Secondary primary malignancies in patients with multiple myeloma treated with
high-dose chemotherapy and autologous blood stem cell transplantation
Roland Fenk, Florian Neubauer, Ingmar Bruns, Christian Saure, Thomas Schröder, Ulrich Germing, Rainer Haas and Guido Kobbe
Abstract # 4087
Dept. of Hematology, Oncology and clinical Immunology, Heinrich Heine University, Duesseldorf, Germany
Introduction and Methods:
Results:
Secondary primary malignancies (SPM) are an emerging issue in
Within 313 patients with a median age of 55 (range: 31-74) years at diagnosis, we observed 18 (5.8%) patients who
Table 2: Univariate Analysis
patients with multiple myeloma (MM) since the lenalidomide arm of the
developed a SPM at various time points during the course of their disease. The number of patients who developed a
of Risk factors for SPM
French IFM 2005-02 trial has been closed as a consequence of a higher
solid neoplasm or a hematologic malignancy was identical. While the types of solid tumor observed varied greatly,
P
HR
95% CI
incidence of SPM in patients who had received lenalidomide as
we noted 8 patients with MDS/AML and only one patient with Hodgkins Disease (Table 1). The median time from
Gender f m
0.2
1.8
0.7 4.5
maintenance treatment compared to the patients in the placebo arm.
diagnosis of MM to the occurrence of SPM was 56 months (range: 14-127). The cumulative incidence of SPM (Figure
MM subtype IgG other
0.2
2.2
0.6 7.7
To evaluate the incidence of SPM in the group of patients, who were
1) was 19.7% with a rate of 0.7%, 5.8% and 15.7% at 2, 5 and 10 years after diagnosis without statistical differences
LC type lambda kappa
0.6
1.3
0.5 3.4
treated with high-dose therapy (HDT) followed by autologous peripheral
between the group of patients with solid tumors (0.3%, 4.4%, 7.5%) and those with hematologic malignancies (0.4%,
blood stem cell transplantation (PBSCT), we retrospectively looked at a
1.8%, 9.3%).
D&S stage 1/2 3
0.1
0.2
0.03 1.6
homogeneous group of 313 consecutive patients, who were diagnosed
OS from the time of diagnosis in our group of 18 patients with SPM was not significantly different from that of patients
Stage A B
0.4
23.2
0.01 >999
with MM and had received HDT and autologous PBSCT at our hospital
without SPM with in median 70 and 83 months (p=0.7, HR 0.9 (0.5-1.7)), respectively (Figure 2). The same was true,
ISS stage 1/2 3
0.9
0.9
0.2 3.9
between December 1994 and January 2009. Induction treatment
when a landmark analysis was performed for patients alive after 2, 5 and 8 years with hazard ratios of 0.9 (95%CI
Prior stage 1 no yes
0.6
0.7
0.2 2.5
consisted of conventional chemotherapy without novel agents in 95% of
0.51.7, p=0.8), 0.6 (95%CI 0.31.4, p=0.2) and 1.0 (95%CI 0.24.3, p=1.0), respectively. In line with this finding, we
Prior MGUS no yes
0.8
1.2
0.2 9.2
patients and maintenance treatment was given with interferon or
found that survival time of more than 5 years from the time of diagnosis was the only prognostic parameter indicating
ß2microglobulin < > 5.5 mg/dl
0.8
0.9
0.2 3.8
thalidomide in 37% und 35% of patients, respectively.
a greater risk for the development of SPM (HR 4.7 (95%CI 1.1-19.8), p=0.04). In particular, we did not find any
Albumin < > 3.5 g/dl
1.0
1.0
0.3 3.6
relationship to the incidence of SPM and the treatment with novel agents (Table 2). The incidence rate of 206
LDH < > 200 U/l
0.7
0.8
0.3 2.4
patients, who were exposed to thalidomide was 6% (n=13, HR1.4 (95%CI 0.5-4.0), p=0.5), while of the 123 patients
CRP < >0.6 mg/dl
0.5
1.4
0.5 4.1
exposed to bortezomib 5 developed a SPM (4%, HR 0.4 (95%CI 0.1-1.1), p=0.1). There were two cases of SPM
Results:
Hemoglobin < > 10 g/dl
0.5
1.5
0.5 4.2
among the 71 patients following lenalidomide treatment (3%, HR 0.4 (95%CI 0.1-1.5), p=0.2).
