Although high-dose therapy and autologous stem cell transplant (ASCT) is superior to conventional chemotherapy for treatment of myeloma, most patients relapse and the time to relapse depends upon the initial prognostic factors. The administration of non-cross-resistant chemotherapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after single autologous peripheral blood stem cell transplant (auto-PBSCT) in 103 mostly newly diagnosed myeloma patients (67 patients were ⩽6 months from the initial treatment). Patients received conditioning with BCNU, melphalan±gemcitabine and auto-PBSCT followed by two cycles of the DCEP±G regimen (dexamethasone, cyclophosphamide, etoposide, cisplatin±gemcitabine) at 3 and 9 months post-transplant and alternating with two cycles of DPP regimen (dexamethasone, cisplatin, paclitaxel) at 6 and 12 months post-transplant. With a median follow-up of 61.2 months, the median event-free survival (EFS) and overall survival (OS) are 26 and 54.1 months, respectively. The 5-year EFS and OS are 23.1 and 42.5%, respectively. Overall, 51 (49.5%) patients finished all CC, suggesting that a major limitation of this approach is an inability to deliver all planned treatments. In order to improve results following autotransplantation, novel agents or immunologic approaches should be studied in the post-transplant setting.
High-dose therapy followed by autologous stem cell rescue has been shown to improve the complete remission (CR) rates, event-free (EFS) and overall survival (OS) in patients with multiple myeloma (MM) when compared to conventional chemotherapy.1, 2, 3, 4, 5, 6 However, the reported 7-year EFS and OS following single autologous stem cell transplant (ASCT) were 10 and 21–35%, respectively, suggesting that the majority of patients will ultimately relapse.1, 7 In the Intergroupe Francophone du Myelome (IFM) 90 trial, achievement of at least a very good partial remission (VGPR) following ASCT in newly diagnosed patients was associated with longer survival.1 Thus, in order to improve the results following a single autotransplant, treatment strategies such as tandem transplant and post-transplant consolidation chemotherapy (CC) have been designed with a goal to eradicate the residual myeloma cells, and therefore increase CR rate and improve EFS and OS.
In an attempt to reduce the relapse rate after transplantation, a clinical protocol of autologous peripheral blood stem cell transplant (auto-PBSCT) with post-transplant consolidation chemotherapy was designed at our institution, which contained the following novel features: (1) In order to overcome myeloma cell chemoresistance to high-dose melphalan, the conditioning regimen was modified to include BCNU in addition to high-dose melphalan and in situations where patients received protracted treatment prior to transplant (>12 months from the initial therapy), gemcitabine was added as well to prevent repair of DNA damage induced by the alkylating agents; (2) consolidation chemotherapy was administered using two non-cross-resistant chemotherapy regimens: DCEP±G (dexamethasone, cyclophosphamide, etoposide, cisplatin±gemcitabine) at 3 and 9 months post-transplant alternating with DPP (dexamethasone, cisplatin, paclitaxel) at 6 and 12 months post-transplant. The DCEP regimen was selected based on its reported activity in MM patients relapsing after autotransplantation.8 In this group of patients, DCEP chemotherapy produced a 41% partial response rate (normal bone marrow (BM) with ⩾75% reduction in serum and ⩾90% reduction in urine paraprotein) and 10% CR rate. As for DPP regimen, the rationale for inclusion of paclitaxel was two-fold: first, tubulin-active agents do not require wild-type p53 for cytotoxicity unlike alkylating agents and p53 alterations have been associated with poor outcome.9, 10 Second, paclitaxel may inactivate the antiapoptotic function of bcl-2, which is frequently overexpressed in myeloma cells and cell lines.11, 12 The aim of the study was to evaluate if consolidation therapy could effectively replace a second transplant.
In this manuscript, we report final results on a cohort of 103 myeloma patients treated with this novel strategy. A full course of post-transplant consolidation chemotherapy was successfully delivered to 49.5% of patients and in some patients resulted in improved responses.
