Autografting

Second auto-SCT for treatment of relapsed multiple myeloma

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Abstract

High-dose therapy and auto-SCT remain integral in the initial treatment of multiple myeloma (MM), and are increasingly being applied for management of relapsed disease. We examined the outcomes in 98 patients undergoing salvage auto-SCT (auto-SCT2) for relapsed MM after receiving an initial transplant (auto-SCT1) between 1994 and 2009. The median age at auto-SCT2 was 60 years (range: 35–74). The median time between auto-SCT1 and auto-SCT2 was 46 months (range: 10–130). Treatment-related mortality was seen in 4%. The median PFS from auto-SCT2 was 10.3 (95% confidence interval (CI): 7–14) months and the median OS from auto-SCT2 was 33 months (95% CI: 28–51). In a multivariable analysis, shorter time to progression (TTP) after auto-SCT1, not achieving a CR after auto-SCT2, higher number of treatment regimens before auto-SCT2 and a higher plasma cell labeling index at auto-SCT2 predicted for shorter PFS. However, only a shorter TTP after auto-SCT1 predicted for a shorter OS post auto-SCT2. Hence, auto-SCT2 is an effective and feasible therapeutic option for MM patients relapsing after other treatments, especially in patients who had a TTP of at least 12 months after their auto-SCT1.

Introduction

Multiple myeloma (MM) is the second most common hematologic malignancy in adults and leads to >10 000 deaths annually in the United States.1 The use of high-dose chemotherapy with auto-SCT improves the response rates and the survival outcomes for patients with MM.2 Several studies support the use of auto-SCT in the front-line setting or at relapse and are considered as a standard of care for eligible patients.3, 4 Unfortunately, patients eventually suffer disease relapse after auto-SCT and require salvage therapy. Novel therapies such as thalidomide, lenalidomide and bortezomib have all been used successfully for the management of relapsed as well as newly diagnosed MM.5, 6, 7, 8 However, patients eventually become refractory to these agents and prolonged treatment leads to significant toxicities, posing a challenge to physicians and highlighting the need for more effective salvage therapies.

Benefit of a second auto-SCT (auto-SCT2) has been demonstrated both in the upfront setting as tandem transplants as well as in the relapsed setting for salvage therapy. There has been a growing interest in the role for auto-SCT2 in the salvage setting and several studies have shown it to be safe and efficacious in selected patients.9, 10, 11, 12, 13, 14, 15, 16, 17 Many of these studies have included small numbers of patients, which limits the ability to identify factors associated with good outcomes in this group of patients. We reviewed our experience of such auto-SCT2 in relapsed or refractory myeloma patients to characterize the efficacy of auto-SCT2, the associated toxicity, and to identify clinical and laboratory characteristics that can help select patients likely to benefit from this approach.

Materials and methods

At the Mayo Clinic Transplant Center, 1033 patients underwent a first auto-SCT (auto-SCT1) for treatment of MM between 1994 and 2009, of whom 153 patients went on to undergo an auto-SCT2. Patients who received a tandem auto-SCT (n=41) had their auto-SCT2 performed at another institution (n=7), or had a planned non-myeloablative allo-SCT immediately after the auto-SCT2 (n=7) were excluded from this analysis. Patients with plasma cell leukemia were also not included in this data set. The auto-SCT2 was defined as ‘salvage’ if the patient had evidence of disease progression after the initial auto-SCT regardless of the number of lines of therapy administered between the two transplants. There were 98 patients who underwent an auto-SCT2 for salvage therapy between January 2001 and June 2011 and their follow-up was updated as of 31 December 2011. In addition, we also selected a control group of 98 patients who did not have a second transplant and were closest to the cases in terms of the time to progression (TTP) after auto-SCT1, age at the time of the first relapse after auto-SCT1 and year of relapse. Approval from the Mayo Clinic Institutional Review Board was obtained in accordance with the federal regulation and Declaration of Helsinki.

