Multidrug Treatments Investigated in Smoldering Multiple Myeloma


Irene Ghobrial, MD discusses multiple trials and their significance for treating patients with smoldering multiple myeloma and newly diagnosed multiple myeloma.

Irene Ghobrial, MD, director of the Clinical Investigator Research Program at Dana-Farber Cancer Institute, Lavine Family Chair for Preventative Cancer Therapies, and professor of medicine at Harvard Medical School, discusses multiple trials and their significance for treating patients with smoldering multiple myeloma (SMM) and newly diagnosed multiple myeloma (NDMM).

Ongoing studies on the efficacy and safety of 3-drug treatments for SMM and NDMM have the potential to improve progression-free survival (PFS) versus the standard of care of lenalidomide (Revlimid) and dexamethasone.

Orally administered lenalidomide (Revlimid) and dexamethasone have been found to result in a significant improvement in PFS in SMM. New trials have evaluated the efficacy of 3-drug regimens. The MAIA phase 3 trial (NCT02252172) combines daratumumab (Darzalex), an anti-CD38 monoclonal antibody, with lenalidomide/dexamethasone in 737 patients with NDMM. Another phase 3 ITHACA trial (NCT04270409) of an estimated 323 patients with high-risk SMM explores the addition of isatuximab (Sarclisa) to lenalidomide/dexamethasone.

Interim results of the MAIA trial in the New England Journal of Medicine concluded that daratumumab led to significantly longer PFS and a 44% lower risk of disease progression or death than lenalidomide/dexamethasone alone. The ITHACA study is ongoing and has not yielded results on isatuximab’s efficacy.

Other combinations being investigated include daratumumab, bortezomib (Velcade), lenalidomide, dexamethasone (RVd) and daratumumab, carfilzomib (Kyprolis), lenalidomide, dexamethasone (KRd).


0:08 | Now once we started saying, "Well, what can we do to intercept smoldering myeloma? What can you do to truly prevent the end organ damage?” The original studies were using lenalidomide and dexamethasone, which is simple oral [regimen], and indeed it shows a huge difference in PFS, and in one study, overall survival benefit. Building on that, there are now 2 phase 3 studies, including the ITHACA study and ECOG study. The ITHACA study is asking the question, can we add an antibody to CD38, which is isatuximab to lenalidomide and dexamethasone compared to lenalidomide and dexamethasone, which is the standard of care. The ECOG study [MAIA] is now comparing daratumumab to lenalidomide and dexamethasone versus lenalidomide and dexamethasone. And both of them are asking a 3-drug vs 2-drug question.

Now, there are other studies that are asking, "Can I bring smoldering myeloma therapy as if you're treating active myeloma and can I bring the active myeloma therapy earlier?" So, these are the 4-drug regimens, which is the best we have right now for active myeloma. And with that, we have either the daratumumab plus KRd study by Maria Mateos, [MD, PhD], in Spain [NCT01998971], or by Shaji Kumar, [MD], in the United States [NCT01863550], or we have the daratumumab plus RVd study [NCT04775550] by Omar Nadeem, [MD], at Dana-Farber; all of those studies are asking [about different] 4-drug regimens.

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