Multiple myeloma (MM) is an incurable malignant plasma cell disorder [1
]. Treatment options for MM have expanded with the introduction of several classes of novel agents, which improve the prognosis considerably [2
]. However, almost all patients will eventually relapse and require further treatment. Determining the optimal salvage regimen at first relapse remains challenging, as numerous factors need to be considered, including prior treatment used as well as the depth and duration of response [4
]. Unfortunately, the further response is usually inferior to initial treatment with progressively shorter duration of remission [6
Therapeutic decisions for first relapse patients should be approached with the use of results from randomized trials in the relapsed setting, which have shown the superiority of triplet (triple combination) in terms of response and progression free survival [7
]. Even so, there are still multiple possibilities and the decision is always influenced by a patient’s functional status and comorbidities. In addition, cost is an unavoidable concern in view of the huge economic disparities, especially for triplet regimens with two novel agents [13
]. Therefore, the decision is not easily justified by using trial data alone, but by gaining more information from real-world practice, which is adapted according to personal resources, healthcare infrastructure, and even local cultures [14
Rising incidence of MM in Asia has been reported, and there are approximately 100 newly diagnosed cases per year in Singapore [15
]. Given the drastic changes of treatment approach and increasing access to novel agents in our daily practice, it is important to study the natural history of first relapsed MM in a real-world setting. Herein, we described the real-world assessment of patients with first relapsed MM, with a focus on identifying prognostic factors for post-relapse survival.
Although MM remains incurable, novel agents have drastically changed the treatment paradigms and offered various possibilities. The choice of treatment at first relapse is critical, as subsequent remissions are typically shorter [6
]. However, the optimal treatment sequence has not been well defined. Recent randomized trials showed the superiority of triplet with two novel agents in the relapsed setting, with a deeper response, higher remission rate, and longer PFS [7
]. Of note, the unprecedented hazard ratios of PFS achieved by adding daratumumab triggered great enthusiasm to consider a daratumumab-based regimen as the preferred choice at first relapse [11
]. However, the decision always needs to be adapted to not only the patient’s characteristics, but costs and availabilities of novel agents. Therefore, it is particularly interesting to study the natural history of first relapsed MM patients in a real-world setting, which could show the salvage treatment chosen during daily practice and hopefully help to identify prognostic factors determining outcomes after relapse.
Our study described clinical features, salvage treatment, and survival outcomes of first relapsed MM patients seen between 2004 and 2019 from two tertiary institutes in Singapore. It is informative to compare the findings of our study with a previous similar study that included relapsed MM patients between 1985 and 1998, the period before novel agents were available [6
]. The study showed the median response duration of initial and salvage treatment as 9.9 and 7.3 months, respectively, which were significantly shorter than our observation. In addition, the median OS from salvage was 17.1 months, as compared with 44.8 months in our current cohort. Both findings are most probably due to increasing access to novel agents during the period of our study, which is also reflected by using newer agents during salvage compared to initial treatment in our cohort. The use of these agents in not only first but subsequent relapses may also explain the significant difference between median PFS and OS in our cohort, implying a chance of successful salvage even after two lines of therapy.
It is important to understand the prognostic factors for MM patients at first relapse, which could guide therapeutic decisions at salvage. Most data on well-known prognostic factors, including a patient’s characteristics (e.g., age and functional status), staging, and disease features (e.g., metaphase cytogenetics and FISH), are from the time of diagnosis [20
]. Their particular values at relapse are not fully clear but are often used to identify high-risk patients in trials. In addition, more parameters, especially initial treatment and features at first relapse, also deserve careful consideration. The three prognostic factors that affect survival after first relapse identified in our study have their unique clinical relevance. Non-hyperdiploid karyotype at diagnosis may identify a more proliferative underlying myeloma clone and has recently demonstrated its consistency with FISH to predict high-risk patients at diagnosis [21
]. Although not informative in the majority of patients, in those with abnormal non-hyperdiploid karyotype, this clearly identifies a subgroup of myeloma with aggressive biology that is associated with difficult salvage and poor post-relapse survival, even in the modern era with novel therapies [22
]. In addition, type of relapse also reflects the aggressiveness of disease, and clinical relapse correlates with inferior outcome [24
]. So far, there is no clear consensus regarding the best regimen at first relapse; therefore, treatment sequence is an area of interest to explore. Although the current study is not designed to demonstrate the significance of a particular sequence, our result is consistent with the notion that at least one novel agent that the patient was never exposed to previously should be used, either by switching the therapeutic backbone or incorporating it directly, which is supported by the idea that initial treatment provides a selective pressure for resistant clones underlying disease relapse [25
It is also interesting to note that ISS, LDH, and high-risk FISH, three traditional prognostic factors at diagnosis, are not significant for post-first relapse survival. These prognostic factors are derived and established in large datasets of newly diagnosed patients; however, the role of baseline ISS, LDH, and FISH in post-relapse outcome has not been systematically studied. Despite this, they are always used as variables to define high-risk disease in the relapse setting. Our study suggests that there may be other more important factors in determining post-relapse survival. One important caveat is that our cut-off for 17p13 del is 10%. Studies have shown that it is those with a high clonal fraction of 17p13 deletion that have poorer prognosis [28
]. This may have affected the prognostic impact of high-risk FISH in our cohort. However, due to the low number, this is unlikely to have a statistically significant impact.
Salvage response was not incorporated into our initial multivariate analysis, as (1) we would like to explore the factors impacting outcome that could help therapeutic decision making before commencement of salvage and (2) there is a well-known relationship between the depth of response and outcome in the relapsed setting [29
]. As expected, there is a significant association between the salvage response and survival.
Our study has its limitations due to its retrospective nature. First, assessment at relapse is not fully standardized and metaphase cytogenetics as well as FISH are not available for most cases. Therefore, we cannot make any conclusions about the usefulness of FISH or metaphase cytogenetics at relapse. Second, the prognostic value of a specific salvage regimen or sequence is not assessable in view of limited cases of each therapy. In addition, the impact of lenalidomide maintenance is not evaluated, as the study period spans over 15 years, a time when major changes in lenalidomide use, its accessibility, and our local government reimbursement have occurred.