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Durable remission with salvage second autotransplants in patients with multiple myeloma
Version of Record online: 15 NOV 2011
Copyright © 2011 American Cancer Society
Volume 118, Issue 14, pages 3549–3555, 15 July 2012
How to Cite
Shah, N., Ahmed, F., Bashir, Q., Qureshi, S., Dinh, Y., Rondon, G., Wen, S., Thall, P., Khan, H., Giralt, S., Champlin, R. and Qazilbash, M. H. (2012), Durable remission with salvage second autotransplants in patients with multiple myeloma. Cancer, 118: 3549–3555. doi: 10.1002/cncr.26662
- Issue online: 2 JUL 2012
- Version of Record online: 15 NOV 2011
- Manuscript Accepted: 12 OCT 2011
- Manuscript Revised: 3 SEP 2011
- Manuscript Received: 20 MAY 2011
- salvage therapy;
High-dose chemotherapy with autologous hematopoietic cell transplant (auto-HCT) has been shown to improve survival in patients with newly diagnosed multiple myeloma. However, the role of salvage auto-HCT for relapsed patients, particularly in the era of novel therapeutics, is not well defined.
The authors performed a retrospective analysis of all 44 myeloma patients (24 men, 20 women) who received a second auto-HCT as salvage between January 3, 1992 and November 4, 2008 at The University of Texas MD Anderson Cancer Center.
Median interval between the first and salvage auto-HCT was 30 months (range, 2-78 months). Median age at salvage HCT was 54 years (range, 38-73 years), and median number of salvage treatment regimens was 2 (range, 0-5). Eleven (25%) patients had high-risk chromosomal abnormalities on conventional cytogenetic studies between diagnosis and salvage auto-HCT. Ten patients (23%) experienced grade 3 or higher nonhematologic toxicity after the salvage auto-HCT. One patient died within 100 days, for a treatment-related mortality of 2%. Best responses after salvage chemotherapy + salvage auto-HCT were as follows: complete response (CR) + near CR, 11%; partial response, 79%; overall response rate, 90%. Eighteen (41%) patients received post auto-HCT maintenance therapy. Median follow-up from salvage HCT was 41 months. Kaplan-Meier estimates of median progression-free survival (PFS) and overall survival (OS) from time of salvage auto-HCT were 12.3 and 31.7 months, respectively. Median OS from the time of diagnosis was 75 months. In a fitted Bayesian multivariate model, shorter time to progression after first auto-HCT, greater number of prior therapies, African American race, and immunoglobulin G subtype were significantly associated with worse OS.
In selected myeloma patients, a second auto-HCT for salvage therapy is well tolerated, with acceptable toxicity. The overall response rate and PFS are comparable to other salvage regimens. Cancer 2012;3549–3555. © 2011 American Cancer Society.
Multiple myeloma is the second most common hematologic malignancy in adults, with >20,000 new cases and 10,000 deaths annually in the United States.1 Several studies have supported the use of autologous hematopoietic cell transplant (auto-HCT) in the frontline setting for patients younger than 65 years with good renal function.2-4 However, this procedure is not curative, and the majority of patients inevitably relapse.
The management of patients who relapse after initial treatment with a single auto-HCT is still being debated. Novel agents such as thalidomide, lenalidomide, and bortezomib are active in the salvage setting; however, prolonged treatment can result in significant toxicities, and many current patients have already been treated with these agents in the induction phase. Numerous promising agents are in development, including newer generation immunomodulatory drugs and proteasome inhibitors, histone deacetylase inhibitors, and plasma cell-specific antibodies. However, the use of these is often limited to those patients who can participate in a clinical trial. Despite the use of approved novel agents, the progression-free survival (PFS) in a majority of patients with persistent or refractory disease is only 6 months to 14 months.5, 6 These numbers highlight the need for more effective therapy, especially in patients with good performance status. Several studies suggest that salvage auto-HCT is reasonably safe for selected patients and may grant additional PFS.7-10 In this study, we performed a retrospective review of all 44 patients who have undergone a second, salvage auto-HCT for multiple myeloma at The University of Texas MD Anderson Cancer Center through 2008.
