Based on available treatment guidelines [2,3], most patients who reach second-line therapy have already been exposed to lenalidomide. “But this is not the only point. We are also going to see more patients who have been at least pretreated with or are refractory to daratumumab and bortezomib,” said Dr Gay.
Drawing from this note, Dr Gay mentioned that there are no optimal definitions of refractoriness. Does it mean relapsing under treatment? And if so, do the dose and schedule matter? Or does it mean relapsing after the end of treatment, and if yes, after how much time?
How can the subsequent therapy be chosen? “In my opinion, it is always better to switch drug class,” said Dr Gay. Based on the prior exposure to lenalidomide, proteasome inhibitors (PIs) or a combination of lenalidomide plus PIs plus CD38 targeted therapies, 4 broad categories can be drawn for subsequent lines: therapies with a lenalidomide backbone, PI backbone, pomalidomide backbone, and novel immunotherapies [1].
Treatment selection must take into consideration several factors: disease related factors (risk status, aggressiveness, renal disease), treatment related factors (expected efficacy, time to first response, toxicity, need for dose reductions), and patient related factors (age, frailty, performance status, comorbidities, organ function, patient preference). Next to these, use of prior therapies as well as response and toxicity should be considered [1].
Lenalidomide backbone therapies include daratumumab plus lenalidomide-dexamethasone (Rd) (DRd; POLLUX trial), elotuzumab-Rd (EloRd; ELOQUENT-2 trial), carfilzomib-Rd (KRd; ASPIRE trial), and ixazomib-Rd (TOURNMALINE-MM1), while PI backbone and anti-CD38 backbone therapies include daratumumab-bortezomib-dexamethasone (DVd; CASTOR trial), carfizomib-dexamethasone-daratumumab (KdD; CANDOR trial) and Isatuximab-carfilzomib-dexamethasone (IsaKd; IKEMA trial). There is also the option of using a pomalidomide backbone with therapies such as pomalidomide-bortezomib-dexamethasone (PVd; OPTIMISMM trial), and daratumumab-pomalidomide-dexamethasone (DPd; APOLLO trial), and in certain cases a bortezomib backbone such as selinexor plus bortezomib-dexamethasone (SVd; BOSTON trial) and venetoclax plus bortezomib-dexamethasone (in patients with t(11;14) or high BCL2) [1].
Currently available therapies include BCMA-targeted CAR T-cell therapies (ide-cel and cilta-cel), BCMA-targeted bispecific antibodies (teclistamab, elranatamab), and GPRC5D-targeted bispecific antibodies (talquetamab). The antibody-drug conjugate belantamab mafodotin was previously available as a single agent therapy, but conditional approval has been since removed in both the USA and Europe. It is currently under investigation in combination with bortezomib-dexamethasone and has shown positive results in DREAMM-7 [1].
“We have highly effective, novel triplets available in the treatment of relapsed/refractory multiple myeloma, also in the setting of lenalidomide-refractory patients,” concluded Dr Gray. “The treatment choice is dependent on therapy-, tumour-, and patient-related factors and the new unmet need is double-refractoriness to immune modulatory agents and monoclonal antibodies and, in particular, this is addressed by new immune therapies which represent the new standard-of-care after the third line of therapy”.
- Gay F, et al. Treatment algorithm at first relapses. Session VI: RRMM patients. EMN 2024, 18–20 April, Turin, Italy.
- Dimopoulos MA, et al. Ann Oncol. 2021;32(3):309-322.
- Moreau P, et al. Lancet Oncol. 2021;22(3):e105-e118.
Medical writing support was provided by Mihai Surducan, PhD.
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