P-159: Increased risk of second primary malignancy and mortality at ten years after stem cell transplant for Multiple Myeloma: an analysis of 14,532 Patients

AbstractAutologous stem cell transplant (aHSCT) is associated with improved survival for multiple myeloma (MM) patients but may be associated with second primary malignancy (SPM) development. Using the California Cancer Registry linked to statewide hospitalization data, we determined the cumulative incidence (CMI) of SPMs more than 1 year after MM diagnosis, accounting for the competing risk of death. AHSCT recipients were matched 1:2 to non-aHSCT patients. Adjusted hazard ratios (aHR) were estimated using the Fine and Gray method. Among 16,331 patients, 933 (5.7%) developed a SPM more than 1 year after diagnosis. The 10-year CMI of developing any SPM was 6.6%, 5.7% for solid tumor SPM and 0.9% for hematologic malignancies. The 10-year CMI of developing any SPM was similar among aHSCT [9.1% (7.7–10.7%)] and non-aHSCT [7.5% (6.5–8.6%)] (P = 0.26) recipients and there was no difference in solid-tumor SPMs (P = 0.98). The 10-year CMI of hematologic SPMs was higher among aHSCT recipients [2.1% (1.4–2.9%) vs. 0.8% (0.5–1.2%); P = 0.005], corresponding to a 1.3% absolute increase and an aHR of 1.51 (1.01–2.27). Ten-year myeloma-specific and non-cancer mortality rates were 59% (58.2–60.0%) and 18.1% (17.4–18.8%), respectively. Although aHSCT was associated with a small increase in hematologic SPMs, mortality was driven by MM and non-cancer causes.

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Acute Lymphoblastic Leukemia following Lenalidomide Maintenance for Multiple Myeloma: Two Cases with Unexpected Presentation and Good Prognostic Features

Case Reports in Hematology ◽

10.1155/2018/9052314 ◽

2018 ◽

Vol 2018 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Abdullah M. Khan ◽

Jameel Muzaffar ◽

Hermant Murthy ◽

John R. Wingard ◽

Jan S. Moreb

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Bone Marrow Biopsy ◽

Lymphoblastic Leukemia ◽

Second Primary ◽

Cell Transplant ◽

Second Primary Malignancy ◽

Primary Malignancy ◽

Prognostic Features

Lenalidomide maintenance following autologous stem cell transplant (ASCT) is considered the standard of care for eligible patients with multiple myeloma (MM). A recent meta-analysis has provided additional evidence that lenalidomide maintenance is associated with a higher incidence of second primary malignancies, including both hematologic and solid malignancies. Acute lymphoblastic leukemia (ALL) as a second primary malignancy is rarely described in the literature. Herein, we describe two patients with MM treated with induction therapy, ASCT, and lenalidomide maintenance that experienced cytopenias while on maintenance. ALL was unexpectedly diagnosed on bone marrow biopsy. One patient was diagnosed on routine biopsy performed as part of requirements of the clinical trial. Both patients had B-cell ALL, without known poor risk cytogenetics, and were managed with standard induction therapies resulting in complete remission. We also reviewed the literature for similar cases of secondary ALL (sALL) in MM patients exposed to immunomodulatory drugs (IMiDs). In conclusion, persistent cytopenias in responding MM patients receiving IMiDs maintenance should be an indication for bone marrow biopsy. Patients develop sALL after median of 32.5 months (range, 20–84) from being on lenalidomide or thalidomide maintenance, often presenting with cytopenias, display low tolerance to chemotherapy, but remission can often be achieved.

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Maintenance Therapy with Thalidomide/Prednisone Post Autologous Stem-Cell Transplant for Patients with Multiple Myeloma Elevates D-Dimer and Possibly Factor VIII Levels.

Blood ◽

10.1182/blood.v106.11.2561.2561 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2561-2561 ◽

Cited By ~ 1

Author(s):

Michael J. Kovacs ◽

Judy-Anne W. Chapman ◽

Lois Shepherd ◽

Ralph Meyer ◽

Michael Keeney ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Maintenance Therapy ◽