MATERIALS AND METHODS
Forty-four patients received a salvage auto-HCT between January 1992 and November 2008. The information from these transplants was prospectively collected in our database and used for the current analysis. Eligible patients had a diagnosis of myeloma and had evidence of relapse (both by International Myeloma Working Group Criteria) after having undergone an auto-HCT. Patients who underwent a second transplant as part of a planned tandem regimen were not included in this study. In general, patients were eligible to receive the second transplant if they had an Eastern Cooperative Oncology Group performance status of <2 and had adequate renal (creatinine ≤2.0), cardiac (left ventricular ejection fraction >45%), pulmonary (diffusing capacity of the lung for carbon monoxide >50%), and hepatic (bilirubin, transaminases <2× upper limit of normal) function.
Hematopoietic Stem Cell Mobilization and Collection
Bone marrow or granulocyte colony-stimulating factor–primed peripheral blood progenitor cells were collected using standard mobilization protocols and apheresis techniques.11 Forty-three patients received a peripheral blood stem cell autograft, whereas 1 patient received a bone marrow–derived graft. Thirty-three patients received stem cells that had been collected before their first auto-HCT, whereas 11 patients underwent a second collection before their salvage auto-HCT. All patients signed written informed consent according to our institutional and the National Marrow Donor Program guidelines. The study was reviewed and approved by the institutional review board at The University of Texas MD Anderson Cancer Center.
Preparative Regimens and Supportive Care
Preparative regimen for the salvage transplant was high-dose melphalan alone (200 mg/m2, n = 21) or a melphalan-based combination (n = 21). Two patients received a combination of thiotepa (750 mg/m2), busulfan (various doses), and cyclophosphamide (120 mg/m2). Melphalan-based combinations used were as follows: 1) melphalan (140 mg/m2) with busulfan (520 mg/m2; n = 2), 2) melphalan (140 mg/m2) with topotecan (17.5 mg/m2) and cyclophosphamide (3 g/m2 n = 6), 3) melphalan (200 mg/m2) with arsenic trioxide (various doses; n = 9), 4) melphalan (200 mg/m2) with arsenic trioxide (various doses) and bortezomib (1 mg/m2 × 3 doses; n = 2), 5) melphalan (120 mg/m2) with busulfan (420 mg/m2) and gemcitabine (150 mg/m2 n = 1), or 6) melphalan (140 mg/m2) with total body irradiation (TBI) (n = 1). Patients received infection prophylaxis with levofloxacin or ciprofloxacin, fluconazole, and acyclovir or valacyclovir. Filgrastim 5 μg/kg was administered subcutaneously daily from day +1 after auto-HCT until the recovery of absolute neutrophil count (ANC) to >0.5 × 109/L for 3 days. Blood products were irradiated and filtered to remove leukocytes before transfusion. After recovery of neutrophil count, patients received infection prophylaxis with sulfamethoxazole-trimethoprim or pentamidine and acyclovir or valacyclovir.
Engraftment and Response
Responses were graded according to International Myeloma Working Group Criteria.12 Initial responses were assessed at approximately day 100 and final, best responses were determined at last follow-up. Neutrophil engraftment was defined as the first of 3 consecutive days with an ANC ≥0.5 × 109/L. Failure to engraft by day 30 was considered primary graft failure. Platelet engraftment was defined as the first of 7 consecutive days with a platelet count of ≥20 × 109/L without transfusion support. Adverse effects were graded according to current National Cancer Institute Common Toxicity Criteria.
