C. Ola Landgren, MD, PhD, discusses important research efforts that led to the launch of the phase 2 MANHATTAN trial, the results achieved with the weekly carfilzomib quadruplet regimen in patients with newly diagnosed multiple myeloma, and the potential for this approach irrespective of transplant eligibility status.
The novel combination of carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone, and daratumumab (Darzalex; KRd-D) yielded high rates of minimal residual disease (MRD) negativity in patients with newly diagnosed multiple myeloma, according to C. Ola Landgren, MD, PhD, who added that this regimen could potentially be used irrespective of transplant eligibility.
In the phase 2 MANHATTAN trial, Landgren and colleagues examined the efficacy of KRd-D in patients with newly diagnosed disease.1 Of the 41 patients evaluated, 71% achieved MRD negativity. The median time to MRD negativity was 6 cycles of therapy (range, 1-8 cycles).Notably, all patients experienced a response to treatment, with 95% achieving a very good partial response or complete response.
“The fact that we treated both patients [who were eligible for transplant and those who were not] and we showed a MRD negativity of 71% beyond the actual primary end point [of the trial] raises a very important question: Should we really think about transplant eligible vs ineligible patients or should we just think about newly diagnosed patients [as a whole], and offer every patient the best possible therapy?” Landgren said. “The answer to that is yes, we should [offer the best option available].”
In an interview with OncLive®, Landgren, the inaugural leader of the Experimental Therapeutics Program at Sylvester Comprehensive Cancer Center, of the Miami Health System, discussed important research efforts that led to the launch of the MANHATTAN trial, the results achieved with the weekly carfilzomib quadruplet regimen in patients with newly diagnosed multiple myeloma, and the potential for this approach irrespective of transplant eligibility status.
Landgren: Daratumumab was FDA approved in November 2015 for [use in] patients with multiple myeloma who have received at least 3 prior lines of therapy. In 2016, combinations [utilizing the agent] were also approved; its [use] just continued to evolve, [even expanding to] include newly diagnosed patients and [combinations] with immunomodulatory drugs.
Immediately, people started to wonder whether [the agent] could be added to the standard backbones. The first combination that was presented was the bortezomib [Velcade], lenalidomide, and dexamethasone [VRd] regimen; this was the first 3-drug combination that Dana-Farber Cancer Institute developed in 2008 and [data on its use were] published 2010. We worked on a second-generation 3-drug combination at the National Cancer Institute and published [data on this approach] in 2015; this was the KRd regimen.
We continued to build on that [foundation]. We have seen [that] the KRd regimen is more effective [than the VRd regimen] in [that it achieves] deeper responses and much higher MRD [negativity] rates. As such, we have worked to see whether we could optimize the KRd therapy with weekly instead of biweekly [dosing]. Very importantly, [we also wanted] to see how the fluid regimen and the anticoagulation regimen could be optimized. Studies have showed that if you give KRd with too much intravenous fluid, [patients can experience] congestive heart failure. [Additionally, because] the KRd regimen is a very effective therapy, you could also trigger hypercoagulation, with thrombosis as a complication.
We have extensive experience with all these types of regimens, so we decided to [evaluate] a once-a-week dosing [schedule] of KRd, with carfilzomib [given at a dose of] 56 mg/m2. Then, [we used] our standard optimized fluid regimen, with only 250 mL of intravenous saline prior to the first dose [of the combination]. We stopped all intravenous fluid after that. [From there, we] put patients on an oral factor Xa tablet once a day for anticoagulation prophylaxis. That’s the backone of the backstory: We saw this very effective therapy and we were aware that the fluid could be a problem and that the right anticoagulation [regimen is needed].
We then paired this [backbone] with daratumumab. We showed that after 8 cycles of this regimen, a MRD negativity rate of 71% [was achieved]. If you look at the older studies that have been done, as well as more recent studies, when VRd was given for 6 cycles with a bone marrow transplantation has resulted in a MRD negativity rate of [about] 20% in newly diagnosed patients; [this rate is] substantially lower [than what was seen with the quadruplet regimen]. Moreover, data from the phase 2 GRIFFIN study [NCT02874742], which were published in Blood last year, examined VRd for 6 cycles in the experimental arm, daratumumab for 6 cycles, plus a bone marrow transplantation; [this approach yielded] a MRD negativity rate of 51%.
[It’s important to note that we] are not talking about a [single] randomized study that compared these different regimens; we are looking at different studies. As such, I really caution to anyone who is looking at these details that a randomized study would [be needed] to do a formal comparison [between these approaches]. Regardless, we see an interesting signal here. A lot of work needs to be done going forward in terms of consolidating and expanding these results, but this [benefit] is real.
The study was designed to test the weekly KRd [regimen] with daratumumab for 8 cycles and to see how deep of a response could be achieved and in what proportion of patients. The primary end point was to rule out 40% MRD negativity after these 8 cycles, and we were able to show that the right answer is 71%.
Patients were allowed to go for a bone marrow transplantation after the 8 cycles [of treatment]. They were encouraged to collect stem cells after 4 to 6 cycles of therapy. [However], because we [administered] 8 cycles of therapy to see how many patients could reach MRD negativity, there was no mandatory transplant in this study. That actually means that patients who were not looking to [undergo] a transplant or those who were even not transplant candidates could be included in the study. At the same time, patients who wanted to do a transplant and who were candidates for transplant could also be enrolled to the study.
The reason why you would not give a powerful therapy such as this is that the patient is maybe frail, has underlying cardiovascular problems, or has other health issues. [For] patients [who are not frail]—forget about age—this type of therapy is very appropriate. [However], you also have to ensure that the patient does not have underlying cardiovascular disease or any other severe, underlying comorbidity that would make them vulnerable.
Landgren O, Hultcrantz M, Diamond B, et al. Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma. JAMA Oncol. Published online April 15, 2021. doi:10.1001/jamaoncol.2021.0611