Patients and methods
Between October 1997 and January 2001, 103 consecutive patients (patients) with MM were treated with high-dose therapy and ASCT according to two University of Maryland School of Medicine, IRB-approved treatment protocols. Eligible patients had confirmed MM, aged 18–75 years, and were required to have adequate organ function as reflected by left ventricular ejection fraction of more than 50% by echocardiogram or MUGA scan, FEV1 and DLCO ⩾50% of the predicted values, serum creatinine ⩽3.0 mg/dl and serum direct bilirubin ⩽2.0 mg/dl. Patients were required to have Southwest Oncology Group (SWOG) performance status of 2 or less, unless poor performance status was due to bone pain. All patients seen at our institution during the time period who were eligible according to the above criteria were offered autotransplants. No patients were excluded based on disease stage or number of prior treatments. Overall, 67 patients (65%) were ⩽6 months from the initial therapy; the remaining 36 patients were either >6–⩽12 months (18 patients, 17.5%) or >12 months (18 patients, 17.5%) from the initial therapy, respectively.
Pretransplant mobilization chemotherapy consisted mainly of cyclophosphamide 4.5 g/m2 intravenously (i.v.) over 12 h with mesna for urothelial protection followed by etoposide 2.0 g/m2 i.v. infusion over 6 h (72 patients; 70%). In all, 28 patients (27%) received cyclophosphamide only. Hematopoietic growth factor support utilized granulocyte colony-stimulating factor (G-CSF) at a dose of 10 μg/kg/day. Large volume leukapheresis procedures (15–30 l over 2–5 h) were performed through indwelling catheters using the COBE Spectra (Gambro BCT, Lakewood, CO, USA) continuous flow cell separator in the manual PBSC mode. As the ASCT protocols were designed to deliver several cycles of post-transplant consolidation chemotherapy, leukapheresis was repeated if necessary, in order to obtain a target of more than 5 × 106 CD34+ cells/kg, so that backup cells could be stored and used in the event of delayed marrow recovery after consolidation chemotherapy. The premobilization chemotherapy varied, but the preferred premobilization treatment was 2 months of dexamethasone pulsing (dexamethasone 40 mg orally on days 1–4, 9–12, 17–20), which was given to 53 patients (51.5%), median two (1–3) cycles. In all, 35 patients (34%) received a median of four cycles (2–7) of VAD, three patients received a median of four cycles (3–6) of melphalan/prednisone, four patients received other chemotherapy regimens and eight (7.5%) patients did not receive any immediate premobilization chemotherapy. After completion of mobilization chemotherapy, patients were restaged and proceeded to receive high-dose chemotherapy at a median of 35 days (range 27–275 days). All patients signed an informed consent for participation in these IRB-approved protocols.
High-dose therapy and ASCT
The transplant conditioning regimen consisted of carmustine (BCNU) 300 mg/m2 i.v. infusion over 2 h on day −2 and melphalan 140 mg/m2 over 20 min i.v. infusion on day −1. Gemcitabine 1 g/m2 was given i.v. over 100 min on day −5 and again 6 h after the administration of carmustine on day −2 to patients who were more than 12 months from the initial therapy at the time of transplantation (18 patients; 17.5%). One patient received melphalan only due to progressive renal dysfunction. On day 0, autologous stem cells were thawed and infused according to standard procedure. A median of 7.6 × 106 CD34+ cells/kg were infused on day 0 after completion of high-dose chemotherapy (range 1.1–38.24 × 106 CD34+ cells/kg). All patients received G-CSF (5 μg/kg/day) starting from day +4 until the absolute neutrophil count (ANC) recovered to 1 × 109/l for 2 consecutive days. Standard antimicrobial prophylaxis was employed.