Primary endpoints were Kaplan-Meier estimates of overall survival (OS) and PFS. Secondary endpoints were response rate, treatment-related mortality (TRM), and toxicity rates. OS was measured from the day of autologous stem cell infusion (day 0) 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. Death from any cause other than relapse before day 100 was classified as TRM. Patient characteristics were summarized using the median (range) for numerical variables or frequencies (percentages) for categorical variables. Differences in the distributions of patient characteristics between groups were assessed using Wilcoxon, Kruskal-Wallis, or generalized Fisher exact tests.13, 14 Unadjusted probabilities of event times were estimated using the method of Kaplan and Meier.15 The log-rank test16 was used to compare unadjusted OS and PFS between subgroups. Bayesian exponential regression models were used to assess the joint effects of patient covariates on OS, with the best fitting model chosen from the exponential, gamma, inverse gamma, Weibull, and log normal models using the Bayesian information criterion.17 In each multivariate regression model, the covariates included age, sex, race, log(CD34+ cell dose), time to progression (TTP) after first therapy sequence, number of prior therapies before salvage auto-HCT, International Staging System (ISS) stage, immunoglobulin subtype, and date of transplant (before or after January 1, 2003). The interaction terms (race = African American) × (histology = immunoglobulin [Ig] G) and (race = African American) × log(time from first to second stem cell transplant [SCT]) were also included into the model first, but were dropped from the model because they were not significant. The exponential model for OS assumes that the mean OS takes the form μ = exp(m), where m is a linear combination of covariate effects and interactions. We assumed that each parameter in the linear term followed a noninformative normal prior distribution value with mean 0 and variance 1000, and a noninformative gamma prior distribution value for r with mean 1 and variance 1000. All statistical analyses were carried out in Splus 6.1,18 and for the Bayesian model fits, in WinBugs 1.4 (MRC Biostatistics Unit, Cambridge, UK).
Patient characteristics are shown in Table 1. Of the 44 patients, 24 were men, and 20 were women. The median age at salvage transplant was 55 years (range, 38-73 years), and the median time between the first auto-HCT and the salvage auto-HCT was 30 months (range, 2-78 years). The median number of therapies received before salvage auto-HCT was 2 (range, 0-5). Eleven patients (25%) had high-risk chromosomal abnormalities on conventional cytogenetic studies at any time between diagnosis and salvage auto-HCT.19 Patients received a mean CD34+ cell dose of 4.1 × 106/kg (standard deviation, 1.8 × 106/kg). Thirty-seven (84%) patients received thalidomide, lenalidomide, or bortezomib in the induction setting, whereas 43 (98%) patients received those agents in the relapsed setting, before the salvage transplant. Fifteen patients (34%) received thalidomide, lenalidomide, or bortezomib maintenance therapy after the second transplant. Eighteen (41%) patients received any type of maintenance therapy.
|All patients, No. (%)||44 (100)|
|Sex, No. (%)|
|Race, No. (%)|
|African American||8 (18.2)|
|Age at salvage HCT, median y [range]||54.5 [37.5-72.9]|
|Time between first and salvage HCT, median mo [range]||30 [2-78]|
|No. of therapies before salvage HCT (after 1st HCT), median [range]||2 [0-6]|
|High-risk cytogenetics, No. (%)||11 (25.0)|
|Durie-Salmon stage, No. (%)|
|International staging system stage, No. (%)|
|CD34, mean (SD)||4.6 (1.8)|
|Histology, myeloma subtypes, No. (%)|
|κ or λ light chain||6 (11.4)|
|Maintenance with novel agent after salvage HCT, No. (%)||15 (34)|
Engraftment and Toxicity
Median time to neutrophil and platelet engraftment after the salvage auto-HCT was 10 days (range, 8-14 days) and 11 days (range, 6-398 days), respectively. Of 44 patients, 1 died within 100 days of the salvage transplant, because of supraventricular tachycardia and possible pneumonia, for a TRM of 2%. Ten (23%) patients experienced a grade 3 or higher nonhematologic toxicity, with symptom distributions detailed in Table 2.
