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Saad Z. Usmani, MD, FACP, discusses the significance of the FDA approval of daratumumab, carfilzomib, and dexamethasone in patients with relapsed/refractory multiple myeloma who have received at least 1 previous line of therapy.
The combination of daratumumab (Darzalex), carfilzomib (Kyprolis), and dexamethasone (KdD) is an important addition to the relapsed/refractory multiple myeloma treatment arsenal, according to Saad Z. Usmani, MD, FACP, who added that this regimen is most impactful for patients who are refractory to lenalidomide.
In August 2020, the FDA approved the KdD combination for use in patients with relapsed/refractory multiple myeloma who have received 1 or more previous lines of treatment based on data from the phase 3 CANDOR (NCT03158688) and the phase 1b EQUULEUS trials (MMY1001; NCT01998971). Two carfilzomib-dosing regimens were approved: 70 mg/m2 once weekly and 56 mg/m2 twice weekly.
“The FDA approval of KdD adds an important option to the armamentarium for our patients who have been exposed to lenalidomide (Revlimid) and have become refractory,” said Usmani. “We need more options for this subset of patients; [before this decision], this is something that we did not have. Looking forward, we must wait for the long-term data to read out to truly understand the benefits [of this approach] in this subset.”
In the randomized, multicenter, open-label, phase 3 CANDOR trial, 466 patients with relapsed/refractory multiple myeloma who received 1 to 3 previous lines of therapy were randomized 2:1 to receive either KdD (n = 312) or the combination of carfilzomib and dexamethasone alone (Kd; n = 154).
Results showed that, at a median follow-up of 17 months, the median progression-free survival (PFS) was not yet reached in the KdD arm versus 15.8 months in the Kd arm (HR, 0.63; 95% CI, 0.46-0.85; P =.0014); this translated to a 37% reduction in the risk of disease progression and death. Moreover, the median overall survival (OS) had not yet been reached in either arm (HR, 0.75; 95% CI, 0.49-1.13; P =.08). Moreover, the overall response rates (ORR) reported in the KdD arm versus the Kd arm were 84.3% versus 74.7%, respectively (P =.0040).
Regarding safety, the rate of treatment-related discontinuation were comparable between the 2 arms; 22.4% of those on the KdD arm discontinued versus 24.8% on the Kd arm. Five treatment-related deaths occurred in the KdD arm; these were because of pneumonia, sepsis, septic shock, acinetobacter infection, and cardiorespiratory arrest.
“To me, the most clinically impacted patient population that could benefit from this combination are the patients who are refractory to lenalidomide because that population was not previously studied in any of the [trials of] lenalidomide-based triplet combinations that have been approved,” stressed Usmani.
In a special episode of OncLive On Air, we passed the mic to Usmani, who is chief of the Plasma Cell Disorders Program and director of Clinical Research in Hematologic Malignancies, at the Levine Cancer Institute, of Atrium Health, who discussed the significance of the FDA approval of KDd in patients with relapsed/refractory multiple myeloma who have received at least 1 previous line of therapy.
OncLive: What treatment options are currently available for patients with relapsed/refractory multiple myeloma?
Usmani: The current landscape for patients with multiple myeloma in the relapsed setting includes several 3-drug combinations as well as 2-drug combinations. We recognized that multiple myeloma needs to be treated with a multipronged treatment approach, consisting of different mechanisms of actions that work together.
We have several combinations in the early relapsed setting that include lenalidomide-based triplets. For example, we have bortezomib (Velcade), plus lenalidomide (Revlimid) and dexamethasone and the combination of carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd). We also have ixazomib (Ninlaro), lenalidomide, and dexamethasone, as well as the combination of elotuzumab (Empliciti), lenalidomide, and dexamethasone.
Moreover, carfilzomib plus dexamethasone is another potential option in this setting. Finally, there are some bortezomib-based options such as panobinostat(Farydak), bortezomib, and dexamethasone.
Several options are available; however, the majority of these options are lenalidomide- based triplets. Specifically within the United States, many patients remain on lenalidomide-based maintenance after receiving induction therapy with or without a stem cell transplant.
What was the rationale to explore KRd in patients with relapsed/refractory multiple myeloma?