At 3 and 9 months post-transplant, patients with a neutrophil count ⩾1.5 × 109/l and a platelet count ⩾100 × 109/l and a serum creatinine ⩽2 mg/dl were eligible to receive DCEP (dexamethasone 40 mg orally/day; cyclophosphamide 300 mg/m2/day continuous infusion (CI); etoposide 30 mg/m2/day CI; and cisplatin 15 mg/m2/day CI; all drugs given for 4 days)±G (gemcitabine 1g/m2 i.v. infusion over 100 min was given on day 3 to patients who were transplanted more than 12 months from the initial therapy). If the neutrophil count was 1–1.5 × 109/l or if the platelet count was 50–100 × 109/l, then DCEP was given without the gemcitabine and further dose reduction was made at the discretion of treating physician. If the neutrophil count was <1 × 109/l or platelet count <50 × 109/l, then either chemotherapy was held or a stem cell boost was given after treatment at the discretion of the treating physician. At 6 and 12 months post-transplant, the patients who were eligible according to the above criteria received DPP (dexamethasone 40 mg orally on days 1–4; paclitaxel 135 mg/m2 CI over 6 h on day 2; and cisplatin 75 mg/m2 CI over 24 h on day 3). Patients received G-CSF (5 μg/kg) and anti-microbial prophylaxis following each consolidation cycle. Backup CD34+ stem cells were available for infusion following consolidation chemotherapy for delayed neutrophil recovery, life-threatening infection or if patient did not recover neutrophil count ⩾1.5 × 109/l and a platelet count ⩾100 × 109/l prior to any consolidation treatment.
Assessment of response
Myeloma burden was assessed by quantitative measures of myeloma protein in serum and urine (electrophoresis and immunofixation) and BM aspiration for plasma cell count, skeletal survey/MRI as deemed necessary. These measurements were performed immediately prior to ASCT, 6 weeks post-ASCT, prior to each consolidation chemotherapy cycle and in follow-up every 3 months or earlier if needed. Response rates were defined according to common criteria proposed by the EBMT, IBMTR and ABMTR.13
For the EFS, an ‘event’ was defined to be either progressive disease or relapse, development of secondary hematologic malignancy (three patients – acute myeloid leukemia (AML)) or death from any cause. The EFS time was measured from the date of transplant to the ‘event’. The overall survival (OS) was measured from the date of transplant to death from any cause. All patients were included in the survival analyses whether or not they received all of the intended treatments. The survival curves and survival rates were generated according to the Kaplan–Meier product-limit method. In the multivariate analysis of prognostic factors, the Cox proportional-hazard model was employed using a stepwise selection technique to determine variables related to EFS and OS.
Patient characteristics are described in Table 1.
High-dose chemotherapy and ASCT
The median number of CD34+ cells infused was 7.6 × 106/kg (range 1.1–38.24 × 106/kg). Neutrophil recovery >0.5 × 109/l occurred at a median of 12 days (range 6–48 days), and platelet recovery to >20 × 109/l at a median14.5 days (range 0–141 days) after PBSCT. Two patients required an infusion of additional stem cells at day 18 post-transplant due to delayed engraftment. As previously reported for 77 patients from this group, due to the high number of CD34+ cells infused, no factors were identified on univariate analysis to correlate with the time to neutrophil or platelet recovery.14
The most common toxicities encountered were febrile neutropenia (72 patients, 70%) and infections (62 patients, 60%) such as bacteremia (43 patients, 42%), catheter infection (17 patients, 16.5%) and pneumonia (14 patients, 13.5%). Gram-positive organisms were the most frequent cause of bacteremia. Cytomegalovirus reactivation occurred in 10 patients with clinical pneumonia and retinitis occurring in one patient each. The majority of gastrointestinal toxicities were mild (nausea, vomiting, diarrhea) and generally
Following transplant (compared to immediate pretransplant disease status), 29 (28.1%) patients were assessed to be in CR, 24 (23.35%) patients in partial remission (PR), seven (6.8%) patients had minimal response (MR), 25 (24.3%) patients had stable disease (SD), seven (6.8%) patients had progressive disease (PD) and for three (3%) patients the restaging data are incomplete.
Overall, 80 (77.6%) patients received at least one consolidation chemotherapy cycle; 51 (49.5%) patients received all four treatment cycles, 12 (11.6%) patients received three, five (4.9%) patients received two and 12 (11.6%) patients received only one consolidation chemotherapy cycle. The main reasons why patients did not complete all planned treatments are depicted in Table 2. Hematologic toxicity was graded according to CTC version 2.0 – BMT toxicity criteria and toxicity data are summarized in Tables 3 and 4 and Figure 1.
