Second-line therapy for multiple myeloma: Where we are now?

There are a multitude of treatment options available for patients with newly diagnosed multiple myeloma [1]. However, many patients relapse following their first-line treatment and will require subsequent therapy [2]. Dr Francesca Gay (University of Torino, Italy) discussed available therapies in the second line and beyond, as well as factors which can be used for treatment selection [3].

Based on available treatment guidelines, most patients who reach second-line therapy have already been exposed to lenalidomide [4,5]. “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.

How do we choose a suited subsequent therapy? “In my opinion, it is always better to switch drug class,” said Dr Gay [6]. Based on prior exposure to lenalidomide, proteasome inhibitors (PIs), or a combination of lenalidomide, PIs, and CD38-targeted therapies, subsequent lines can exist of therapies with a lenalidomide backbone, PI backbone, pomalidomide backbone, or novel immunotherapies [2].

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) (see Figure) [2]. Next to these, use of prior therapies as well as response and toxicity should be considered [2].

Figure: Relevant parameters for treatment selection in RRMM patients [2]



AE, adverse events; LDH, lactate dehydrogenase; R-ISS, revised international staging system; R-MCI, revised myeloma comorbidity index.

Reprinted from Gengenbach L, et al. Cancers. 2021;13(17):4320. DOI:10.3390/cancers13174320, under the terms of the Creative Commons Attribution (CC BY) license.

Triplet combinations can be used after a first relapse, including PIs and/or immunomodulatory drugs  and/or monoclonal antibodies [2]. Following a bortezomib- and dexamethasone-based first-line therapy (without lenalidomide or daratumumab), lenalidomide-dexamethasone-based regimens are recommended [2]. Lenalidomide-dexamethasone backbone therapies include daratumumab plus lenalidomide-dexamethasone (DRd; POLLUX) [7], elotuzumab plus lenalidomide-dexamethasone (EloRd; ELOQUENT-2) [8], carfilzomib plus lenalidomide-dexamethasone (KRd; ASPIRE) [9], and ixazomib plus lenalidomide-dexamethasone (TOURNMALINE-MM1) [10].

Patients refractory to lenalidomide can switch to bortezomib-dexamethasone (Vd)-, carfilzomib- dexamethasone (Kd)-, or pomalidomide-dexamethasone (Pd)-based regimens. Including for example, daratumumab plus bortezomib-dexamethasone (DVd; CASTOR) [11], carfilzomib plus daratumumab-dexamethasone (KdD; CANDOR) [12], Isatuximab plus carfilzomib-dexamethasone (IsaKd; IKEMA) [13], pomalidomide plus bortezomib-dexamethasone (PVd; OPTIMISMM) [14], and daratumumab plus pomalidomide-dexamethasone (DPd; APOLLO) [15].

Ongoing trials in early relapse (≥1 prior lines) with novel therapies include B cell maturation antigen (BCMA)-targeted CAR T-cell therapies (ciltacabtagene autoleucel [cilta-cel] [16]), BCMA-targeted bispecific antibodies (teclistamab [17,18], elranatamab [19]), and GPRC5D-targeted bispecific antibodies (talquetamab [20]). The antibody-drug conjugate belantamab-mafodotin, previously available as a single-agent therapy, is currently under investigation in combination with bortezomib-dexamethasone and has shown positive results in DREAMM-7 [21].

“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 [2]. “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” [2].

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Posted on 23 April 202410 December 2024