|Organ System||Patients, No. (%)||Details|
|All organs||10 (23)|
|Cardiovascular||5 (11)||2 tachycardia, 1 hypotension, 1 bradycardia, 1 other|
|Gastrointestinal||3 (7)||2 diarrhea, 1 mucositis|
|Infectious||5 (11)||5 neutropenic infections|
|Pulmonary||2 (5)||1 effusion, 1 pneumonia|
|Skin||1 (2)||1 rash|
Response and Survival
Five patients (11%) eventually achieved complete response (CR) or very good partial remission, and the best overall response rate (ORR) from the time of relapse was 90%. Two patients (5%) had stable disease, and 1 patient (2%) had progressive disease. Median follow-up time from salvage auto-HCT in surviving patients was 41 months. After salvage auto-HCT, the median PFS was 12.3 months (range, 2 months to 98 months), and the median OS was 31.7 months (range, 0-96 months; Fig. 1). The median OS from time of diagnosis was 74.9 months (range, 25-165 months). In all, 8 patients (18%) had an improvement in their disease status from salvage chemotherapy after the salvage transplant. At last follow-up, 16 patients were alive, and 8 patients were alive who had not progressed.
We studied the impact of age, (log)CD34+ cell dose, TTP after first therapy sequence, number of prior therapies before salvage auto-HCT, sex, race, ISS stage, immunoglobulin subtype, and date of transplant (before or after January 1, 2003) on OS after salvage auto-HCT. The fitted Bayesian multivariate regression model for OS showed that shorter TTP after first transplant, larger number of prior therapies, race being African American, and IgG subtype were significantly associated with worse OS, where a significant effect in the fitted Bayesian model was defined as having a posterior probability of a harmful effect either >.95 or <.05 (Table 3, Fig. 2). There was no significant independent impact of any other factor on the OS, which may be a reflection of a heterogeneous population and relatively small number of events in each group. Detection of high-risk chromosomal abnormalities showed a trend toward a shorter OS (P = .07, data not shown).
|Beta||SE||Harmful Effect, P|
|TTP after 1st||−0.357||0.214||.038|
|No prior therapy||0.385||0.145||.995|
|Patients before 2003||−0.184||0.447||.343|
Despite numerous advances, multiple myeloma remains an incurable disease. Although novel agents and high-dose chemotherapy have improved response rates, patients eventually relapse and die from their disease. Given the rapid development in the field in recent years, we are now faced with the challenge of systematically determining how to best use our tools to improve survival and quality of life.
The idea of using a second, salvage transplant is appropriate, given the data with tandem transplants. In addition, patients who had a durable response to a first transplant may fare best after the salvage transplant.7, 20 For many patients, the issue of a second transplant at relapse is important. For these patients, the results of this study suggest 2 important conclusions: 1) a salvage transplant done at the time of relapse is safe, and 2) the benefit of the salvage transplant is comparable (or potentially superior) to other salvage regimens. In addition, our survival and toxicity data are comparable to published and preliminary reports from several other institutions with similar sample sizes.9, 21-23 Combining the results of our study with those of others, it appears that the salvage transplant is a viable option for select patients.
Another pressing issue facing myeloma physicians is having a long-term treatment plan, as our patients are living longer with their disease. In this setting, it is crucial to offer patients therapies that strike a balance between intensity and duration, such that toxicities can be limited. Although the salvage transplant does have an initial risk of significant toxicity, the potential of having a year or longer without treatment or with low-dose maintenance treatment may be appealing to many patients. In addition, other preparative regimens that build on melphalan may offer an opportunity to enhance the benefit of a salvage auto-HCT. Phase 2 studies combining melphalan with other agents in this patient population are ongoing at our institution.
In interpreting the results from this retrospective analysis, there are certainly limitations. The most obvious of these is a selection bias; more favorable patients were likely recommended for salvage auto-HCT, and thus these results may not be applicable to all patients. In addition, the sample size is small and distributed over >15 years. However, most of the patients did receive novel therapeutics at some point, making these results more pertinent to the contemporary patient population.