A total of 262 CC cycles were administered and dose adjustments were made for 20 (7.6%) cycles. The majority of dose adjustments were needed in two overlapping groups of patients: (i) Among patients who were transplanted >12 months from initial therapy (gemcitabine group). Within this group, gemcitabine was withheld in 13 of 28 DCEP-G cycles administered with further dose reductions of 25–50% of cyclophosphamide and/or etoposide in eight of these 13 cycles; (ii) among 20 patients (19.4%) who were transplanted with <5 × 106 CD34+ cells/kg, dose adjustments were made for 16 of 59 (27%) CC cycles administered. However, 60% of patients in the latter group belonged to the gemcitabine group as well. Overall, 66% of patients in the gemcitabine group and 60% of patients transplanted with <5 × 106 CD34+ cells/kg finished all four CC cycles. Among the subgroup of patients who were >age 60 years (n=44), 52.2% patients received all four CC cycles and the dose adjustment was made for 6.7% of cycles administered to this group. A stem cell boost was required following only six (2.3%) CC cycles. However, five of the six patients received a stem cell boost following the first CC cycle due to incomplete marrow recovery following transplant and therefore it should not be necessarily viewed as evidence of intolerance of CC.
The administration of CC resulted in an objective improvement in response in 19 patients (17 patients with durable improvement of more than 6 months duration), of whom eight achieved CR. The improvement in response occurred following first CC cycle in eight patients, following 2nd CC cycle in six patients, following 3rd CC cycle in two patients and 4th CC cycle in three patients. In four of 19 patients, a gradual improvement in response was observed.
EFS and OS
As shown in Figure 2, for the entire cohort (n=103), the EFS at 5 years was 23.1% (95% CI, 14.0–32.2%). The median EFS time is 26 months (95% CI, 18.2–36.5 months). There were 79 events out of the 103 patients, meaning that 24 patients (15 patients in CR, four patients in PR and five patients with SD) are still surviving event-free at last follow-up (median follow-up for surviving patients is 57.4 months, range 43.4–68.8 months). Figure 3 depicts the Kaplan–Meier OS for the 103 patients in the cohort. There have been 56 deaths out of the 103 patients, resulting in a 5-year OS of 42.5% (95% CI, 31.5–53.5%). The median OS has been reached and is 54.1 months (95% CI, 45.3–64.1 months). The median follow-up for the entire cohort is 61.2 months (95% CI: 41.7–80.6 months).
A multivariate analysis of the EFS and OS data was performed using the following covariates: age, gender, race, stage at enrollment (stage 1+2 vs 3; A vs B), MM type (IgG vs IgA and others vs IgG), β2-microglobulin (>2.5 vs ⩽2.5 mg/dl), CRP (>4 vs ⩽4 mg/dl), cytogenetics (normal vs abnormal of chr 11 or 13 vs others), the presence of three or more chromosomal abnormalities (complex cytogenetics), disease sensitivity prior to transplant (sensitive vs resistant), disease status prior to transplant, post-transplant disease status, months of treatment prior to transplant, months from diagnosis to transplant (>12 vs ⩽12 months), months from first treatment to transplant (>12 vs ⩽12 months), number of CD34+ progenitor cells infused at the time of transplant, number of different types of treatment prior to transplant. The results from the Cox regression model using stepwise selection revealed that higher number of CD34+ cells infused and better pretransplant disease status (CR+PR) were significantly associated with better EFS, while MM type IgA, stage 3 and abnormal cytogenetics were negatively associated with EFS (Table 5). As for OS, again higher number of CD34+ cells infused was associated with better OS, while MM of IgA type, stage 3 and the presence of complex cytogenetics were associated with poorer OS (Table 6).
The time from first treatment to transplant (>12 vs ⩽12 months; gemcitabine group) or months of treatment prior to transplant were not found to be statistically significant (P<0.05) in a multivariate analysis of the EFS and OS data.