Factor Viii ◽

Stem Cell Transplant ◽

Clinical Laboratory ◽

P Value ◽

Cell Transplant ◽

Increased Risk ◽

D Dimer

Abstract Background: Thalidomide is commonly used for the treatment of multiple myeloma (MM). Several studies have observed that venous thromboembolism (VTE) is a complication for up to 10% of patients receiving thalidomide therapy, especially when used as combination chemotherapy as part of primary treatment. Elevated Factor VIII and D-dimer levels are well described markers of thrombin generation and for an increased risk of VTE. The purpose of this study was to assess whether MM patients allocated to receive maintenance therapy with thalidomide and prednisone (thal/pred) post stem cell transplant for MM have increased levels of Factor VIII and D-dimer as laboratory confirmation for the reported increased clinical occurrence of VTE with thalidomide therapy. Methods: This is a correlative sub-study of NCIC CTG MY.10 which is an open-label randomized multicentre trial assessing the efficacy (time to progression) of maintenance therapy with the combination of thalidomide 200mg/day and prednisone 50mg every other day compared to no maintenance therapy post stem cell transplant. No clinical outcomes are available at this time as the study is ongoing. This laboratory companion study was incorporated in MY.10 a priori. Eligible patients were registered and randomized 60–100 days post transplantation. All consenting patients had plasma samples collected and frozen at baseline and two months post study enrollment. An unmatched comparison by MY.10 treatment arm was performed to assess the change in D-dimer and Factor VIII from baseline to two months for the first 79 patients entered into the trial. Results: There were 37 patients allocated to thal/pred (28 males, 76%) and 42 on observation (29 males, 69%). The mean ages were 56.6 and 55.8 years respectively. Based on continuous log D-dimer and log Factor VIII using two-way ANOVA, the results are shown in Table 1. Since D-dimer is also reported as positive or negative (<200 or =/>200μg/l) this was also assessed and the results as shown in Table 2. D-dimer results were significantly different (Bonferroni, p = 0.05) at two months compared with baseline for patients allocated to thal/pred rather than observation alone. At two months there were also significantly more patients allocated to thal/pred who had elevated D-dimers, 13 (72%) versus 5 (28%), (Bonferroni p < 0.05). There was a trend towards higher Factor VIII levels in patients allocated to thal/pred than on observation. Conclusion: These results provide clinical laboratory evidence of thrombin activation with the use of thal/pred post autologous transplant in patients with MM, and offer a potential mechanism, as well as, potential predictive markers for the clinical observations to date that patients receiving treatment with thalidomide for MM have an increased risk of VTE. Table 1 Mean Unadjusted Baseline 2 months p-value thal/pred Observation thal/pred Observaton (D-dimer μg/l) 119 101 137 75.6 0.03 FVIII (units/ml) 1.25 1.30 1.60 1.26 0.09 Table 2 D-dimer # ≥200(μg/l) Unadjusted p-value N thal/pred Observation Pearson Exact Chi-square Fisher Baseline 23 10 (43%) 13 (57%) 0.70 0.81 At 2 months 18 13 (72%) 5 (28%) 0.01 0.02

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Rituximab Administration Following Autologous Stem Cell Transplant for Multiple Myeloma Is Associated with Severe IgM Deficiency.

Blood ◽

10.1182/blood.v104.11.4897.4897 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4897-4897

Author(s):

Seah H. Lim ◽

Yana Zhang ◽

Zhiqing Wang ◽

Rupa Varadarajan ◽

Phillip O. Periman ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

B Cells ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Control Group ◽

Cell Transplant ◽

Increased Risk ◽

Igm Deficiency

Abstract Clonotypic B cells are frequently isolated from the peripheral blood of patients with multiple myeloma (MM). These clonotypic B cells may be clonogenic cells of MM. We hypothesized that rituximab may be a useful maintenance therapy in MM after autologous stem cell transplant (ASCT). The rationale was that CD20 antibody would deplete the clonotypic and, hence, clonogenic B cells to reduce the risk of disease relapse. ASC were mobilized with Cytoxan (3g/m2) and G-CSF from patients with MM. Two weeks after ASC collection, high dose IV melphalan (200 mg/m2) was administered followed 24 hours later by the infusion of at least 2x106/kg CD34+ cryopreserved ASC. Rituximab infusion (375 mg/m2) was started on day +30. Each patient received one antibody infusion every 3 months for 2 years or until disease progressed. All patients continued on monthly zoledronate and did not receive any other antimyeloma treatment. A total of 10 patients have been treated. Seven patients who have had post-transplant follow-up periods of >12 months were evaluated. The immunoglobulin recovery and incidence of infections in this group of patients were compared to 6 patients with MM who have undergone an ASCT without rituximab maintenance. The total normal IgM level in all 7 patients was severely depressed following rituximab administration. IgG and IgA were variably affected in these patients. The IgM immunosuppression was prolonged and consistent, being seen in all patients, regardless of the disease status after transplantation. In contrast, the control group showed normalization of the total IgM levels by 3 months after transplant. Two patients treated with rituximab received pneumococcal vaccines 12 months after transplant and neither developed any IgG response to the vaccines. The data indicate that rituximab infusion following ASCT for MM severely impaired B-cell immune reconstitution. Six of the 7 patients developed moderate to severe infections during the first 12 months after initiation of rituximab infusion. There were a total of 23 episodes of infections: 21 pneumonia and 2 septicemia (one pneumococcus and one Pseudomonas). A patient died in CR due to pneumonia. In contrast, only one episode of pneumonia was observed in the control group during the same follow-up period. Therefore, the IgM deficiency probably predisposed the patients to infection. Of the 7 patients who have had more than 12 months of follow-up periods, 4 had disease refractory to standard induction chemotherapy. Of all the 10 patients treated, 6 achieved CR (2 were in CR before treatment, 2 achieved CR 3 months and 2 achieved CR 6 months after starting rituximab). All 4 patients with refractory MM (all had a follow-up of more than 12 months) achieved CR, one before and 3 after starting rituximab. One of the refractory patients has since relapsed, one died of pneumonia in CR 12 months and the other 2 have remained in CR 12+ and 18+ months after ASCT. With a follow-up of 29 months after transplant, the progression-free survival was 56.5% and the overall survival 71.4%. Rituximab infusion after ASCT for MM is therefore associated with severe IgM deficiency and an increased risk of infection. Further works are needed to determine the antitumor activities of rituximab in MM in the setting of minimal residual disease, but this should only be carried out with special attention to the prevention of infection.

