Expert Highlights Research Developments Across the Spectrum in Multiple Myeloma

Maria Chaudhry, MBBS

A variety of triplet and quadruplet regimens continue to be investigated and move through the pipeline in newly diagnosed multiple myeloma as well as in the relapsed/refractory setting, explained Maria Chaudhry, MBBS.

Newly diagnosed patients are also being treated with quadruplet regimens. In the phase II GRIFFIN trial, investigators examined the addition of daratumumab to bortezomib (Velcade) and Rd (D-RVd) in transplant-eligible patients with newly diagnosed multiple myeloma. At a median follow-up of 22.1 months, results showed that the stringent complete response (sCR) rate was 62.6% with daratumumab plus D-RVd compared with 45.4% with RVd alone.²

In the relapsed/refractory setting, Chaudhry said there is a plethora of options, though the triplet regimens have not yet been compared head to head; therefore, the superiority among them is unclear.

“There are a lot of combination therapies that have been approved,” he added. “There are a lot of clinical data in patients who have relapsed/refractory disease. All of these 3-drug regimens have not been compared head to head, meaning any rational sequencing is fine. As long as a patient gets all active drugs in some form of rational sequence, they will do well.”

In an interview during the 2019 OncLive State of the Science Summit on Hematologic Malignancies, Chaudhry, a hematologist at The Ohio State University Comprehensive Cancer Center—James, discussed recent and ongoing research in newly diagnosed and relapsed/refractory multiple myeloma.

OncLive: What regimens are being used in the frontline setting in multiple myeloma?

Chaudhry: The SWOG S0777 trial, published in Lancet in 2017, compared bortezomib, lenalidomide, and dexamethasone with lenalidomide and dexamethasone; it showed that 3 drugs are better than 2 drugs. VRd is now the standard of care in the management of patients who are transplant-ineligible and in the frontline setting with multiple myeloma.

There is a new trial that was published in the New England Journal of Medicine in 2019: the MAIA trial. In that study, transplant-ineligible patients were randomized into 2 groups. In the experimental arm, patients received daratumumab, lenalidomide, and dexamethasone while in the control arm they received lenalidomide and dexamethasone. The patients in both groups continued treatment until progression. About 44% of patients in this clinical trial were 75 years of age or older—meaning the study was looking specifically at elderly patients.

The daratumumab-containing regimen in this trial is the winner, with a hazard ratio for PFS of about 0.64. It showed that daratumumab-containing triplet therapy is better than lenalidomide and dexamethasone alone. In terms of efficacy, the overall response rate (ORR) with daratumumab was also better, at about 93%.

It is important to note that patients who received a daratumumab-containing regimen had more incidence of grade 3 or higher neutropenia. We have to be careful [and manage those adverse events appropriately]. DRd is now approved in the frontline setting in patients who are transplant-ineligible. This is not a direct comparison of DRd versus VRd, so we cannot say which regimen is better.

In my clinical practice, if there is a patient who is approaching 80 years old, I would want to treat them with the best regimen, because I know that down the line they will be more fragile, have more toxicities, and might not be able to tolerate incremental therapy. I will be using this regimen in my clinical practice.

Could you discuss the emergence of 4-drug regimens?

Right now, we have the GRIFFIN trial that was presented at the 2019 ASH Annual Meeting. It showed that quadruple regimen, which contains daratumumab, is better than 3-drug therapy. I would like to have longer follow-up in this group of patients to know if this is a regimen we would like to use in all patients, which means including standard-risk as well as high-risk patients. Are there patients who would benefit more from 4-drug therapy? More is not always better. This is an exciting time in multiple myeloma.

What are the unmet needs in multiple myeloma?

The unmet need in multiple myeloma is with patients who have relapsed/refractory disease. At second relapse and later, patients have difficult-to-control disease and they have toxicities that add up. The patients who are relapsing this year and next year are those who have received bortezomib or carfilzomib (Kyprolis) as frontline therapy; the anti-CD38 agent in the relapsed/refractory setting is still relevant.

The data from the CANDOR trial [of daratumumab, carfilzomib, and dexamethasone] are very promising and gives us a regimen that is free of immunomodulatory drugs. I will be using this regimen. In the future, we will be using daratumumab more in the frontline setting. Now, for these patients at a time of relapse, we need drugs with different mechanisms of action.

There are more drugs and more clinical trials happening, and there were some data on monoclonal antibodies, and also bispecific T-cell engagers that targets plasma cells in myeloma. We will see a few approvals [perhaps in 2020], and that would be the option for these patients.

