations when the surrogate does not behave as you want it to behave, so you could have an MRD improvement but without a sustained benefit in terms of time. Ultimately, what we give our patients in terms of myeloma is time—time off of relapse and time in remission; this is the most important and valuable [factor] for those patients. It is important to keep in mind that MRD is a surrogate and it is here to stay; it’s a key signal.

In the relapsed/refractory studies, for both teclistamab and CC93269, the MRD negativity points to the fact that very deep remissions can be achieved with those agents as single agents; again, this speaks to the potency of these drugs and [shows] that they can work well in that setting.

What is your advice with regard to sequencing?

The sequencing of these BCMA-directed agents, such as CAR T-cell therapies, antibody-drug conjugates, and BiTEs, remains an unanswered question right now. We have a little bit of a signal from 1 anecdotal case series where patients who had [progressed on] CAR T-cell therapy did respond to belantamab mafodotin (Blenrep). Other than that, most studies exclude patients with prior BCMA exposure. Now, studies are being designed for patients who progressed on a BCMA and are going onto another agent. That field is completely up in the air right now and I wouldn't be able to predict its future.