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Factors Contributing to Renal Failure in Patients Undergoing Stem Cell Transplant for Multiple Myeloma and Amyloidosis.

Blood ◽

10.1182/blood.v108.11.5464.5464 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5464-5464

Author(s):

Elie M. Richa ◽

Jeffrey L. Winters ◽

Douglas J. Padley ◽

Robert E. Stowers ◽

Sandra C. Bryant ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Renal Failure ◽

Stem Cell ◽

Creatinine Clearance ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Increased Risk ◽

The Mean ◽

Chi Square Analysis

Abstract Autologous stem cells transplant in tandem is considered the standard therapy for patients with Multiple Myeloma (MM) and Primary Amyloidosis. The collection as well as the infusion of stem cells, which are preserved in dimethyl sulfoxide (DMSO), may cause serious side effects including renal failure. We reviewed the charts of MM patients undergoing stem cell transplant from 2001 through the end of 2005. Patients were grouped into one of 3 categories: Amylodosis, MM with Immunoglobulin G (IgG) and MM with non IgG. Creatinine and creatinine clearance values were collected 14 days prior to, the day of, 3 days post, and 28 days post infusion. The volume of the transplant as well as the number of CD 34+ stem cells reflect the dose of DMSO infused since all the cryopreservation of cells were done with 105 DMSO solution. We also collected data about the administration of nephrotoxic agents such as Aminoglycoside antibiotics, Vancomycin and Amphotercin B because these patients are at increased risk of developing infections. We also reviewed the dose of consolidation chemotherapy (Melphalen) as a potential nephrotoxic agent. Chi-square analysis was used. 645 patients were included [380 (58.82%) males and 265 females (41.18%)]. 384 received Vancomycin, 7 received Gentamycin and 8 received Amphotericin B with total of 146 missing data. 191 (29.57%) had Amyloidosis, 285 (44.12%) IgG MM and 169 (26.32%) non IgG MM. Only 6 transplants were allogeneic. The dose of Melphalen ranged between 0–200 mg/m2 over 2 days at the discretion of the physician. The mean weight was 82.25 Kg and median weight was 81.8 Kg. The mean age 57.12 years and median age was 58 years. 608 patients (94.12%) had one transplant, 35 (5.42%) had 2 transplants and 3 (0.46%) had 3 transplants. The mean volume was 289.20 ml and median volume was 245 ml. The mean number of CD34+ cells was 5.39 × 10(6)/kg with a median of 4.74 × 10(6). The mean and median Creatinine levels were 1.26 mg/dl and 1 mg/dl respectively at 2 weeks prior to transplant, 1.23mg/dl and 1mg/dl on the day of transplant, 1.18 mg/dl and 1mg/dl at 3 days after transplant and finally 1.16mg/dl and 0.9mg/dl at 4 weeks interval. 67 males as well 50 females had renal failure prior to transplant but there was no statistical difference due to gender (p 0.001). Creatinine clearance levels were 83.96 ml/min at 2 weeks prior, 83.84 ml/min at day zero, 88.57 ml/min and 91.89 ml/min respectively. The median were 83.37 ml/min, 82.77 ml/min, 86.43 ml/min and 91.29 ml/min respectively. Even though 35 creatinine values were missing within the first 3 days period, there was no acute renal failure (ARF) (0.5 mg/dl increase) noted with a 95% C.I. 95% in 494 patients with normal creatinine. The creatinine level improved in 93 patients with an abnormal level and only 24 were left with abnormal levels. This might represent a dilutional effect due to fluid administration during the transplant. Concerning the incidence of chronic renal failure (CRF) at 4 weeks interval, considering that only 47 laboratory values were missing the results was as follows: 4 patients had > 0.5 mg/dl creatinine increase from the 485 normal patients with C.I. 95%. CRF was still observed in 38 patients of the 72 patients with baseline renal failure. Even though 9 had very poor creatinine clearance <10ml/min (p 0.01) only 5 were left with severe creatinine clearance after transplant (p 0.05) We found that DMSO does not induce ARF or an exacerbation of CRF in transplants patients for Amyloidosis and Multiple Myeloma.

