Stage B multiple myeloma patients: a long-term, single center outcomes research study

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1 DCTH ORIGINAL ARTICLE Stage B multiple myeloma patients: a long-term, single center outcomes research study Monica Galli 1, Ettore Sabadini 2, Paola Stefanoni 1, Federica Delaini 1, Elena Oldani 1, Alessandro Rambaldi 1 1 Unit of Hematology; 2 Unit of Nephrology, Ospedale Papa Giovanni XXIII, Bergamo, Italy SUMMARY The major determinants of treatment respoe were analyzed in 71 newly diagnosed stage B multiple myeloma (MM) patients, whose treatment allocation was based on age and performance status but not on serum creatinine. Forty-one patients entered programs of high-dose therapy (HDT) with autotraplantation (autotx), while the other 30 received non-autotx-based therapies. At the end of the treatment program, serum creatinine returned below 2 mg/dl in 65% of patients. The median overall survival (OS) and event-free survival (EFS) of the 41 patients who entered programs of HDT were 32 and 26 months, respectively, which increased to 41 and 32 months for the 28 patients who received at least one autotx. The other 30 patients allocated to non autotx-based therapies had median OS and EFS of 17 and 14 months. Overall, 60% of patients reached at least a partial respoe. Requirement of dialysis at diagnosis was the strongest independent predictor of worse OS and EFS. Anemia, hypercalcemia and Bence Jones positive proteinuria were adverse predictors of EFS. In conclusion, an appropriate treatment of stage B-MM patients allows restoring a normal renal function in the majority of the cases. When feasible, HDT and autotx represent an important treatment option also for these patients. INTRODUCTION A variable degree of renal failure occurs in approximately 20-40% of patients with newly diagnosed multiple myeloma (MM) (1). Precipitation of Key words: multiple myeloma, renal failure, stage B, autotraplantation. Correspondence: Monica Galli Unit of Hematology Ospedale Papa Giovanni XXIII L.go OMS, Bergamo, Italy [email protected] monoclonal light chai (LC) in the distal tubules, hypercalcemia, dehydration, hyperuricemia and use of potentially nephrotoxic drugs are coidered the main causes of renal failure in these patients. Results from treatment of MM patients presenting with renal failure (stage B-MM) are generally poor, as most of them are not coidered eligible for high-dose treatment (HDT) and autotraplantation (auto- Tx) programs. A few studies on the outcome of stage B-MM patients treated with HDT and autotx suggested that this treatment modality is feasible (2-6), may revert

2 14 M. Galli, et al. renal failure (7) and improve overall survival (OS) and event-free survival (EFS), although morbidity and mortality remain substantial. In our Hospital, HDT and autotx is the treatment of choice for all newly diagnosed symptomatic MM patients aged up to 65 years and also for selected patients aged up to 70 years. Conversely, renal failure at diagnosis does not represent per se an exclusion criterion. Here, we describe the overall long-term (up to more than 10 years) outcomes of a large series of uelected, coecutive, newly diagnosed stage B-MM patients, treated - in most cases - before that the so-called new drugs (i.e., thalidomide, lenalidomide and bortezomib) became widely available. MATERIALS AND METHODS Source of data The Outcomes Research in Oncology (ORO) study was set up in 1999 to evaluate the relatiohip between patter of care and long-term outcomes in selected groups of neoplasms, among which there is MM. Data were collected using an ad hoc specifically developed data base containing all relevant information (8). Patients From January 1997 to December 2009, 742 patients were referred to our Hospital for newly diagnosed MM. Of them, 130 (18%) were asymptomatic (stage IA according to Durie and Salmon) (9) and the other 612 (82%) had symptomatic MM (10). Among this latter group of patients, 110 (18%) presented with renal failure, as defined by a serum creatinine level >2 mg/ TABLE 1 Demographics and laboratory data of 71 stage B-multiple myeloma patients at diagnosis. Gender M/F 41/30 Age, years Median (range) 65 (31-90) Type of MM G/A/D Light chain Non secretory Plasma cell leukemia 34/9/ Durie & Salmon stage I/II/III 4/4/63 Serum creatinine, mg/dl Median (range) 3.75 ( ) Serum calcium, mg/dl Median (range) 9.7 ( ) Serum calcium >12 mg/dl No. of patients (%) 16/64 (25) Hemoglobin, g/dl Median (range) 8.40 ( ) Bence Jones positive proteinuria, g/dl Median (range) Positive but not quantified, No. Not available, No (0-35.0) 8 13 b2-microglobulin >3.5 mg/dl No. of patients (%) 5/30 (17) MM, multiple myeloma. dl (stage B, according to Durie and Salmon) (9). After the initial diagnosis of stage B-MM, 39 patients received their treatment in other hospitals. Therefore, the present analysis includes the 71 patients who were regularly treated and followed-up at our Centers. Table 1 shows their main demographics and laboratory data at diagnosis. At the time of diagnosis 15 patients (21%) were on dialysis. The presence of amyloid light-chain amyloidosis was not routinely investigated, as no