Response was defined by the International Myeloma Working Group criteria.18 M-protein measurements at the time of auto-SCT2 were used as baseline for response assessments for those patients going directly to auto-SCT in relapse; whereas for those with a response arising from the prior regimen leading to the auto-SCT2, the values from the start of that prior regimen were used as baseline for response assessments. The primary end points of the study were OS and PFS after auto-SCT2. OS was measured from the day of autologous stem cell infusion (day 0 of auto-SCT2) to death from any cause, with censoring performed at the date of last contact. PFS was determined from the day of stem cell infusion to the day of documented relapse or progression, with those alive and relapse free censored at the day of last follow-up. Death from any cause other than relapse before day 100 was classified as TRM. Initial responses were assessed at approximately day 100 and best responses were determined in the period between day 0 and the start of next line therapy for progression. Neutrophil and platelet engraftment was defined as achievement of ANC 0.5 × 109/L and a platelet count of 50 × 109/L without transfusion support. For patients who had a FISH analysis performed before their auto-SCT2, they were categorized as having high-risk disease if they had any of the following abnormalities: t(4;14), t(14;16), t(14;20) and del17p.

Prognostic variables before the auto-SCT2 which were examined for significance in univariate analyses included: age, response to auto-SCT1, TTP after auto-SCT1, time interval between auto-SCT1 and auto-SCT2, number of prior lines of therapy, responsive disease at the time of salvage transplant, BM plasma cell percentage, presence of high-risk FISH, conditioning regimen, and pre-transplant International Staging System (ISS) stage, plasma cell labeling index (PCLI), serum M spike, urine M spike, hemoglobin, creatinine, creatinine clearance, C-reactive protein and lactate dehydrogenase (LDH).

Statistical analysis was performed using the SAS biostatistical software JMP 9.0.1 (SAS Institute Inc., Cary, NC, USA). Chi-square tests and Fisher exact tests were used to compare differences between nominal variables, and the Mann–Whitney U-test or the Kruskal-Wallis test was used for continuous variables. Kaplan–Meier analysis was used to analyze and create the OS and PFS curves, and log-rank test was used to compare survival curves. Finally, a multivariable analysis was performed using the Cox proportions hazards model to assess the influence of various prognostic factors on OS and PFS. Due to the small sample size of this cohort, only those variables that were found to be significant in a univariate analysis with a P-value of 0.01 were included in the multivariable analysis.

Results

Patient characteristics

Demographics and clinical characteristics at the time of auto-SCT1 and auto-SCT2 are shown in Table 1. The median age at diagnosis was 54 years (range: 24–72 years) and at auto-SCT2 was 60 years (range: 35–74). Median time between auto-SCT1 and auto-SCT2 was 46 months (range: 10–130) and the median number of regimens used between the two auto-SCT was 3 (range: 1–11). The median time between first relapse after auto-SCT1 and auto-SCT2 was 14.5 months (range: 2–71). Before auto-SCT2, 52 patients (50%) were treated with bortezomib; 42 patients (40%) were treated with lenalidomide and 34 patients (32%) were treated with thalidomide.

Table 1 Demographic and clinical characteristics of patients at auto-SCT1 and auto-SCT2

Conditioning regimens used for auto-SCT2 included melphalan 200 mg/m2 in 80 patients (82%), reduced dose melphalan (100–140 mg/m2) in 8 patients (8%) and other regimens in 10 patients (10%). Seventy-five (76%) patients had their original stem cells (collected before auto-SCT1) re-infused during the auto-SCT2. The median (range) CD34 cells infused was 4.6 (2.5–26 million/kg). In all, 38 patients (39%) had complex cytogenetics and 25 of the 73 patients with a FISH test result had high-risk disease (25%). Twenty patients (20%) received maintenance therapy after completion of their auto-SCT2.

Engraftment and toxicity

Details regarding engraftment and toxicities after auto-SCT1 and auto-SCT2 are described in Table 2. Hospitalization was required for 53 patients (50%) and was similar to that observed after auto-SCT1; but the median (range) hospital stay was longer for auto-SCT2 (7 days (2–132) vs 3 days (0–30); P=0.01 (paired t-test)). Post-transplant mucositis and bacteremia were encountered in 26 (27%) and 30 (31%) patients, respectively. Treatment-related mortality was seen in 4%.