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Development of Second Primary Malignancies in Multiple Myeloma Patients Treated with Lenalidomide: An Alberta Perspective

Blood ◽

10.1182/blood.v128.22.4528.4528 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4528-4528

Author(s):

Katherine Fung ◽

Peter Duggan ◽

Carole Chambers ◽

Patrick Shui-Lun Yau ◽

Deonne Dersch-Mills ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Radiation Therapy ◽

Stem Cell ◽

Stem Cell Transplant ◽

Alkylating Agents ◽

Second Primary ◽

Cell Transplant ◽

Immunomodulatory Agents ◽

Second Primary Malignancies

Abstract Background: Use of immunomodulatory agents such as lenalidomide have increased overall survival rates in multiple myeloma patients, but has been linked to increased development of second primary malignancies (SPM). The estimated incidence of SPM in multiple myeloma patients treated with lenalidomide ranges from 2.3- 7.2% in the literature. Objectives: The primary objective of this study was to identify the proportion of patients in Alberta who used lenalidomide to treat multiple myeloma and developed a SPM. Secondary objectives were to evaluate the types of SPM that occurred, examine duration of lenalidomide therapy, evaluate the impact of exposure to other immunomodulatory agents, alkylating agents, radiation therapy and stem cell transplant on the development of SPM, and compare overall survival between patients with and without a SPM. Methods: A retrospective chart review was conducted using the electronic medical record system ARIA Medical Oncology, the Alberta Cancer Registry, and the pharmacy dispensing system BDM Pharmacy from January 1, 2008 to June 30, 2015. Patients were eligible to be included if they received at least one dose of lenalidomide for multiple myeloma during the study timeframe and were ≥ 18 years of age. In addition to patient demographics, data collected included date and cause of death, cancer diagnoses prior to multiple myeloma, diagnosis of SPM, duration of lenalidomide therapy, and treatment with other immunomodulatory agents, alkylating agents, radiation therapy and stem cell transplantation. Non-invasive malignancies, such as squamous cell and basal cell carcinoma were excluded from the primary outcome. Results: A total of 777 charts were reviewed, of which 768 patients were included. The average age at diagnosis was 63.7 years (33 - 89 years), and 59.8% were male. Mean duration of follow up from the start of lenalidomide therapy was 27 months (1 -144 months). The average number of lenalidomide cycles received was 19 (1 - 121 cycles). There were 41 SPM, including 30 solid tumours and 11 hematological SPM, that developed in 35 lenalidomide treated patients resulting in an occurrence rate of 5.3%. Five patients developed more than one SPM, with one patient found to have as many as three different SPM. No difference was identified in the rate of SPM in patients who received alkylating agents, other immunomodulatory agents or radiation therapy. Patients who developed a SPM received treatment for a longer duration (26.5 vs. 19 mean cycles, p= 0.021) and were less likely to have had a stem cell transplant (34.3% vs. 52.3%, p=0.038). Prior to the diagnosis of myeloma, 127 malignancies had been diagnosed in 107 patients, and was similar between the two groups (22.9% vs. 13.5%, p=0.086). There was no difference found in overall survival between those patients with a SPM and those without (96.9 vs. 95.0 mean months, p=0.872). Conclusions: In this population-based study, rates of SPM identified in Alberta were similar to rates reported in the literature and overall patient survival was not found to differ between patients who developed a SPM and those who did not. Patients that developed a SPM received more cycles of lenalidomide and were less likely to have had stem cell transplant. There appeared to be higher rates of SPM in those patients who had a malignancy diagnosed prior to the development of multiple myeloma, but the difference was not statistically significant. Further research is needed to investigate the correlation between the development of a SPM and the number of malignancies found prior to being diagnosed with multiple myeloma. Disclosures No relevant conflicts of interest to declare.

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