3 Stage B multiple myeloma patients: a long-term, single center outcomes research study 15 patient underwent fine needle aspiration of peri-umbelical fat. Renal biopsies were performed in only 6 patients: five of them showed findings coistent with light chain deposition disease and the remaining one had evidence of tubulointerstitial nephropathy. Conventional cytogenetics or fluorescence in situ hybridization (FISH) data were available in 8 out of the 71 patients: a complex karyotype was found in three of them and other five patients carried the deletion q14 of chromosome 13 by FISH. Treatments First-line non autotx-based treatments included: 1) cycles of melphalan and prednisone, either alone (n=20) (11) or in combination with thalidomide (n=1) (12) or bortezomib (n=1) (13); 2) cycles of dexamethasone, either alone (n=7) or in combination with adriamycin and vincristine in the setting of the VAD protocol (n=1) (14). The induction phase before HDT and autotx included: 1) three cycles of dexamethasone, either alone (n=1) or in the setting of the VAD protocol (n=22); 2) three cycles of dexamethasone in combination with bortezomib and/ or thalidomide (n=13) (15); 3) four monthly chemotherapy cycles, according to the so-called Total Therapy II program (TTII) (n=5) (16). Collection of at least 6x10 6 CD34+ cells/kg body weight from peripheral blood occurred after the so-called CAD (cyclophosphamide, adriamycin and dexamethasone) cycle for the five patients enrolled in the TTII program, and after one cycle of cyclophosphamide, at a dose ranging from 4 to 7 g/ m 2, for the other patients. One or two autotx procedures were administered after conditioning with melphalan, at a dose ranging from 100 to 200 mg/m 2. One patient received a single autotx, followed by allogeneic stem cell traplantation from a sibling donor after conditioning with melphalan 140 mg/ m 2 and total body irradiation (TBI, 12 Gy in six fractio). Hemodialysis was performed according to standard procedures. No patient underwent dialysis with selective filters for free light chai. Outcome definitio Respoe to treatment, i.e., complete remission (CR), partial remission (PR), minimal respoe, stable disease, disease progression and relapse, were defined essentially according to the International Myeloma Working Group (17). In particular, CR required negative immunofixation of serum and urine and normal bone marrow trephine. We also included the definition of very good PR to indicate a decrease of paraprotein in serum and urine >90%. Respoe was evaluated after induction therapy, the first and the second autotx or at the end of the non-autotx-based program. Thereafter, paraprotein, immunoglobin level, Bence Jones positive proteinuria, serum creatinine, serum calcium, and other hematological parameters were evaluated every 1-3 months. Bone marrow examination and other tests were performed as needed. OS was calculated as the time from initiation of therapy to death for any cause or last contact. EFS was calculated as the time from initiation of therapy to

4 16 M. Galli, et al. FIGURE 1 HCONSORT diagram flow of 41 stage B-multiple myeloma patients enrolled in HDT with auto-tx programs. The doses of melphalan (mg/m2) administered as pre-autotx conditioning regimen and the reaso to exclude patients from autotx programs are reported. VAD, cycles of vincristine, adriamycin and dexamethasone; VAD/DCEP/CAD/DCEP, monthly cycles of VAD, DCEP (dexamethasone, cyclophosphamide, etoposide and cis-platinum), CAD (cyclophosphamide, adriamycin and dexamethasone); TBI, total body irradiation. either progression of disease or death from any cause or last contact. Statistical analysis Survival curves were estimated by the product-limit method and compared using the log-rank test. Univariate and multivariate analysis took into account the following variables: age (<65 vs >65 years), anemia (Hb <10 vs >10 g/ dl), pre-therapy dialysis, level of serum calcium (<12 vs >12 mg/dl), level of serum monoclonal component (<1 vs >1 g/dl), Bence Jones positive proteinuria (<1 vs >1 g/dl), type of MM (LC vs non-lc) and persistence of renal failure (creatinine >2 vs <2 mg/dl) at the end of therapy. P values <0.05 were coidered statistically significant. RESULTS Forty-one patients (58%) entered programs of HDT and autotx: their flow through the treatment programs and the reaso to stop them prematurely are shown in Figure 1. The other 30 patients (42%) received non-auto- Tx-based treatments. Reaso to exclude them from HDT and autotx were age >65 years in 27 cases and poor performance status in the other three. The degree of renal failure was not a reason to exclude patients from intent to HDT and autotx, since the two groups of patients were similar with respect to their median values of serum creatinine and prevalence of cases on dialysis at diagnosis (Table 2).