In an effort to delay or prevent relapse after ASCT for MM, we introduced a series of post-transplant CC treatments. Although administered infrequently, at least theoretically post-transplant chemotherapy may provide further cytoreduction and therefore improve disease-free survival and ultimately OS in patients with MM and may be as effective as a second transplant. On the other hand, it may carry a risk of additional morbidity and mortality and its long-term role in the development of myelodysplasia (MDS) and secondary leukemias remains unknown.
In this study several observations were made. First, all four planned courses of post-transplant CC using DCEP±G alternating with DPP were successfully administered to 51 patients (49.5%). Moderate to severe myelosuppression occurred in the majority of patients following DCEP±G and to a lesser extent after DPP. Dose adjustments were made for 20 (7.6%) cycles of 262 administered. The majority of dose adjustments were needed in a group of patients who were heavily pretreated (gemcitabine group) 32% (17/53 CC cycles) or in a partially overlapping group of patients who were transplanted with <5 × 106 CD34+ cells/kg 27% (16/59 CC cycles). Although 60% or more patients in each group finished all four CC cycles, the more frequent dose adjustments required suggests that this form of therapy may be harder to deliver to patients with extensive previous treatment. Other studies testing post-transplant consolidation chemotherapy in patients with MM following tandem transplant and in lymphoma patients following single ASCT reported similar rates of 40–50% of patients finishing all planned treatments.15, 16, 17 Three (2.9%) cases of secondary MDS/AML have been documented in our study patients at 5, 3.5 and 1.5 years following transplant. All three patients received <6 months of treatment prior to transplant and did not receive any alkylating agents in past. However, the first patient did receive 30 Gy irradiation to the lower spine and pelvis and the latter patient was treated extensively with radioactive iodine in past for metastatic thyroid cancer. Although longer follow-up is needed, at this point it does not appear that administration of CC in MM patients significantly increases the risk of secondary leukemias.
Second, with the long median follow-up of 61.2 months, the median EFS and OS have been reached and are 26 and 54.1 months, respectively. The 5-year EFS rate was found to be 23.1%, and 5-year OS rate was 42.5%. There are 24 patients who are event-free at the time of last follow-up, of whom 15 received all four CC cycles, while three CC cycles, one CC cycle and none were given to three patients each. Since this study was not randomized (post-transplant CC vs none), the contribution of CC to improvements in EFS and/or OS cannot be ascertained. In addition, comparisons with published reports are of limited value due to different conditioning regimens used, source of stem cells, patients (newly diagnosed or not) and pretransplant treatments. Two pivotal studies IFM90 and MRC VII that established superiority of ASCT over standard therapy in newly diagnosed MM patients reported median EFS of 28 and 34 months and median OS of 57 and 54 months in the transplant arm, respectively.1, 2 These results appear similar to ours, however, there are certain points to be made: First, in both of these studies median EFS and OS were calculated from the time of randomization (occurring on average 4–5 months prior to transplant). Second, there are certain patient characteristics pertinent to our study population such as age (19.4% patients in our study were older than 65 years) and duration of previous treatments (15.6% patients in our study received more than 12 months of chemotherapy prior to transplant) that might place them in a higher risk category and therefore affect final EFS and OS results. In both IFM90 and MRC VII studies, patients received at least four to six chemotherapy cycles prior to ASCT,1, 2 while more than 50% of patients in our study received dexamethasone only prior to mobilization chemotherapy. The above data raise the issue of whether better pretransplant cytoreduction was achieved in IFM90 and MRC VII studies so that in part our post-transplant CC may have served the role of pretransplant chemotherapy in these studies. Both IFM90 and MRC VII study also incorporated the interferon maintenance.
