Sequencing Challenges Emerge in Myeloma After Recent Approvals

Sham Mailankody, MBBS

A number of novel agents alone and in combination have become available for patients with multiple myeloma in recent years, with several more on the horizon, explained Sham Mailankody, MBBS, adding that the surge of therapies poses sequencing challenges.

“Myeloma is a poster child for all of the advances that have happened in oncology in the last 15 or 20 years. There are no fewer than 9 different FDA approvals in the last 20 years for multiple myeloma and some of us were worried that we peaked and would not see many more new drugs coming along,” said Mailankody. “However, there are newer drugs being approved. We had selinexor approved recently, as well as CAR T cells, bispecific antibodies, and antibody-drug conjugates [on the horizon].”

Selinexor was approved by the FDA in July 2019 in combination with dexamethasone based on efficacy data in a subgroup of patients from the phase IIb STORM trial, which showed activity in patients whose disease was refractory to bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), pomalidomide (Pomalyst), and daratumumab (Darzalex). The overall response rate (ORR) was 25.3%, as assessed by an Independent Review Committee.

Other trials are looking at intriguing combinations for patients with relapsed/refractory disease. For example, the OPTIMISMM study examined a triplet of pomalidomide, bortezomib, and low-dose dexamethasone versus bortezomib/dexamethasone alone in patients with ≤3 prior lines of therapy, ≥2 having contained lenalidomide.

Results showed an ORR of 82.2% with the triplet versus 50.0% with the doublet. Additionally, the progression-free survival (PFS) benefit was most evident in patients who had received 1 line of therapy (HR, 0.54; 95% CI, 0.36-0.82; P = .0027), but it was also shown in the intent-to-treat (HR, 0.61; 95% CI, 0.49-0.77; two-sided P <.0001) and lenalidomide-refractory populations (HR, 0.65; 95% CI, 0.50-0.84; P <.001).

“This is the continued pace of new drugs, new targets, and new advances in multiple myeloma, which is exciting and provides a great amount of optimism and hope for patients and the physicians who treat them,” added Mailankody.

In an interview during the 2019 OncLive^® State of the Science Summit^™ on Hematologic Malignancies, Mailankody, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed ongoing research and recent advances in relapsed/refractory multiple myeloma.

OncLive: Could you give an overview of recent trials in the relapsed/refractory setting?

Mailankody: The OPTIMISMM study looked at bortezomib and dexamethasone in combination with pomalidomide. This was a randomized study that showed that the 3-drug combination had an improved response rate and PFS; the overall survival (OS) rate is immature. This is an important treatment option for patients with at least 2 prior lines of treatment for patients with relapsed/refractory multiple myeloma.

The ARROW trial looked at 2 different dosing schedules of carfilzomib for patients with relapsed/refractory multiple myeloma; this is a combination of carfilzomib and dexamethasone. As a standard, carfilzomib is generally given twice weekly at 27 mg/m² and the study looked at giving a higher dose once a week at 70 mg/m², which showed that the higher dose has a comparable safety profile and an improved PFS compared with twice-weekly carfilzomib dosing. This has changed practice for those patients who are getting a doublet of carfilzomib and dexamethasone.

There is also a combination of elotuzumab (Empliciti) with pomalidomide and dexamethasone. Elotuzumab has been approved by the FDA already in combination with lenalidomide, based on a randomized study that showed improvements in response rate and PFS. This [pomalidomide/dexamethasone combination] was tested in a phase II randomized study that shows improvements in response rate and PFS with a trend towards improved OS, as well, although not statistically significant. These data have led to an FDA approval for this combination in the setting for patients with relapsed/refractory multiple myeloma.

The recent approval of selinexor is based on the STORM trial, which was a phase II, single-arm study for patients with heavily pretreated relapsed/refractory multiple myeloma. The approval is for patients who have received 2 prior proteasome inhibitors, 2 prior immunomodulatory drugs, and a CD38-directed antibody in the advanced myeloma setting.

The STORM study showed a response rate of 25.3% in this patient population with a PFS of about 3.7 months. There were toxicities, which included cytopenia, fatigue, diarrhea, and gastrointestinal adverse events (AEs). Twelve patients had deaths from treatment-related AEs, which is an important consideration in managing patients who receive selinexor. [Selinexor] does provide an important option for patients who have already seen other available standard treatments and can produce durable responses.