5 Stage B multiple myeloma patients: a long-term, single center outcomes research study 17 TABLE 2 Characteristics at diagnosis and outcomes after first-line treatment of 71 stage B-multiple myeloma patients. Treatment Allocation Characteristics at diagnosis Age, years Median (range) No. of patients (%) aged <65 years, years, >71 years Serum creatinine, mg/dl Median (range) Requirement of dialysis No. of patients (%) Renal outcomes Serum creatinine, mg/dl Median (range) Serum creatinine <2 mg/dl No. of patients (%) Chronic requirement of dialysis No. of patients (%) HTD with autotx N=41 59 (31-70) 35 (85) 6 (15) ( ) 8 (20) 1.25 ( ) 28/37 (76) 4/8 (50) Non autotx-based therapies N=30 75 (57-90) 3 (10) 5 (17) 22 (73) 3.75 ( ) 7 (23) 2.0 ( ) 15/29 (52) 3/7 (43) Clinical outcomes, No. of patients (%) Complete remission/very good partial remission Partial remission Minimal respoe Stable disease Progressive disease Death Overall number Early death (<60 days from start of therapy) HTD, high-dose therapy; autotx, autotraplantation. 16 (39) 13 (32) 1 (2) 1 (2) 2 (5) 8 (20) 0 4 (13) 8 (27) 0 2 (7) 6 (20) 10 (33) 7 (10%) Patients outcomes at the end of firstline therapy are summarized in Table 2. Thirteen of the 41 patients eligible to HDT and autotx (32%), among which the eight cases on dialysis at diagnosis, did not proceed to HDT and auto- Tx, mostly because of death or severe complicatio during induction therapy. Only one of them failed to mobilize CD34+ cells. Twenty-eight patients (68%) received at least one autotx procedure. Only four of them maintained a serum creatinine value >2 mg/dl (ranging between 2.3 and 4.0 mg/dl). Eleven of them did not proceed to the second autotx, in only two cases because of the worsening of renal failure. At the time of the second autotx, serum creatinine values remained >2 mg/dl in two patients and ranged between 1.3 and 1.9 mg/dl in other two. Only four patients received a reduced dose of melphalan (100 mg/sqm) in the conditioning regimen, because of age >65 years (n=2), serum creatinine value of 3.8 mg/dl (n=1) and relatively poor performance status (n=1), respectively. One patient entered into a program

6 18 M. Galli, et al. FIGURE 2 Overall survival (OS) and event-free survival (EFS) of 71 stage B-multiple myeloma patients according to their treatment allocation. Dashed line refers to the 41 patients enrolled in high-dose therapy with autotx programs and the bolt line to the 30 patients enrolled in non autotx-based programs. of tandem auto/allotx. Unfortunately, he died day +56 from allogeneic stem cell traplantation, due to acute graft versus host disease. No autotx-related mortality was recorded. As of April 2013, the median OS of the entire group of 71 stage B-MM patients was 23 months (range ) and 63 of them had died. Their median EFS was 17 months (range ) and 65 of them experienced an event. The median OS and EFS were 32 and 26 months, respectively, for the 41 patients eligible to HDT and autotx (34 of them are dead) and decreased to 17 and 14 months, respectively, for the 30 Table 3 Univariate and multivariate analysis of predictors of worse outcomes of 71 stage B-multiple myeloma patients. Parameters Univariate analysis Multivariate analysis OS EFS OS EFS Age >65 years Hemoglobin <10.0 g/dl Requirement of dialysis at diagnosis Creatinine >2 mg/dl at the end of therapy Serum calcium >12 mg/dl Serum MC >1 g/dl Bence Jones positive proteinuria >1 g/dl Light chain MM OS, overall survival; EFS, event-free survival;, not significant; MM, multiple myeloma.

