Baz Highlights Emerging Regimens in Relapsed/Refractory Myeloma

Rachid Baz, MD

Patients with relapsed/refractory multiple myeloma have a plethora of options based on positive findings from the ARROW, ELOQUENT-3, and OPTIMISMM trials, calling attention to the importance of dosing, scheduling, and choice of regimen, explained Rachid Baz, MD.

“There is no real algorithm on how to manage relapsed/refractory multiple myeloma,” said Baz. “However, those studies add to the therapeutic armamentarium that we have and to the options that patients have when they face their disease.”

Findings from the phase III ARROW trial showed that a once-weekly dose of carfilzomib (Kyprolis) at 70 mg/m² with dexamethasone improved progression-free survival (PFS) compared with the standard twice-weekly schedule at 27 mg/m² without compromising safety. Carfilzomib given once weekly at the higher dose showed a median PFS of 11.2 months (95% CI, 8.6-13.0) versus 7.6 months (95% CI, 5.8-9.2) with the standard schedule (HR, 0.69; 95% CI, 0.54-0.83; P = .0029).^1,2

In the phase II ELOQUENT-3 trial, the addition of elotuzumab (Empliciti) to pomalidomide (Pomalyst) and dexamethasone outperformed the standard of care, dexamethasone and pomalidomide, resulting in a 46% reduction in the risk of disease progression. The median PFS was 10.3 months (95% CI, 5.6-not evaluable) versus 4.7 months (95% CI, 2.8-7.2) with the elotuzumab combination and the pomalidomide/dexamethasone combination, respectively (HR, 0.54; 95% CI, 0.34-0.86; P = .0078).³

Another regimen to come forth is pomalidomide, bortezomib (Velcade), and low-dose dexamethasone (PVd), which provides patients with prior exposure to lenalidomide (Revlimid) a suitable alternative. In the phase III OPTIMISMM trial, the regimen induced a median PFS of 11.20 months compared with 7.10 months with bortezomib and low-dose dexamethasone (Vd) alone at a median follow-up of 16 months (HR, 0.61; 95% CI, 0.49-0.77; P <.0001).⁴

Although these regimens resulted in prolonged PFS, many variables remain at play, noted Baz, such as the role of venetoclax (Venclexta), as well as strategies for frail patients and those with penta-refractory disease.

OncLive: What studies have informed the management of patients with relapsed/refractory multiple myeloma?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Baz, associate member, head of the Myeloma Section at Moffitt Cancer Center, discussed these studies and highlighted others that are demonstrating equally impressive response rates in patients with relapsed/refractory multiple myeloma.Baz: There is a lot of excitement in relapsed/refractory multiple myeloma. I focused on 3 studies that affect the management of patients. The first one is the ARROW study, which demonstrated that the weekly schedule of carfilzomib was more efficacious than a twice-weekly schedule. It was also more convenient for patients. This was without increased side effects.

This weekly schedule is certainly something we can take to the clinic. It has already changed my practice in terms of administering carfilzomib. There is also a trial combining carfilzomib and daratumumab (Darzalex). The response rates are very encouraging. It's another option for patients who are lenalidomide refractory. That is a particularly important population to focus on, given a lot of patients receive lenalidomide maintenance.

I also spoke about the OPTMISMM study combining pomalidomide, bortezomib, and dexamethasone versus bortezomib and dexamethasone. The study showed the superiority of the addition of pomalidomide. While this study is not very surprising in terms of its endpoint, it gives yet another option for lenalidomide-refractory patients.

What was the rationale for ARROW?

What is also interesting is the ELOQUENT-3 study looking at pomalidomide in combination with elotuzumab and dexamethasone versus pomalidomide and dexamethasone alone. The ELOQUENT-3 study showed that [the addition of elotuzumab] was superior to pomalidomide with dexamethasone. The side effect profile is very manageable. There is less neutropenia and infection with the elotuzumab combination therapy and a higher response rate. That also slots in elotuzumab for patients with advanced multiple myeloma, whereas the ELOQUENT-2 study looked at patients who were mostly lenalidomide-naïve or -relapsed.The ARROW study stems from the CHAMPION-1 study, which looked at weekly dosing. The response rate of the CHAMPION-1 study was very intriguing. If you go back to the phase I study of carfilzomib, the dose stopped escalating at 27 mg/m² on a twice-weekly schedule because of renal toxicity and tumor lysis syndrome. That's where that 20/27 hybrid dosing came about.

In hindsight, perhaps we haven't explored the full range of carfilzomib dosing. There was also a SWOG study looking at high-dose versus low-dose carfilzomib—–a 20/56 versus 20/27 twice-weekly schedule. In that study, the superiority arm was not met. It does look a little bit better. The design was a little bit different with 12 cycles versus continuous treatment as in the ARROW study.

What is the prevalence of lenalidomide-refractory patients and what are the available treatment options?

