Introduction: Patients with RRMM who have been exposed to 4 classes of treatment (quadruple-class exposed; QCEx) with proteasome inhibitors (PI), immunomodulatory drugs (IMiD), anti-CD38 antibodies (anti-CD38), and anti-B-cell maturation antigen (BCMA) therapies face poor prognoses and lack an established standard of care. This study tracked treatment journeys of this population across lines of therapy (LoT), documenting clinical outcomes and highlighting critical unmet needs for novel therapeutic options.

Methods: We conducted a retrospective study using the Flatiron Database (Jan 1, 2011-Dec 31, 2024), which is derived from Electronic Health Records in US community oncology practices and cancer centers. Eligible patients had a diagnosis of MM; received treatments with a PI, IMiD, anti-CD38, and anti-BCMA therapy (QCEx); and subsequently initiated a new therapy (index therapy). Patient and disease characteristics were summarized using descriptive statistics. Patients' treatment journeys after QCEx were illustrated with Sankey plots. Event (progression, next treatment, or death)-free survival (EFS) and overall survival (OS) since the index therapy start date (index date) were estimated using the Kaplan-Meier method.

Results: A total of 533 patients with QCEx RRMM were identified. Among these patients, 208 (39%) initiated an index therapy, 99 (19%) proceeded to the first post-index LoT, 44 (8%) to the second, and 23 (4%) to the third. Notably, 97 patients (18%) died before receiving any index therapy. The proportion of patients who died before starting the next LoT was 25% (51/208) after the index therapy, 26% (26/99) after the first post-index LoT, and 25% (11/44) after the second post-index LoT.

At the time of index therapy (n=208), patients had a median age of 67 years (range: 37-85), 98% had Revised International Staging System (RISS) stage II-III, 18% had high tumor burden, and 44% had high-risk cytogenetics. At index, patients had a median of 6 prior LoT (range: 1-15), 91% were triple-class (PI, IMiD, anti-CD38) refractory, and 50% were quad-class (PI, IMiD, anti-CD38, anti-BCMA) refractory. Index therapies were received between 2020 and 2024 in community (55%), academic (36%), or both settings (9%).

The most common (≥5%) drug classes for the index therapy were GPRC5D bispecific antibody (BsAb; 13%), anti-BCMA (12%), chemo (11%), and PI+chemo (7%); for the first post-index LoT were anti-BCMA (30%), chemo (14%), IMiD+others (8%), and GPRC5D BsAb (6%); for the second post-index LoT were anti-BCMA (18%), chemo (11%), anti-BCMA+chemo (7%), GPRC5D BsAb (7%), PI+chemo (7%), PI+others (7%), and IMiD+others (7%); and for the third post-index LoT were anti-BCMA (17%), chemo (17%), PI+others (9%), and GPRC5D BsAb (9%).

The most common (≥5%) agents were talquetamab (13%) and teclistamab (8%) for the index therapy; teclistamab (20%), talquetamab (6%), and elotuzumab+pomalidomide+dexamethasone (5%) for the first post-index LoT; teclistamab (11%) and talquetamab (7%) for the second post-index LoT; and ciltacabtagene autoleucel (13%), talquetamab (9%), and cyclophosphamide+doxorubicin+etoposide (9%) for the third post-index LoT. Clinical study drugs, either as monotherapy or in combination with approved agents, were also used in 8% of patients for the index therapy, and in 5%, 9%, and 13% of patients for the first, second, and third post-index LoTs, respectively.

After a median follow-up of 7.8 mo (range 0.1-49.1) since the index date, 76% (158/208) of patients had an EFS event and 48% (99/208) of patients died. Median EFS and OS were 4.6 mo (95% CI, 3.9-5.8) and 15.6 mo (95% CI, 11.5-24.5), respectively.

Conclusions: This real-world study highlights the profound clinical challenges faced by patients with QCEx RRMM. In this heavily pretreated population, often with triple- or quadruple-class refractory disease, nearly one-fifth died before initiating any subsequent therapy, and approximately one-quarter died before advancing through each additional LoT. Clinical outcomes were poor, with rapid disease progression and limited survival duration, reflecting the aggressive nature of the disease and the limited efficacy of currently available treatments. Early intervention with novel and effective therapies is crucial to improving outcomes and reducing mortality in patients with QCEx RRMM.

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2025
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