7 Stage B multiple myeloma patients: a long-term, single center outcomes research study 19 ineligible patients (29 are dead) (Figure 2). The median OS of the 28 patients who received at least one autotx was 41 months (range months). Their median EFS was 32 months (range months). By univariate analysis, age >65 years, anemia, requirement of dialysis at diagnosis and persistence of renal failure at the end of therapy were associated with significantly inferior outcomes (Table 3). Multivariate analysis confirmed anemia and requirement of dialysis at diagnosis as adverse predictors of outcome for both OS and EFS. Limited to EFS, also hypercalcemia and Bence Jones positive proteinuria were adverse predictors of outcomes (Table 3). Due to their paucity, we did not use conventional cytogenetics or FISH data for univariate or multivariate analysis. DISCUSSION Outcomes research allows to evaluate how effectively medical interventio - that have proven to be efficacious in the context of clinical trials - may be delivered to patients populatio not included in such trials. The aim of the ORO project was to document the traferability of the results of randomized clinical trials into the clinical practice of a big Italian Hospital and to understand how the degree of traferability could influence patients outcomes. This work exemplifies the yield of outcomes research when applied in an area where there are effective treatments, but characterized by complex technologies and serious side effects. Renal failure does not qualify newly diagnosed MM patients for participation in many randomized clinical trials. Therefore, a substantial proportion of patients coidered at poor prognosis are, paradoxically, excluded from receiving new drugs or effective treatment modalities. The optimal treatment strategy of stage B-MM patients should create a positive loop, in which the quick improvement of renal function allows the timely administration of the most appropriate anti-mm treatment, which, in turn, ameliorates MM clinical outcomes in terms of OS and EFS. The choice of the initial treatment is, therefore, of the utmost importance. Dexamethasone-containing first-line regime are active on MM and may improve renal function (18). The inclusion of thalidomide and/or bortezomib in the early phase of treatment is another possible strategy, as both drugs may be safely given even in case of severe renal impairment (18), which improves in approximately 40% of patients (19, 20). Recently, Dimopoulos et al. (21) reported 74% renal improvement, 50% independence from dialysis and 8% early mortality among 133 stage B newly diagnosed MM patients treated with bortezomib, thalidomide or lenalidomide. These outcomes are very similar to those observed in our patients who received at least one autotx, even though the majority of them were treated before the so-called new drugs became widely available. None of our patients on dialysis who entered HDT with autotx, however, went further enough through the program to actually receive the autotx procedure, because of early death or severe complicatio that stopped prematurely the program. Thus, dialysis remai a serious obstacle to the administration

8 20 M. Galli, et al. of HDT and autotx programs and the strongest independent predictor of worse outcomes. The administration of thalidomide, lenalidomide or bortezomib in the early phase of treatment of stage B-MM patients may be particularly useful in those cases who, because of advanced age or comorbidities, are uuited for HDT and auto- Tx, as suggested by Dimopoulos study (21). Our patients excluded from HDT and autotx were on average 15 years older than patients enrolled in auto- Tx-based programs and showed the worst outcomes and a high rate of early death, even though age was not an independent predictor of outcome. At present, HDT and autotx programs remain the standard of treatment of all newly diagnosed symptomatic young MM patients (22). When compared to those of stage A-MM patients (8), the outcomes of stage B-MM patients who receive at least one autotx procedure, although encouraging, remain significantly poorer. Thus, one may wonder whether the combination of the new drugs with HDT and autotx (23, 24) might provide even better outcomes and, thus, be coidered the most appropriate treatment strategy also for young stage B-MM patients. Our study suffers a number of limitatio. Firstly, its retrospective design, which prevents from drawing firm conclusio. Secondly, although coistent, the number of patients is iufficient to perform some statistical analysis, such as the comparison between different treatments or different era of diagnosis or to stratify patients according to their degree of renal iufficiency. Thirdly, the rather long period of patients enrolment - approximately 12 years during which MM treatment has changed. As a coequence, our patients received heterogeneous therapies. On the other side, our analysis provides a useful tool to compare the results that are currently being obtained with the new drugs, and confirms that the rapid and efficient improvement of renal function improves the quality of remission and the proportion of patients achieving the ultimate goal of receiving HDT and autotx. Only further clinical studies on large cohorts of patients will, anyway, establish whether curability is a reachable goal for stage B-MM patients. Conflict of interests: The Authors declare no conflict of interests. REFERENCES 1. Knudsen LM, Hippe E, Hjorth M, et al. Renal function in newly diagnosed multiple myeloma: a demographic study of 1353 patients. Eur J Haematol 1994; 57: San Miguel JF, Lahuerta JJ, García-Sanz R, et al. Are myeloma patients with renal failure candidates for autologous stem cell traplant? Haematol J 2000; 1: Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell traplant in multiple myeloma patients with renal failure. Br J Haematol 2001; 114: Sirohi B, Powles R, Kulkarni S, et al. Glomerular filtration rate prior to high-dose melphalan 200 mg/m2 as a surrogate marker of outcome in patients with myeloma. Br J Cancer 2001; 85: Knudsen LM, Nielsen B, Gimsing P, et al. Autologous stem cell traplantation in multiple myeloma: outcome in patients with renal failure. Eur J Haematol 2005; 75: Raab MS, Breitkreutz I, Hundemer M, et al. The outcome of stem cell traplantation in patients with plasma cell

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