Isa-Kd Stands Out Among Subsequent Regimens in Multiple Myeloma

Cristiana Costa Chase, DO

Assistant Professor of Medicine

Duke University School of Medicine

Durham, NC

CRISTIANA COSTA CHASE, DO: The National Comprehensive Cancer Network [NCCN] guidelines break it down by [whether] they were on bortezomib [Velcade] or lenalidomide [Revlimid] as their maintenance and what you are expecting them to be refractory to. In this particular scenario…category 1 options [include] daratumumab [Darzalex], carfilzomib [Kyprolis], and dexamethasone; daratumumab, bortezomib, and dexamethasone; and isatuximab [Sarclisa], carfilzomib, and dexamethasone [Isa-Kd].¹

There are other regimens that would be considered. I don’t use liposomal doxorubicin very often; there is infusion chemotherapy that I reach for [in some] patients, but that’s usually a different scenario. Carfilzomib plus dexamethasone [Kd]…I tend not to reach for that kind of therapy. For a lenalidomide-refractory patients, elotuzumab [Empliciti], lenalidomide, and dexamethasone is perhaps not the best pairing, but there are pomalidomide [Pomalyst] and selinexor [Xpovio] regimens. I think selinexor is a great drug. I know not everybody feels great about it. The way it was used as monotherapy was extremely toxic, but I like it as a once-weekly drug and we use a lot of it.

How do you approach evaluating the trials of the category 1 regimens for lenalidomide-refractory RRMM?

We get a median progression-free survival [PFS] of about 5.5 years after [first-line lenalidomide, bortezomib, dexamethasone] and autologous stem cell transplant.² But we know with each subsequent relapse, myeloma becomes more resistant, PFS becomes shorter, and responses become lower.

Maybe the best way to break down [the trials] is to look at the median PFS that we may expect with single agents [plus dexamethasone in the comparator arms of these trials]. With pomalidomide and dexamethasone [Pd] from the ICARIA-MM [NCT02990338] and the APOLLO [NCT03180736] studies, we may expect a median PFS of 6 to 7 months for these patients,^3,4 and for patients receiving bortezomib plus dexamethasone [Vd], another 7 months [based on CASTOR (NCT02136134) and OPTIMISMM (NCT01734928)].^5,6 Carfilzomib, being a more potent proteasome inhibitor, as a single agent we may get 15 to 20 months median PFS [based on CANDOR (NCT03158688)].⁷ So what we‘re looking at is what can we pair these drugs with, and how can we improve those numbers, if that‘s what we are expecting.

We have several different studies. We havethe IKEMA trial [NCT03275285], which was for isatuximab, also a CD38 monoclonal antibody. The No. 1 question I get is, what makes it different [from daratumumab]? It targets a different epitope. I have a lot of times where I love using isatuximab for a couple of very specific instances…. But the IKEMA data are extremely impressive. Without trying to cross-compare the median PFS in this particular study, 41.7 months is fairly impressive [in the context of] 28, 24, 16, 11, 12, and 11 months median PFS [in the experimental arms of the CANDOR, CASTOR, ICARIA-MM, APOLLO, and OPTIMISMM trials, respectively].^3-8

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 3.2024. Accessed April 2, 2024. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf

2. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925

3. Richardson PG, Perrot A, San-Miguel J, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022;23(3):416-427. doi:10.1016/S1470-2045(22)00019-5

4. Dimopoulos MA, Terpos E, Boccadoro M, et al. 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

5. Spencer A, Lentzsch S, Weisel K, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103(12):2079-2087. doi:10.3324/haematol.2018.194118

6. Richardson PG, Oriol A, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781-794. doi:10.1016/S1470-2045(19)30152-4

7. 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

8. Facon T, Moreau P, Spicka I, et al. Long-term outcomes with isatuximab-carfilzomib-dexamethasone (Isa-Kd) in relapsed multiple myeloma patients with 1q21+ status: Updated results from the phase 3 IKEMA study. J Clin Oncol. 2023;41(16):8029. doi:10.1200/JCO.2023.41.16_suppl.8029