Table 2 Toxicity/engraftment profiles and responses at diagnosis and at auto-SCT1 and auto-SCT2

Response and survival

Overall responses after auto-SCT1 and auto-SCT2 are described in Table 2. The median estimated follow-up from diagnosis was 129 months (95% confidence interval (CI): 111–139) and from auto-SCT2 was 57 months (range: 45–67). At last follow-up, 42 patients were still alive. Ninety-four (96%) patients were evaluable for disease response. A partial response or better was seen in 85 (86%) patients, including a complete response (CR) in 30 (31%) patients and a very good partial response in 52 (53%) patients. Stable disease or progression was seen in nine patients and four patients died before disease assessment. Eighty-one (83%) patients have relapsed to date.

The median PFS after auto-SCT1 among these 98 patients was 25.3 months (range: 4–124 months). The median PFS from auto-SCT2 for the entire cohort was 10.3 (95% CI: 7–14) months (Figure 1a), and was 11.9 months (95% CI: 7.5–15) for the 78 patients receiving no maintenance therapy. The median OS from diagnosis was 101.6 months (95% CI: 94–119), from auto-SCT1 was 90 months (95% CI: 80–96) and from auto-SCT2 was 33 months (95% CI: 28–51) (Figure 1b). Among the patients receiving no maintenance, the OS from auto-SCT2 was 41.6 months (95% CI: 29.3–53.7). The relationship between PFS and OS after auto-SCT2 and the response duration after auto-SCT1 are shown in Table 3. We also examined the median OS from the time of relapse after auto-SCT1 and the impact of additional therapy before auto-SCT2. The median OS from the time of relapse after auto-SCT1 was 60 months (95% CI: 51–67) and was similar for the 26 patients not getting any chemotherapy before auto-SCT2 (57 months) compared with 60 months for the rest (P=0.015).

Figure 1
figure1

The Kaplan–Meier curve for PFS (a) and OS (b) after salvage auto-SCT is shown (shading in a and b represents the 95% CI).

Table 3 Time to progression after auto-SCT1 and its effect on PFS and OS after auto-SCT2

There were 72 patients (73%) who received more salvage therapy upon progression after auto-SCT2 and the median number of salvage regimens administered was 2 (range: 1–9). Several regimens with various combinations of drugs were used as salvage therapy. There were 43 (44%) patients treated with bortezomib; 32 patients (33%) treated with lenalidomide; 26 patients (27%) treated with thalidomide and 32 patients (33%) treated with therapies involving enrollment in clinical trials. Finally, three patients (4%) also underwent a third auto-SCT during their lifetime post progression after auto-SCT2.

Prognostic variables

We examined several variables from the time of auto-SCT2 for their impact on outcomes after auto-SCT2. In a univariable analysis, a shorter time interval between the auto-SCTs, shorter TTP after auto-SCT1, more number of lines of therapy received before auto-SCT2, not achieving a CR after auto-SCT2 and a higher PCLI at time of auto-SCT2 were all significantly associated with a reduced PFS. Shorter TTP after auto-SCT1, the presence of refractory disease at auto-SCT2, more number of lines of therapy received before auto-SCT2, higher percentage of plasma cells in the BM before auto-SCT2 and a higher PCLI were associated with an inferior OS in a univariable analysis (Table 4). In the multivariable analysis that included only those factors highly significant in the univariable analysis (P0.01), shorter TTP after auto-SCT1, more lines of therapy before auto-SCT2, not achieving a CR after auto-SCT2 and a higher PCLI at auto-SCT2 predicted a shorter PFS (Table 4). Moreover, only shorter duration of response or TTP after auto-SCT1 predicted a shorter OS post auto-SCT2.

Table 4 Multivariable Cox regression models for PFS and OS after auto-SCT2

The PFS and OS were not affected by the presence of high-risk disease per FISH testing. There was no difference in PFS or OS between the patients who were re-infused with their previously stored stem cells vs stem cells obtained from re-mobilization. Specifically examining the outcome based on TTP after auto-SCT1, the median PFS for those patients with a TTP of <12 months was only 5 months compared with 11.5 months for those with a TTP of 12 months; P<0.001 (Figure 2a). Similarly, the OS for patients with TTP <12 months was 12.6 months compared with 41.6 months for the rest; P<0.001 (Figure 2b).