How could the combination of venetoclax and carfilzomib fit into practice?

Once you develop a regimen that is effective, there are tweaks in the way we've learned how to use those drugs. This is one of the ways we found that the once-weekly schedule with carfilzomib looks to be the preferred one. If you go back to bortezomib, it started out as a twice-weekly schedule. Much of what we use now in practice is the once-weekly schedule [that shows] less neuropathy, etc. There is always a need to look back at the schedule that was devised in a phase I study [because of the] limited sample set or number of patients. [We do this to] see whether there is a way to make the schedule more patient friendly but also more effective.Most transplant-eligible patients will typically receive RVd induction, transplant, and lenalidomide maintenance. When there is disease progression, the management of this patient set is not very clear. A lot of prior studies, such as ASPIRE and ELOQUENT, didn't look specifically at lenalidomide-refractory patients. Options for them include a CASTOR-like regimen with bortezomib, daratumumab, and carfilzomib-based therapies such as pomalidomide or cyclophosphamide. The combination of carfilzomib and daratumumab is something that needed to be examined. If you look at the ENDEAVOR trial comparing carfilzomib and bortezomib, it suggests that carfilzomib is, in fact, the better proteasome inhibitor. In which case, combining carfilzomib with daratumumab was going to be a successful strategy, which that study suggested.Single-agent venetoclax shows that it has considerable activity in patients who have t(11;14). The response rate was also high when in combination with bortezomib for those who do not necessarily have the translocation. It’s hard to know whether this was due to bortezomib activity or the fact that bortezomib and venetoclax are synergistic. It's hard to tease this out from a phase II study.

The study that was presented at the 2018 ASCO Annual Meeting of carfilzomib with venetoclax is a natural extension of combining a proteasome inhibitor with a BCL-2 inhibitor. In this setting, it didn't give us a lot of new information. We knew venetoclax was likely to be active in those patients with t(11;14). They had a 100% response rate, if I recall correctly.

What is another area of unmet need?

In the general patient population who received carfilzomib and venetoclax, the response rate was about 80%. How different is that from carfilzomib alone? Do you really need venetoclax? The big question is the role of venetoclax in patients who don't have the translocation—be it in combination or [otherwise]. Additionally, is there a way to identify a subset of patients who don’t have t(11;14) but still benefit from venetoclax?Despite many new treatments, we still face situations where patients have multirefractory disease, or what is called quad- or penta-refractory disease. Outcomes of those patients remain very poor, so looking at additional therapies or strategies is important. Certainly, chimeric antigen receptor (CAR) T cells are evolving in that landscape. We have several trials coming about at Moffitt Cancer Center and at several other institutions. There have been very exciting reports of CAR T cells in myeloma.

Can you discuss the potential with selinexor?

There is a more unmet need in elderly and frail patients. A lot of those studies don't include many frail patients. The key things are how do we put it all together, how do we sequence therapies, and how do we personalize treatment? This is something that we have to work on better as a group. We have a number of agents or regimens that have response rates in the early-relapse setting. Response rates in the late-relapse setting are lower. Older patients who are trying a regimen are going to be exposed to its side effects, whereas only a small proportion are going to benefit. The key will be identifying patients who are likely to benefit from a specific therapy and personalizing that therapy.We have had selinexor in the clinical trial setting at Moffitt Cancer Center for the past 4 to 5 years, since the first phase I trial in hematologic malignancies. It certainly has activity in patients who have penta-refractory disease. Perhaps it would be interesting to look at combinations with selinexor. In that case, you could use a weekly schedule of it. There are combinations with bortezomib, carfilzomib, and lenalidomide that look to have a high response rate so far.

Teasing out where those combinations will fall will be important. I don’t foresee selinexor used in the clinic with dexamethasone. It will likely be selinexor plus something. Finding out what that something is for which patients will be the most interesting thing to me. The key thing is to continue to think about clinical trials. That's how the field moves forward and how we get more options for our patients.

References

1. Mateos MV, Moreau P, Berenson JR, et al. Once-weekly vs twice-weekly carfilzomib (K) dosing plus dexamethasone (d) in patients with relapsed and refractory multiple myeloma (RRMM): results of the randomized phase 3 study A.R.R.O.W. J Clin Oncol. 2018;36(suppl; abstr 8000).
2. Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomized, phase 3 study. Lancet. 2018;19(7):953-964. doi:10.1016/S1470-2045(18)30354-1.
3. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide/dexamethasone (EPd) vs Pd for treatment of relapsed/refractory multiple myeloma (RRMM): results from the phase 2, randomized open-label ELOQUENT-3 study. In: Proceedings from the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract LB2606.
4. Richardson PG, Rocafiguera AO, Beksac M, et al. Pomalidomide (pom), bortezomib, and low&#8208;dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (len)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): phase 3 OPTIMISMM trial. J Clin Oncol. 2018;36(suppl; abstr 8001).