Thrombocytes < > 100 *10^6/ml
0.6
0.05
0.0 >999
Characteristics of patients with MM and secondary primary malignancies (SPM)
Having a closer look at the maintenance setting (Figure 3), which is associated with a longer duration of drug
Cytogenetics normal abnormal karyotype
0.7
0.7
0.1 3.5
exposure, we did not find a higher incidence of SPM in patients treated with thalidomide maintenance after HDT in
Secondary
Sex
Treatment
Time from
Age at
Time from
Dead/
Cause of
Conditioning regimen M200 M reduced
0.4
23.6
0.01 >999
primay
(femal
before SPM
diagnosis to
SPM
SPM to follow-
alive
Death
comparison to patients who had received interferon or no maintenance therapy (HR 1.0, 95%CI 0.3 3.2, p=1.0).
malignancy
e/
SPM
(years)
up (months)
Age at HDT < > 60 years
0.07
0.4
0.2 11
male)
(months)
Best response CR/vgPR other
0.1
2.2
0.8 6.1
MDS
f
HDT-T
23
66
39
alive
First diagnosis before after 2000
0.1
0.4
0.1 1.2
Figure 1: Cumulative Incidence of SPM
Figure 2: Overall Survival
First diagnosis before after 2004
0.4
0.6
0.2 2.0
MDS
m
HDT-IFN
44
65
10
dead
unknown
OS < > 5 years
0.04
4.7
1.1 19.8
MDS
f
HDT-IFN; T, B
61
59
9
dead
pneumonia
Thalidomide no yes
0.5
1.4
0.5 4.0
Bortezomib no yes
0.1
2.6
0.9 7.4
MDS
m
HDT-T
78
49
52
alive
Lenalidomide no yes
0.2
2.8
0.7 12.4
MDS
m
HDT-T; L, B,
95
61
4
dead
MM
2.HDT
Figure 3: Risk of Death and Risk of SPM
MDS
m
HDT-T; B
127
50
78
alive
MDS/AML
m
HDT-T
50
63
14
dead
SPM related
AML
m
HDT-IFN; T, B
61
56
6
dead
SPM related
Hodgkin's
f
HDT-T
109
67
5
alive
disease
Breast
f
HDT-no
25
63
0
alive
cancer
Breast
f
HDT-m-allo
40
62
3
dead
MM
cancer
Breast
f
HDT-T; B
99
52
2
alive
cancer
Smallcell
m
HDT-IFN
53
65
9
dead
SPM related
endocrine
lung cancer
Conclusions:
Non smallcell
f
HDT-T; L, B
73
61
23
dead
SPM related
lung cancer
Squamous-
f
HDT-T
14
62
11
alive
In conclusion, the incidence of SPM in patients with MM treated with HDT is increased, especially for patients with a
cell
prolonged life span. SPM were not related to various treatment modalities including maintenance treatment with
carcinoma
thalidomide. As a consequence on the available data, physicians should be aware of the risk of SPM and diagnostic
(eyebrow)
measures to detect SPM should be included in the daily clinical workup of patients with MM.
Pancreatic
f
HDT-no
44
51
2
dead
SPM related
cancer
Parotid
m
HDT-no; T, B
51
57
1
dead
SPM related
cancer
Disclosure:
This work was supported by Leukämie-Liga e.V., Duesseldorf.
Prostate
m
HDT-T
59
69
32
dead
MM
1. Research Support: Celgene 1)2), Amgen 2)
5. Speakers Bureau:
no
cancer
2. Employee:
no
6. Honoraria:
Celgene 1)2) , OrhtoBiotec 1)2)
Corresponding author:
Leukämie
3. Consultant:
Celgene 1)2) , OrhtoBiotec 1)2) , Amgen 2) 7. Scientific Adisory Board: no
Roland Fenk, University of Duesseldorf;
Liga
HDT-T: high-dose chemotherapy with Thalidomide as maintenance therapy; HDT-IFN: high-dose chemotherapy with
4. Major Stock Holder: no
1) Fenk, 2) Kobbe
e-mail: Fenk@med.uni-duesseldorf.de
Interferon as maintenance therapy; HDT-no: high-dose chemotherapy without maintenance therapy; T: Thalidomide as
salvage therapy; L: Lenalidomide as salvage therapy; B: Bortezomib as salvage therapy