Both post-transplant consolidation chemotherapy and the tandem transplant approach have been designed with the idea of increasing the CR rates and therefore EFS and OS. The data from tandem transplant studies have so far yielded the following conclusions: (1) double transplant in comparison to single ASCT results in improved EFS and OS;7 (2) the improvement in CR rate appears not to be primarily responsible for improved survival results and it appears that tandem transplantation improves survival end points by primarily prolonging the duration of response;3, 7 and (3) the tandem transplant approach is feasible in 70–80% of patients.3, 4, 7, 18 Although all patient groups in IFM94 study appear to benefit from this approach, the major advantage of second transplant was seen in patients who did not achieve VGPR by 3 months following single transplant.7
Nonetheless, it should be emphasized that attainment of CR or near CR after autotransplantation is perhaps the most important predictor of long-term survival.7, 19, 20, 21 Our data do show that incremental improvement in myeloma responses is possible during or after CC (an additional eight patients entered CR and 19 patients overall had objective improvements in response), suggesting that CC may have contributed to the observed EFS and OS rates. It is also noteworthy that 18 of the 24 (75%) patients who were surviving event-free at last follow-up had received three or four consolidation treatments. As in other studies of CC, a major limitation of this approach remains inability to deliver all planned treatments (49.5%) for a variety of reasons including early disease progression, medical reasons or patient refusal.15, 16, 17 The ability to deliver the planned treatment in almost 70–80% of patients in double transplant studies suggests that this approach may be ultimately better tolerated and easier to deliver.3, 4, 7, 18 Furthermore, the CC appears to have little impact on those patients relapsing early after transplant, suggesting that intrinsic resistance of myeloma cells to even high-dose chemotherapy is unlikely to be overcome by repetitive cycles of standard chemotherapy. This is further supported by the finding that improved EFS was observed in patients with good responses to initial induction chemotherapy (CR+PR), indicating that patients sensitive to standard chemotherapy and glucocorticoids are likely to benefit most with further chemotherapy treatments. Similar to tandem transplant studies, abnormal or complex cytogenetics negatively impacted EFS and OS of patients in our study as well. Other poor prognostic factors for EFS and OS in our study were advanced stage and IgA type of MM, while infusion of higher dose of CD34+ cells had positive impact, which may be related to a lower tumor burden at the time of mobilization.
As for BCNU/melphalan±gemcitabine conditioning regimen, we observed the higher TRM than most studies. Although increased TRM was primarily observed in patients of older age, it still remained above 5% even in patients younger than 65 year, or in patients with <6 months of prior therapy. Only in patients who were both younger than 65 years and with <6 months of treatment, TRM was found to be 4.5%, which is similar to most of the studies. Therefore, these data are unlikely to support further use of this conditioning regimen, particularly in elderly or heavily pretreated myeloma patients. Furthermore, it is becoming clear that high-dose melphalan alone is the most effective conditioning regimen in MM.22
In conclusion, four courses of post-transplant CC following single ASCT was feasible for about 50% of patients and was well tolerated. Thus, myelosuppressive consolidation therapies can be difficult to deliver to many patients during the post-transplant phase. For patients who are less likely to tolerate such treatments (e.g. extensive prior therapy), thalidomide-based maintenance may have an emerging role.23 Clearly, new strategies are needed to improve upon results of both single and tandem transplants since the beneficial impact of treatment intensification alone on EFS and OS has been limited. Perhaps, administration of novel targeted (bortezomib) or immunomodulatory therapeutics (thalidomide, lenalidomide)24, 25, 26, 27, 28, 29, 30 or novel immunologic approaches such as nonmyeloablative allo-BMT,31, 32 post-transplant vaccine or autologous T-cell infusions33, 34 may be better suited for future explorations.
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We thank the nurses of the BMT unit for outstanding patient care. APR is a Clinical Scholar of the Leukemia and Lymphoma Society.
About this article
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Relationship between beta-herpesviruses reactivation and development of complications after autologous peripheral blood stem cell transplantation
Journal of Medical Virology (2012)
Combination immunotherapy using adoptive T-cell transfer and tumor antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma
Journal of International Medical Research (2008)
High-Dose Treatment With Autologous Stem Cell Transplantation in Multiple Myeloma: Past, Present, and Future
Seminars in Hematology (2007)