What other therapies are on the horizon?

We are very excited about many different BCMA CAR T-cell studies. There are about a dozen different trials that are ongoing, some of which are in advanced stages of clinical development. We recently saw a publication about bb2121, which is published in the New England Journal of Medicine. This is a BCMA CAR T-cell product that was used for treatment of patients with relapsed/refractory multiple myeloma and has very high response rates. The ORR was upwards of 80% in this cohort of patients with advanced, relapsed/refractory patients with multiple myeloma. The complete response rate was about 45% and is unprecedented in this patient population. However, relapses are common and in this initial cohort of patients, the median PFS was 11.7 months, showing that there is room for improvement.

There are other BCMA-targeted approaches, apart from CAR T cells. The two that have received a lot of attention are antibody-drug conjugates (ADCs), such as belantamab mafodotin.

There are also bispecific antibodies, such as AMG 420. The data was presented at the 2019 ASCO Annual Meeting, and preliminary data show that at the higher doses, it looks to be a fairly effective regimen. This is being evaluated further in other formulations. The big challenge with AMG 420 is the continuous infusion, similar to blinatumomab (Blincyto) in acute lymphoblastic leukemia, where these drugs need to be infused 24/7 continuously.

With all these approvals, how is sequencing determined?

I didn't cover all of the things we already have available for multiple myeloma. There is another half dozen drugs and several more combinations that we currently have.

A big challenge in myeloma is how to sequence these different drugs. Much of the data focus on more advanced patient populations, including patients who have received more than 3 prior lines of treatment. Sequencing the choices of different regimens for patients with relapsed/refractory myeloma boils down to toxicity profiles, prior treatments, and switching along classes of drugs. Toxicity profiles will inform treatment choices.

Unfortunately, there are several different regiments for relapsed/refractory multiple myeloma. Most of them have not been tested head-to-head, meaning we have limited comparative effectiveness data for these different trials. It boils down to prior treatments, toxicities, other options available in the specific setting in which these patients are seen, whether this is 1 to 3 prior lines [of therapy] or more than 3 prior lines. It's not uncommon for patients with multiple myeloma to have 5, 6, or 7 prior lines, which is a good problem to have. This is the challenge of sequencing these different treatments in the appropriate order.

How does minimal residual disease (MRD) play a role in this disease?

It's clear from multiple studies from different groups that achieving MRD negativity is associated with better outcomes, in terms of PFS and OS. We do not know if treatment decisions should be driven by MRD negativity and how much that should matter. That's something that's being actively evaluated at Memorial Sloan Kettering Cancer Center. We test MRD status of patients at different time points, including the end of induction therapy, the end of transplant, and during follow-up at maintenance. We use flow cytometry—based MRD testing, as well as next-generation sequencing–based MRD tests.

We do think this provides valuable prognostic information. We use it on a case-by-case basis to determine whether treatments need to be tailored. For instance, for patients who achieve MRD negativity after induction therapy, we give them the option of collecting their stem cells and deferring consolidated autologous transplant to the time of relapse. This is not yet established based on large randomized studies, but emerging evidence suggests this is a reasonable strategy for at least a select group of patients with newly diagnosed multiple myeloma.

There are ongoing studies currently evaluating this strategy. For instance, what if a patient is MRD negative consistently for 3 years and maintenance? Is that a patient who can come off of maintenance therapy safely, or do they need to be on indefinite maintenance therapy? That is something that will need clinical trials to answer; those studies are being designed or are ongoing.

What are some remaining challenges in the relapsed/refractory space?

We are seeing a lot of new drugs, new targets, and new combinations, which are exciting. We still see that most patients, unfortunately, relapse eventually and need additional treatment options. We have not yet had a definitely curative treatment in the horizon. One big challenge for relapsed/refractory multiple myeloma is to identify new targets and treatments that might provide durable, long-term remissions.

The second challenge is to come up with optimal regimens that minimize toxicities. Many of our patients live with this disease for several years. As we get better with efficacy for these different regimens, we need to focus on minimizing toxicities and minimizing duration of treatment. For many patients now, maintenance therapy is indefinite. Can we curtail that to 2 years, 3 years, or even 5 years? Using biomarkers, such as MRD assessments, to determine optimal duration of treatment will be another challenge.

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). doi: 10.1200/JCO.2018.36.15_suppl.8001.