Usmani Discusses Significance of Latest Daratumumab Findings in Myeloma

Saad Z. Usmani, MD

Saad Z. Usmani, MD

Several key trials examining daratumumab (Darzalex) for the treatment of multiple myeloma were presented late last year at the 2016 ASH Annual Meeting.

Researchers shared long-term data from the pivotal CASTOR¹and POLLUX²trials, which supported the November 2016 FDA approval of 2 daratumumab-based triplet regimens. CASTOR randomized patients with relapsed/refractory multiple myeloma to bortezomib (Velcade) and dexamethasone alone or with daratumumab. POLLUX randomized patients with relapsed/refractory multiple myeloma to daratumumab combined with lenalidomide (Revlimid) and dexamethasone or lenalidomide plus dexamethasone alone.

The CASTOR update showed that at a median follow-up of 13 months, the overall response rate (ORR) was 84% in the daratumumab arm versus 63% in the bortezomib/dexamethasone arm. The 12-month progression-free survival (PFS) rate was 60% in the daratumumab arm versus 22% in the control arm.

In the POLLUX update, at a median follow-up of 17.3 months, the ORR was 93% in the daratumumab arm versus 76% in the lenalidomide/dexamethasone arm. The median PFS was still not reached in the daratumumab arm versus 17.5 months with lenalidomide/dexamethasone alone.

Data from another important daratumumab study presented at ASH, the phase Ib PAVO trial,³showed that subcutaneous delivery of the drug was well tolerated with comparable efficacy to the FDA-approved intravenous (IV) dose in patients with relapsed/refractory multiple myeloma.

In an interview withTargeted Oncology, Saad Z. Usmani, MD, department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System, who presented the POLLUX update and PAVO findings at ASH, discussed the latest developments with daratumumab.

TARGETED ONCOLOGY:What is the significance of the CASTOR and POLLUX trial results for patients with multiple myeloma?

Usmani:

The CASTOR and POLLUX trials are perhaps 2 of the most exciting trials that have been reported out this year. As we already know, as a result of those 2 studies, daratumumab is now approved for every line of therapy within the relapsed myeloma setting.

The POLLUX study was a large randomized phase III study. It was a global study comparing daratumumab, lenalidomide, and dexamethasone versus lenalidomide/dexamethasone in patients who have had 1 to 3 prior lines of therapy.

The CASTOR trial had a very similar inclusion criteria, but the combination was with daratumumab plus bortezomib/dexamethasone compared with bortezomib/dexamethasone.

Both of those trials showed that daratumumab can be partnered with either an immunomodulatory agent or proteasome inhibitor in that setting, and the 3-way combination seemed to be superior to the 2-way combination. There are some differences in the patient populations that accrued to both the studies and the way that the [trials] were designed.

The way that daratumumab partners with these mechanisms—either immunomodulatory agents or proteasome inhibitors—is probably a little different. That's why we do see a difference in the efficacy and depth of response. It would be unfair to compare both the studies head to head, but it does appear that lenalidomide/dexamethasone is a very strong partner for daratumumab in that line of therapy.

Looking at the efficacy data and trying to look at subgroup analyses, it appears that in patients who had earlier relapses and/or had higher cytogenetics, daratumumab plus lenalidomide/dexamethasone has a superior depth of response, as well as PFS compared with the control arm on either of the studies.

TARGETED ONCOLOGY:What role do you think these findings will play in the landscape going forward?

Usmani:

Now that daratumumab is approved for earlier lines of therapy, both of those studies will be impactful for practice in the United States. My feeling is that, depending on the kind of therapies the patients have received as their first-line treatment, you may be able to pair daratumumab either with lenalidomide or bortezomib. The concern here—in the grand scheme of things—is the long-term effects of daratumumab on the immune system. We haven't seen any clinically meaningful concerns there.

TARGETED ONCOLOGY:You presented findings at ASH of a phase I study looking at the subcutaneous infusion of daratumumab. Can you give some background?

Usmani:

One of the challenges of giving daratumumab, after it was FDA approved, was that the intravenous (IV) infusion takes a long time to administer—especially the first dose, which can take up to 7 or 8 hours. Once the patients get to their third or fourth weekly dose, the infusion time can be cut down to 3 or 4 hours. However, it becomes a convenience issue.

This particular phase I trial of daratumumab is a subcutaneous infusion and was developed to alleviate that concern. To cut down the administration time and the technology that was utilized, we combined daratumumab with the recombinant hyaluronidase, which is an enzyme that can break down the hyaluronic acid within the subcutaneous soft tissue. This creates a deposit of daratumumab under the skin in the subcutaneous tissue. This was a multicenter phase Ib trial.

We found that both the 1200-mg fixed dose and the 1800-mg fixed dose appeared to be tolerable. The infusion-related reaction rate was significantly low compared with the data to be published with the IV formulation, even though this is a small phase I study. The drug appears to be at least as efficacious as the IV formulation.

TARGETED ONCOLOGY:What are the next steps, after these findings?

Usmani:

In other settings, I think it is feasible to do. It will cut down the infusion time, alleviate a lot of the infusion reactions, and replace the IV formulation in the coming years.

TARGETED ONCOLOGY:Is there anything else with daratumumab you would like to highlight?

Usmani:

With the daratumumab/lenalidomide/dexamethasone combination, we are seeing an unprecedented depth of response. We are seeing patients achieve minimal residual disease (MRD) negativity in a much higher proportion in the relapse setting. With the daratumumab/lenalidomide/dexamethasone combination, depending on which MRD negativity cut off you look at—minus 4, minus 5, or minus 6 across the board—you're seeing patients reach MRD negativity. This is something that we haven't seen in this kind of a setting to this degree.

References:

1. Mateos MV, Estell J, Barreto W, et al. Efficacy of daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory myeloma based on prior lines of therapy: updated analysis of CASTOR. Presented at: 58th ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 1150.
2. Usmani SZ, Dimopoulos M, Belch A, et al. Efficacy of daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma patients with 1 to 3 prior lines of therapy: updated analysis of POLLUX. Presented at: 58th ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 1151.
3. Usmani SZ, Nahi H,Mateos M-V, et al. Open-label, multicenter, dose escalation phase 1b study to assess the subcutaneous delivery of daratumumab in patients (pts) with relapsed or refractory multiple myeloma (PAVO). Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 1149.