Given the relatively small sample size, it is not surprising that most of the prognostic factors studied did not affect OS significantly. The negative impact of shorter TTP and greater number of therapies is consistent with the known biology of the disease. However, the association between African American race and shorter OS is interesting. Although it is known that African Americans are disproportionately affected by multiple myeloma in incidence,24 there is debate over whether there is a difference in outcome in the era of auto-SCT. Preliminary analysis at our institution of all myeloma patients (including those not undergoing auto-SCT) in the era of novel therapeutics suggests that African Americans have a similar OS in comparison to Caucasian patients, but that fewer African Americans undergo auto-SCT.25 Although this is only a small analysis, one could hypothesize that an as yet undetermined factor is linked both to accessibility and success of auto-SCT, which might explain our current and previous findings in African American patients.
Our finding that IgG subtype was associated with a worse OS was also surprising. Although there are few studies examining the prognostic significance of Ig subtype, at least 1 retrospective analysis suggests that IgG subtype is not a poor prognostic indicator in myeloma patients as a whole.26 The relevance of subtype in the setting of second, salvage auto-HCT is less clear and may be an artifact of small sample size.
In deciding whether a salvage transplant for relapsed myeloma is the best treatment choice in comparison with other salvage regimens, the answer remains unclear. The ORR of the second auto-HCT in our study (90%) is comparable to that reported with lenalidomide/dexamethasone27, 28 or bortezomib-containing regimens29-36 for relapsed patients—although the chance of obtaining a CR or very good partial remission is likely greater with lenalidomide or bortezomib chemotherapy combinations. Our ORR also suggests that salvage pharmacotherapy and salvage auto-HCT are not mutually exclusive. The use of novel agents in combination with salvage auto-HCT may offer patients the best chance of response, because 98% of patients received a novel agent as part of their salvage regimen. The PFS in our study is also comparable to those achieved in the lenalidomide and bortezomib combination studies. However, it is hazardous to compare results between all of these studies, as there is marked heterogeneity in how many patients had previously been treated with thalidomide, lenalidomide, or bortezomib.
The ideal study to answer the question of salvage chemotherapy versus salvage auto-HCT would randomize patients to receive either combination chemotherapy only (for example bortezomib/dexamethasone/oral cyclophosphamide) or combination chemotherapy and a second, salvage transplant. In the absence of prospective, multicenter studies, we can turn to smaller, single-center studies. One British group study found no difference in outcomes whether relapsed patients received salvage chemotherapy or salvage auto-HCT.20 However, only a minority of these patients received thalidomide or bortezomib (none received lenalidomide) as part of their salvage therapy.
In conclusion, a second, salvage auto-HCT appears to be a safe and feasible treatment option for select patients with relapsed myeloma. This intervention can yield a durable remission and survival. Thus, patients with relapsed myeloma after a single auto-HCT should be considered for a salvage auto-HCT in an effort to provide an opportunity for a therapy-free interval.
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
- 1Cancer Facts and Figures. Atlanta, GA: American Cancer Society; 2006.
- 13Introduction to the Theory of Nonparametric Statistics: New York, NY: John Wiley & Sons; 1979., .
- 14On the interpretation of χ2 from contingency tables, and the calculation of P. J R Stat Soc. 1922; 85: 87-94..
- 18Modern Applied Statistics With S-PLUS. 3rd ed. New York, NY: Springer; 1999., .
- 21Second autologous stem cell transplant (ASCT) as salvage therapy in patients with relapsed multiple myeloma: improved outcomes in patients with longer disease free interval after first ASCT [abstract]. Blood. 2007; 110. Abstract 946., , , et al.
- 24SEER Cancer Statistics Review, 1975-2005. Bethesda, MD: National Cancer Institute; 2008., , , et al.
- 25Survival disparities between African-American and Caucasian patients with multiple myeloma are blunted in the era of novel therapeutics and autologous stem cell transplantation. Paper presented at: American Society of Hematology Annual Meeting; December 5-8, 2009; New Orleans, La., , , et al.