What novel agents are currently being used in the relapsed/refractory setting?

One novel agent that we are using right now in the relapsed/refractory setting is daratumumab. Most of us use daratumumab at the time of first relapse and combine it with pomalidomide and dexamethasone.

Carfilzomib is a very potent proteasome inhibitor. Most of us are still using it at the time of first and second relapse. That's another agent that we can combine with pomalidomide and dexamethasone. It's important to know that there are at least 5 clinical trials that use pomalidomide and dexamethasone as a backbone. Two of those are phase II clinical trials, but they still provide good data and are relevant to clinical practice in the United States.

There is another monoclonal antibody called isatuximab. It has broadly the same mechanism of action as daratumumab, but maybe there are subtle differences. We don't know the clinical elements of those differences, but the ICARIA-MM trial was published in 2019 and the results are quite promising. Isatuximab was combined with pomalidomide and dexamethasone and compared with pomalidomide and dexamethasone. The isatuximab-containing arm was the winner. However, this monoclonal antibody will compete with daratumumab. Maybe it will put some pressure on the cost of these drugs, but it is always good to have more active drugs in the relapsed/refractory setting.

We have seen selinexor (Xpovio), which is a selective inhibitor of nuclear export. Based on the data from the STORM trial, it was approved in combination with dexamethasone. This is for patients who have heavily relapsed/refractory disease. The ORR with selinexor and dexamethasone was up to 25%, which is promising, but the highlight of this drug is toxicity— primarily gastrointestinal toxicity and neurological toxicity.

We also have elotuzumab (Empliciti), [which is added to] pomalidomide and dexamethasone. It's a combination that was approved based on data from the ELOQUENT-3 trial. Elotuzumab remains very relevant because most of us eventually lean on elotuzumab after patients are relapsing on daratumumab or carfilzomib. Eventually, we use [elotuzumab]. During the ELOQUENT-3 trial, the patients who were enrolled had not received daratumumab before. [Elotuzumab] is well tolerated and is not associated with too many toxicities. Gradual patients who have end-stage renal disease and dialysis find that this drug is very well tolerated, causing me to use [elotuzumab] in that setting.

Then we have the OPTIMISMM trial that was done in the same setting. In the OPTIMISMM trial, bortezomib was combined with pomalidomide plus dexamethasone and compared with pomalidomide/dexamethasone alone. It is important to note that about 70% of patients in this trial were lenalidomide-refractory. This is very relevant to our practice in the United States. Patients who receive 3 drugs in this trial did better compared with the patients who received pomalidomide/dexamethasone. Patients who received pomalidomide, bortezomib, and dexamethasone, at the time of first relapse, had a median PFS of up to 20 months. At the time of first relapse—and in patients who received VRd induction followed by transplant and has been on lenalidomide—we can reintroduce bortezomib along with pomalidomide and dexamethasone and get good responses.

Could you briefly discuss bb2121 and the use of CAR T-cell therapy in multiple myeloma?

bb2121 is a BCMA targeting CAR T-cell therapy and [an ORR of at least 80%] has already been published in the New England Journal of Medicine. Data are great, with a median PFS of up to about 11 to 12 months. These are the patients with heavily relapsed/refractory disease. There is room for improvement, in terms of efficacy for CAR T-cell therapy, as well as controlling the toxicity. If we move CAR T-cell therapy to earlier lines of therapy in the right patients, we will see better efficacy and duration of response.

References

1. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380, 2104-2115. doi: 10.1056/NEJMoa1817249.
2. Voorhees PM, Kaufman JL, Lauback JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update. Presented at: 2019 ASH Annual Meeting; December 7-10; Orlando, FL. Abstract 691.

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For example, the phase III MAIA trial looked at the addition of daratumumab (Darzalex) to lenalidomide (Revlimid) plus dexamethasone (DRd) versus lenalidomide/dexamethasone alone (Rd) in newly diagnosed, transplant-ineligible patients with multiple myeloma. At a median follow-up of 28.0 months, disease progression or death had occurred in 26.4% of patients who received DRd versus 38.8% of patients who received Rd.¹ The 30-month progression-free survival (PFS) rate was 70.6% and 55.6% with DRd and Rd, respectively (HR, 0.56; 95% CI, 0.43-0.73; P <.001). There were 47.6% of patients in the DRd group who had a complete response or better compared with 24.9% in the Rd group (P <.001).