Frontline treatment with lenalidomide- and bortezomib-based therapies have prolonged survival in patients with newly diagnosed multiple myeloma; however, when patients relapse, especially when they become refractory to both immunomodulatory drugs and to bortezomib, the progression- free survival (PFS) and OS becomes fairly short for patients. In fact, prior lenalidomide exposure and refractoriness appears to be an independently negative prognostic factor at the time of relapse. Therefore, developing regimens that address that patient population and are lenalidomide free makes sense.
Since carfilzomib and daratumumab are very effective single agents and have received regulatory approval for use in relapsed/refractory multiple myeloma as monotherapies and in combinations, KRd was examined in the phase 1 EQUULEUS trial and was found to be efficacious and safe. This provided the rationale to develop the CANDOR trial, which compared the 3-drug combination to the standard-of-care arm comprised of carfilzomib and dexamethasone.
What was the design of the CANDOR trial?
The CANDOR study was designed with a 2:1 randomization schema for patients who've had 1 to 3 prior lines of treatment. The 2:1 schema means that for every patient who is randomized to the carfilzomib/dexamethasone arm, 2 are randomized to KdD. The treatment was continued until disease progression, relapse, or intolerance, with the primary end point being PFS. Notably, other important secondary end points [were evaluated], such as overall response rate, minimal residual disease (MRD) status, specifically a landmark analysis of MRD-negative CR at 12 months, and OS.
What did the patient population look like?
The patients who were enrolled in this trial had to have at least 1 to 3 prior lines of treatment. A total of 466 patients were randomized; 312 were randomized to the KdD arm and 154 were randomized to the Kd arm. The median age, at the time of enrollment, was about 64 years on the 3-drug–combination arm and 65 years on the 2-drug–combination arm.
When looking at the karyotypic abnormalities, roughly 15% to 16% of the patients had high-risk features [in terms of] cytogenetics and more than 50% of patients had received 2 or more prior lines of treatment. Furthermore, 28% of the patients had prior bortezomib refractoriness and about one-third of patients were refractory to lenalidomide.
What were the key findings from this research?
After a median of a little over 16 months of follow-up, the primary end point of PFS was met, with KdD significantly prolonging PFS compared with Kd. The median PFS was reached in the Kd arm at 15.8 months whereas it was not reached in the KdD arm. The hazard ratio was 0.63 with a one-sided P value of 0.001.
What safety data were reported with the combination?
When looking at safety, it's also important to appreciate that the drug exposure was more prolonged in the 3-drug combination, primarily showing the efficacy of that regimen. However, the relative dose intensity was similar across the 2 arms for carfilzomib as well as dexamethasone.
From a safety standpoint, 99% of the patients experienced some grade of treatment-emergent adverse effects (TEAEs), whereas 96% of those on the Kd arm experienced TEAEs. Grade 3 or higher TEAEs were seen in 82% of the patients on the KdD arm versus 74% and primarily included infections. If we start looking at fatal treatment-related toxicities, 5 were reported on the KdD arm versus none on the Kd arm. Notably, of those 5 fatal events, 4 were infection-related and 1 was cardiac arrest.
In terms of hematologic AEs, there were higher rates of thrombocytopenia, as well as grade 3 or higher neutropenia on the Kd arm. Again, infection rates with upper-respiratory tract infections and pneumonias were also higher. Interestingly, grade 3 or higher cardiac failure appeared to be numerically lower on the KdD arm, at about 4% versus 8.5%, respectively. However, grade 3 or higher respiratory-tract infections were certainly higher on the KdD arm versus the Kd arm, at almost 29% versus 15.7%, respectively.
Are there any remaining questions with this regulatory approval that need to be addressed?
A big question with this FDA approval is how we will adopt KdD as a community. Is carfilzomib going to be given on a weekly basis based on EQUULEUS data in the United States? Or will there be twice weekly dosing? Many of us may feel that once-weekly dosing will probably be more convenient for patients. However, we have to see how these trends emerge. I do not believe any clinical trials are planned [to answer]. This will probably end up being a post-marketing analysis that many of the myeloma investigators may evaluate in the future.
Usmani SZ, Quach H, Mateos M-V, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (RRMM): primary analysis results from the randomized, open-label, phase 3 study Candor (NCT03158688). Blood. 2019;134(suppl_2; abstr LBA-6). doi:10.1182/blood-2019-132629.