Figure 2
figure2

The Kaplan–Meier curves for PFS (a) and OS (b) after salvage auto-SCT, based on TTP after initial auto-SCT (<12 months vs 12 months) are shown.

Control group comparison

We used a control population to examine the overall impact of providing an auto-SCT2 in patients who relapse after an auto-SCT1. We matched using the TTP after auto-SCT (important prognostic factor and often the key determinant for deciding on an auto-SCT2), age at relapse from auto-SCT1 (determinant of transplant eligibility) and the year of relapse (similar availability of salvage therapies). No significant differences were seen between the two groups in terms of the baseline characteristics at diagnosis or at the time of the auto-SCT1, except for higher plasma cell percentage at the time of auto-SCT1 among the cases (14% vs 7%, P=0.02). The median OS from diagnosis for patients receiving auto-SCT2 was 102 months vs 92 months for those not receiving auto-SCT2 for relapsed disease, P=0.1 (Figure 3a). The median OS from the time of relapse post auto-SCT1 for patients receiving auto-SCT2 was 57 months vs 46 months for those not receiving auto-SCT2 for relapsed disease (log rank P=0.08, Wilcoxon P=0.01, Figure 3b).

Figure 3
figure3

The Kaplan–Meier curves for OS from the time of initial diagnosis (a) and OS from the time of relapse after initial auto-SCT (b) based on the use of a salvage auto-SCT vs no salvage auto-SCT (matched control group) are shown.

Discussion

MM patients have seen the emergence of several new therapeutic drugs in the last decade that have prolonged OS. Unfortunately, none of them have provided a cure. The most likely explanation of the high incidence of relapse after auto-SCT1 or the use of novel agents even after the CR achieved is the persistence of residual clonal myeloma cells.19 Auto-SCT2 has been employed in the management of recurrent MM by several groups.9, 10, 11, 12, 13, 14, 15, 16, 17 In the era of novel agents, our study tries to define the role of an auto-SCT2 as salvage therapy in patients who have had a previous auto-SCT (auto-SCT1). In our single center experience, auto-SCT2 appears to be a safe and effective treatment strategy for relapsed MM. The overall response rate was 86% in assessable patients with a median PFS and OS of 10.3 months and 33 months, respectively (Figures 1a and b). Furthermore, the rate of TRM was only 4% suggesting a favorable benefit-to-risk ratio.

Our study demonstrated that the TTP after an auto-SCT1 was independently predictive of PFS and OS after auto-SCT2; this is consistent with other previous reports of auto-SCT2 (Table 5). In our group of patients, an initial TTP after auto-SCT1 of <12 months was associated with a median survival of 12.6 months, compared with 43 months in patients with an initial TTP of at least 12 months. This is consistent with other reports of auto-SCT2, where TTP after first remission of 12, 18 or 24 months could be identified as a prognostic parameter.9, 10, 11, 12 A similar observation was seen in our institution where a TTP of <12 months after auto-SCT1 was predictive of shorter OS in a large group of patients irrespective of subsequent therapies given at relapse.20 It is not surprising that our data demonstrate that patients achieving a CR after their auto-SCT2 tend to benefit the most in terms of duration of response.

Table 5 Summary of various single center experiences with auto-SCT2 in relapsed myeloma

The proliferative rate of the malignant plasma cells measured by PCLI is a powerful and independent predictor of survival in newly diagnosed myeloma patients.21 Our study demonstrated its independent predictive value with a worse PFS after auto-SCT2 which may essentially correlate with the aggressiveness of the disease. Similarly, the more prior lines of therapy experienced by a patient was also a strong predictor in the multivariate model for an inferior PFS likely indicating the presence of more chemoresistant disease at the time of the auto-SCT2.

