Douglas Sborov, MD, MS, discusses and compares the many triplet therapies for patients who show disease progression after several lines of therapy in this first article of a 2 part series.
A 60-year-old White woman, with a history of heavy smoking, was diagnosed with stage II multiple myeloma. Cytogenetics showed gain(1q21) and her ECOG performance score was 0. At the time, she was treated with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induction therapy, followed by autologous stem cell transplant. She achieved a complete remission with VRd and transplant and was also minimal residual disease (MRD) negative. The patient was then placed on lenalidomide maintenance therapy.
Targeted OncologyTM: What do the National Comprehensive Cancer Network (NCCN) guidelines suggest for a patient case like this?
SBOROV: Full disclosure, I'm on the NCCN guidelines [and I also] think that these data are…limited. We have so many new drugs, and we don't have a lot of great trials to do head-to-head [comparisons with], so what we try to do is break down [treatment decisions and decide] what is going to work for our patients.
Early relapse is [defined as having] 1 to 3 prior lines of therapy, [and a patient] who relapsed over 6 months may repeat [their primary therapy].1 For example, somebody who is on lenalidomide maintenance who comes off treatment…for 3 and a half years but then progresses could be considered for going back to daratumumab [Darzalex], lenalidomide, and dexamethasone [DRd] in a situation like that. So, for patients who are still sensitive to bortezomib and/or lenalidomide, any of the [category 1 regimens in the NCCN guideline] may be appropriate.
Because the patient [in this case] is lenalidomide-refractory, I’ll start there. [In the] category 1 treatments, we have daratumumab with carfilzomib [Kyprolis]; bortezomib, daratumumab with a proteasome inhibitor [PI]; isatuximab [Sarclisa] with carfilzomib and dexamethasone; and then we also have carfilzomib, pomalidomide, dexamethasone, but with that we don't have randomized phase 3 trial data to inform us about that decision-making. Then for after 1 prior therapy, including lenalidomide and a PI, we also have daratumumab, pomalidomide, and dexamethasone, and after 2 prior therapies, including lenalidomide and a PI, we have isatuximab, pomalidomide, and dexamethasone.
If a patient progresses up to the fourth line of treatment, what would you recommend?
In the space of multiple myeloma, we're pretty sure what we should be doing at first progression, second progression, and after 4 prior lines of therapy, but then we have this—I call it a black hole—at the space between what we should be doing at second line and what we should be doing at fourth line, and that's where these regimens come in.
Basically, what we're saying in [the NCCN guidelines is to] take a drug that the patient is not refractory to, that's the next best option, and try to find a partner for a triplet. We shouldn't be using doublets for anybody anymore. Triplets should be the way to go across the board, so we want to try to identify the [right] triplets [to use].
The NCCN lists carfilzomib/dexamethasone [K/D] twice weekly here; you could also use it once weekly for the ARROW trial [NCT02412878], but in general, we're not including K/D as a treatment option for patients in the relapsed refractory setting anymore.
What data back up these treatment decisions?
We can't do [comprehensive] cross-trial comparisons, and now that I've said that let's do some cross-trial comparisons. When we're looking at all of these different trials, it's important to look at them in the setting of refractoriness. What is this patient population that we're looking at? [For example, in the] IKEMA study [NCT03275285], with a median progression-free survival [PFS] of 41.7 months, is that the same population of patients as what we're looking at with the APOLLO trial [NCT03180736], with a median PFS of 12.5 months?2,3
With the IKEMA trial, 20% of the patients are PI- and IMiD-refractory, whereas in APOLLO, 42% are duo-refractory. In the CANDOR trial [NCT03158688], we don't know duo-refractoriness, but 30% of the patients [in that trial] were considered to be lenalidomide-refractory and 28% were bortezomib-refractory.4
A third of the patients were lenalidomide-refractory in the IKEMA trial and a third of the patients were lenalidomide-refractory in CANDOR. Thirty-percent [of patients] were bortezomib-refractory in IKEMA, and then again, the duo-refractoriness was 20% in IKEMA, but we don't know [that percentage] in the CANDOR study. But it’s [ultimately a] similar patient population [between the 2 studies].
Now, let's compare both of those to what we see in APOLLO. All of these trials include patients with 1 to 3 prior lines of therapy and the median [number of prior lines of therapy] was 2 across the board. However, in APOLLO, 80% of the patients were lenalidomide-refractory, 40% were bortezomib- or PI-refractory. I'm trying to make the point that in those patients who were on IKEMA and APOLLO are going to have a decreased median PFS, maybe because of performance of the drugs, but also because those patients were more heavily pretreated.
1. National Comprehensive Cancer Network Guidelines. Multiple myeloma; version 3.2023. Accessed: May 23, 2023. tinyurl.com/yckvrxuc
2. Moreau P, Dimopoilos M, Mikhael J, et al. Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Presented at: 2022 Annual European Society of Medical Oncology Meeting; May 19-20, 2022; Paris, France. Abstract VPS-2022. https://bit.ly/3N2cc2d
3. Dimopoulos MA, Terpos E, Boccadoro M, et al; APOLLO Trial Investigators. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(6):801-812. doi:10.1016/S1470-2045(21)00128-5
4. Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197. doi:10.1016/S0140-6736(20)30734-0