Effect of novel agents on the risk of early death of newly diagnosed symptomatic multiple myeloma patients: A single Centre retrospective analysis
Authors: Monica Galli, Laura Paris, Chiara Pavoni, Federica Delaini, Alessandro Rambaldi
Journal: American Journal of Hematology (2018)

Incorporation of novel agents (ie, proteasome inhibitors, bortezomib and carfilzomib, and immunomodulatory drugs, thalidomide and lenalidomide) in the first line treatment of patients suffering from multiple myeloma (MM) has led to an unprecedented improvement in clinical outcomes1. Nonetheless, a substantial proportion of patients still dies early in the course of treatment, mostly due to infections. Male gender, hypercalcemia, increased LDH serum level, decreased albumin serum level, renal failure, low body mass index, high Charlson comorbidity index, thrombocytopenia and plasma cell leukemia have been identified as predictors of an increased risk of early death (ED).2 It is worth noting, that some of these risk factors exclude patients from enrollment in clinical trials, thus making it difficult to extrapolate their results to daily practice. In reality, if regulatory Agencies make novel agents available outside of clinical trials, more and more elderly and/or fragile patients are likely to receive them. Whether these patients also benefit from programs containing one or more novel agents has not been clearly established yet. We hereby analyzed the clinical outcomes of 991 unselected newly diagnosed MM patients, consecutively treated before and after the introduction of novel agents-containing programs. We focused on their risk of ED, defined as the death occurring within 90 days from diagnosis of symptomatic MM. Details on source of data, treatments of MM and statistical analysis are reported in Supplemental Material. The consort diagram of MM patients diagnosed between 1997 and 2015 is shown in Supporting Information Figure S1. The main demographic data of the patients who started their medical treatment at our Institution is shown in Supplemental Table. During the 18 years of analysis, 708 patients (71.4%) died. Of them, 92 patients died ≤90 days (ED cohort) (9.3% of the entire patients' population and 13% of all deaths) from starting treatment (Supporting Information Figure S1). By univariate and multivariate analysis, older age, lambda light chain, stage B, and plasma cell leukemia were significantly more common in the ED group patients, whereas incorporation of at least a novel agent in the first line treatment resulted in a significant reduction of ED (Table 1). This beneficial effect was only seen in patients not enrolled in high-dose treatment with autotransplantation (ASCT) programs, in whom the incorporation of novel drugs reduced the prevalence of ED from 22% to 9% (adjusted odds ratio 0.09, 95% CI 0.03-0.22, P < .0001). Conversely, the prevalence of ED of patients enrolled in ASCT programs was 7% irrespective of inclusion of novel agents in induction. Information about the cause of ED was available in 65 (71%) patients: progression of MM (n = 34), infections (n = 16), cardio-vascular complications (n = 13), hepatotoxicity (n = 1), other cause while in partial remission (n = 1). ED has been defined quite differently in the studies. We set its cut-off at 90 days from starting treatment, in order to focus on the role of the first line treatment and to avoid the confounding effect of further therapies on this clinical outcome. Indeed, among the ED cohort only one patient received a second line treatment. The prevalence of ED in our cohort closely resembles that reported by a tertiary care Korean Institution.3 These Authors found pneumonia to be the leading cause of ED of a large group of newly diagnosed MM patients. Bacterial and viral infections show a bimodal incidence in patients with MM, the first peak occurring during the induction phase and the second one at the time of relapse/recurrence. This coincides with moments in which MM requires treatment and is not yet under proper control. Although we were unable to analyze in detail the role of infections as cause of ED in our cohort, their contributing role is highly likely, since infections were documented in approximately one quarter of our MM patients at the time of death. Antiviral prophylaxis was routinely administered to our patients receiving a novel agent. In contrast, we did not administer antibiotics prophylaxis during the first 90 days of treatment, unless in the case of neutropenia or in high-risk situations. However, our policy is going to change on the basis of the recently reported results of a large randomized clinical study,4 which showed that prophylactic use of 12 weeks levofloxacin reduced febrile episodes and deaths in patients undergoing MM treatment. Our data confirms that the upfront treatment with novel agents significantly decreases the rate of ED of MM patients. Not unexpectedly, this effect was restricted to patients not enrolled in ASCT programs, due to the evident selection bias inherent in being eligible for ASCT. Over time we observed the decrease of the number of patients eligible for ASCT, which goes well along with the increase of the number of elderly patients. This does not support the possibility that the exposure to novel agents is just a surrogate for selecting younger and fitter patients, who are less likely to experience ED. The contribution of supportive therapy with bisphosphonates to treat skeletal involvement and hypercalcemia to the reduction in ED rate is questionable, as we should have observed this effect also in patients enrolled in ASCT programs. Renal failure, lambda light chain and plasma cell leukemia were independent factors of ED, indicating that an aggressive MM presentation adversely affects the survival probability of the patients. In a previous study, we showed that dialysis dependance was the strongest negative predictor of outcome among 71 newly diagnosed stage B MM patients, because none of the patients on dialysis who entered high-dose therapy with ASCT went further enough through the program to actually receive the ASCT procedure. Dimopoulos et al.5 showed that bortezomib-based induction treatments caused 49% independence from dialysis among 52 newly diagnosed MM patients with severe renal failure. Nevertheless, a 16% ED rate was reported, which was mostly due to infections. Our observation of increased ED of patients with lambda light chain MM is not surprising, since this light chain is more commonly observed in patients with amyloid deposits, which may negatively affect organ function. We may only speculate about such a role in our patients, because we did not routinely look for the presence of AL amyloidosis. Primary plasma cell leukemia is a very severe and aggressive form of MM, which is associated with a poor prognosis. A recent phase II prospective French trial6 enrolled 40 patients aged <70 years with primary plasma cell leukemia, who received an alternate regimen combining standard chemotherapy, bortezomib, and ASCT followed by either allogeneic transplantation or bortezomib/lenalidomide maintenance. Three patients died of sepsis, one of them within 1 day from enrolment. The improvement in ED by novel agents goes well along with that of overall survival (OS) in all patients, irrespective of age groups (Supporting Information Figures S2A-C). The doubling of the median OS of patients aged >70 years is particularly noticeable, even though a 2.5 years median OS remains rather dismal and leaves ample room for improvement. A net gain of 2 years in median survival was also obtained among younger patients. The use of novel agents in the salvage treatments also contributed to prolonging the survival of the patients after relapse. Indeed, 70% of our patients who were treated without novel agents in the first line setting received one or more of them in the salvage treatment programs. The analysis of progression-free survival allows one to focus on the effect of the first line treatment: again, the incorporation of novel agents improved this outcome, which, nevertheless, remains poor (Supporting Information). Our study has some points of strength and some limitations as well. Referring to the former, the large number of patients enrolled, the lack of patients'selection, and the long period under analysis. With respect to the latter, the retrospective design of the study and the partial unavailability of data on prognostic factors and of information on comorbidities, which did not allow us to evaluate the role of the international prognostic index and frailty score on ED. Also the partial unavailability of data on toxic effects of treatments was rather a limitation of this study. In conclusion, our study confirms that the inclusion of novel agents in the initial treatment is of the utmost importance, because it creates a positive loop, in which the quick improvement of the general conditions and of hematological and biochemical parameters allows the timely administration of the most appropriate antiMM treatment, which, in turn, reduces ED rate and ameliorates MM survival. We wish to thank Mrs Lesley Gowland for reviewing the article. This study was partly supported by Associazione Italiana lotta alla leucemia - Sezione “Paolo Belli, Bergamo”. Nothing to report Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.