The presence of high-risk or adverse cytogenetics did not play a role in determining the benefit of auto-SCT2. Thus, one could speculate that patients classified by our current definition as having high-risk FISH who go on to have a prolonged TTP after auto-SCT1 may not necessarily behave as a high-risk or poor prognosis phenotype. Only 20 patients received maintenance therapy after their auto-SCT2 and there was a non-significant trend (P>0.01) to both an inferior PFS and OS (Table 4). This most likely demonstrates the higher risk biology of the disease itself among these patients that led their physicians to place them on maintenance therapy to begin with instead of just observation. One of the questions we tried to address was to see if the outcomes would be better with stem cells that were collected early on in the treatment of myeloma. Hypothetically, these cells may have better immunological effect against the myeloma cells, related to antigenic drift that may have occurred in the tumor cells over time. There was no difference in PFS or OS between the patients who were re-infused with their previously stored stem cells vs stem cells obtained from re-mobilization.

The results of our study and other similar single institution studies are described in Table 5; however, the debate on the role of an auto-SCT2 vs novel agents as salvage therapy in relapsed disease continues. Even though it is neither appropriate nor effective in comparing results from different studies, the overall response rates of auto-SCT2 in our study were 86% which is comparable to those reported with salvage therapy regimens containing novel agents.5, 6 Hence, with comparable efficacy between novel agents and auto-SCT2, it is crucial to offer therapies that strike a balance between intensity and duration of therapy with the goal of reducing toxicity. Auto-SCT2 has an initial risk of significant toxicity but it may also provide the potential of having a prolonged time of treatment in appropriately selected patients. On the other hand, novel agents such as thalidomide, lenalidomide or bortezomib are associated with a higher risk of grade III or IV toxicities such as neuropathy, myelosuppression and thrombosis.22, 23, 24, 25 Hence, providers and patients may prefer the transient toxicity associated with auto-SCT2 in place of the continuous toxicities of novel agents. There is no evidence that the efficacy of future novel agent salvage therapies may be compromised by the prior sequence of salvage transplantation therapy.26 Moreover, with the increasing cost of novel agent-based regimens in terms of drugs and prophylaxis costs; considering an auto-SCT2 as a salvage regimen could be cost effective and safe while at the same time capable of providing durable benefit in appropriately selected patients such as those who have had a prolonged TTP after their auto-SCT1.

Given the limitations of the retrospective nature of the study, we cannot definitively compare the outcomes among those who had an auto-SCT2 with those who had non-auto-SCT-based salvage therapies only. The comparison with the matched control suggests a trend towards improved OS with the auto-SCT2 compared with non-auto-SCT therapies. However, the small patient numbers in the current study do not allow us to draw definitive conclusions. Moreover, due to its retrospective nature, this study does not provide any information regarding quality of life issues that would be a very important determinant in choosing auto-SCT vs other systemic therapy. Hence, in deciding whether auto-SCT2 for relapsed myeloma is the best choice in comparison with other salvage regimens, the answer remains unclear and difficult to discern in the absence of comparative trials. Until then we can use studies such as ours and other smaller, single-center studies as shown in Table 5 to gain insight into the appropriate use of auto-SCT2.

In conclusion, we believe that auto-SCT2 has a favorable risk/benefit profile and it should be considered as an option in relapsed/refractory patients who have had at least 12 months TTP after the auto-SCT1 irrespective of the presence of high-risk cytogenetics. Those patients who do not meet these criteria should be treated with combinations of immunomodulatory drugs and proteasome inhibitors or within investigational studies.

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Acknowledgements

This work is supported in part by Mayo Clinic Hematological Malignancies Program, Paul Calabresi K12 Award (CA96028). Supported in part by grants CA 107476, CA 62242, CA100707 and CA 83724 from the National Cancer Institute, Rockville, MD, USA. Also supported in part by the Jabbs Foundation, Birmingham, UK and the Henry J Predolin Foundation, USA.

Author contributions: SKK designed the study, collected and analyzed the data and wrote the manuscript; WIG collected the data and contributed to writing the manuscript; AD, MQL, MAG, SRH, FKB, DD and WJH contributed to writing and reviewing the manuscript.

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Correspondence to S K Kumar.

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Keywords

  • multiple myeloma
  • auto-SCT
  • salvage therapy

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