A registry study of relapsed or refractory multiple myeloma pre‐exposed to three or more prior therapies including a proteasome inhibitor, an immunomodulatory agent and CD38‐targeted monoclonal antibody therapy in England

Abstract Some patients with multiple myeloma are receiving treatment in clinical practice in England after prior exposure to a proteasome inhibitor, an immunomodulatory agent, and an anti‐CD38 monoclonal antibody. We investigated the characteristics of these patients, their outcomes, and the salvage therapies they received using the national cancer registry for England and linked healthcare data. After a median follow‐up time of 6.4 months from T 0, median overall survival and time to next treatment were 8.2 and 5.3 months, respectively. This real‐world data provide useful clinical insight into a little‐studied patient population and highlight the poor outcomes in the UK setting.


INTRODUCTION
The advent of anti-CD38 monoclonal antibodies (MoABs) has led a new relapsed or refractory multiple myeloma (RRMM) population to emerge in recent years encompassing patients pre-exposed to at least one proteasome inhibitors (PI), one immunomodulatory agent (IMiD), and an anti-CD38 MoAB, separately or in combination (hereafter referred to as 'triple-class exposed'). In England, National Health Service (NHS) patients pre-treated with a PI and IMiD will generally become triple-class exposed upon receiving anti-CD38 MoAB-based therapy after 1 [1] or, more commonly, 3 [2,3] prior lines of treatment (LOTs) since second-line CD38-targeted therapy has become available relatively recently [1].
Few options are available for the treatment of triple-class-exposed RRMM [4]; these include conventional chemotherapy, salvage autologous stem cell transplantation, and/or re-treatment with previously received regimens [4]. Recently, the first treatment post CD38targeted therapy -belantamab mafodotin -was approved in Europe, although this is not currently available on the NHS.
There are very limited data on triple-class-exposed RRMM, but what data there are point toward the poor prognosis in US patients [5,6] and more so in UK patients [7,8]. To this end, we set up a retrospective cohort study to describe the clinical picture of heavily pre-treated (after three prior LOTs), triple-class-exposed RRMM in England.

METHODS
The study utilised several linked datasets available through the Dataset (NCRD) [9], Hospital Episode Statistics database (HES) [10], and the Systemic Anti-Cancer Therapy dataset (SACT) [11]. As LOTs are not reported in SACT, they were derived using a regimen-based algorithm (Supporting Information Materials Section S2).

To identify patients with refractory disease per International
Myeloma Working Group (IMWG) [12], we utilised the duration of the treatment-free interval between LOT, as information reflecting the formal IMWG criteria is not readily available in the SACT dataset. In consultation with clinicians, refractory disease to a prior therapy was defined whenever patients started the next LOT ≤60 days after ending the preceding LOT, assuming that in clinical practice, patients whose disease becomes refractory to a LOT are likely to move to the next LOT within 2 months to prevent organ damage. The 60-day treatment-free interval was also utilised in a validated algorithm to derive refractory status [13].

RESULTS
The cohort had 366 patients (Supporting Information Materials Section S3). Median follow-up time was 6.4 months from T 0 (95% CI 5.9- For over 65% of the patients, the index LOT consisted of a pomalidomide-based regimen ( Table 1). The next most used therapy, albeit after a large gap, is panobinostat plus bortezomib, with around 10% of patients receiving it as their index LOT. Demographics, baseline characteristics, and prior therapy are described in Table 2.

DISCUSSION
To our knowledge, this study is the first to investigate triple-class-  -there is substantial unmet need associated with triple-class-exposed RRMM where quality of life worsens, disease burden increases, organ function continues to be impaired, and long-term exposure to successive treatments requires strategies to manage cumulative toxicities [14]. Median TTNT, reflecting several factors including end-organ damage, patient preference, and the nature of relapse (indolent vs. proliferative) [13], is also considerably short at 5.3 months. Furthermore, upon disease progression, patients are left with few, suboptimal treatment options [4], highlighting the need to recruit into clinical trials for investigational targets.
In our study, only 1295 (4.6%) of all MM patients in England diagnosed between 2013 and 2018 were triple-class exposed. This will increase in the future as CD-38 targeted therapy is now routinely available and moving up the treatment pathway. In fact, regimens combining all three drug classes are being developed for first-line treatment [15], so some patients may soon become triple-class exposed on their first LOT, highlighting the need for novel treatment modalities as the disease becomes increasingly difficult to treat in earlier settings.