Multiple Myeloma (MM) following other malignancies is a
rare type of malignant plasma cell disorder. To the best of
our knowledge, only 23 cases of MM following other malignancies
and its coexisting symptoms have been documented
in PubMed MEDLINE[1-23] (Table 1). MM can occur after the appearance
of solitary tumors, such as those in lung cancer and
gastric cancer, or hematological malignancies, such as MyeloProliferative
Neoplasm (MPN) and lymphoma. We report the
first case of a patient with MM following bladder cancer. The
satisfactory clinical recovery of this patient after treatment
with bortezomib is also discussed.
A 71-year-old male patient was admitted to the Second Affiliated
Hospital of TianJin Medical University in January
2010 after being diagnosed with approximately one-month
totally painless gross hematuria. The patient did not have a
history of dysuria, urinary urgency, or urethral discharge that
could indicate an infectious or inflammatory process. No
fever was evident, but the patient occasionally complained
of blood clot discharges and flank pain. B-scan ultrasound
revealed multiple hypoechoic masses or nodules in the anterior
bladder wall and bladder neck. Complete blood count,
renal function, and globulin levels were normal. No other
evidence of metastatic disease was found elsewhere in the
body. Transurethral Resection of Bladder Tumor (TURBT)
was performed. The pathological diagnosis was low-grade
papillary transitional epithelium carcinoma (Figure 1). After
four cycles of intravesical Pharmorubicin RD instillation
(50 mg/m2, day 1; one week/cycle)after surgery, the patient
exhibited satisfactory clinical recovery. However, a follow-up
B-scan ultrasound evaluation five months after chemotherapy
revealed hyperechoic uplifted shapes on both sides of the
bladder neck, which suggested relapse of bladder cancer. No
symptoms and abnormalities were found upon laboratory examination.
Cystoscopic examination and TURBT were again
performed. Pathological analysis revealed intrinsic-membrane
fibrous tissue hyperplasia, as well as chronic inflammation
in the tissue overlying the transitional epithelium. No evidence of recurrence was observed, and no further therapy (including chemotherapy) was provided for four months after
the last surgery.
In July 2011, the patient was again referred to the hospital
with major complaints of intermittent fever and pain in
both lower limbs. The blood count [hemoglobin (Hb) 81 g/L;
mean corpuscular volume, 81.7 fl; mean corpuscular hemoglobin
concentration, 328 g/L; white blood cell and platelet
counts, normal] indicated normocytic, normochromic anemia.
The bone marrow contained an excess of plasma cells
(40.0%) (Figure 2). Immunohistochemical analysis of the
bone marrow showed that the tumor cells were positive for
monoclonal κ light chains, CD38, and CD138, but negative for
CD79a, CD5, and CD10. Flow cytometric results are as follows:
R5 2.0%: CD38 (47.8%), CD138 (31.1%), CD56 (40.2%),
and CD20 (-).
Immunoelectrophoresis and immunofixation showed a spike
in the γ globulin region corresponding to a monoclonal protein
(M protein) in the serum and in the urine. The patient had
hyperglobulinemia (IgA 3550.0 mg/dL, κ light chain 2810.0
mg/dL), with a noticeably high κ/λ ratio of 30:1. The creatinine
level was 108 µmol/L. Plasma albumin (ALB) and lactate
dehydrogenase levels were normal (37 g/L and 128 U/L, respectively).
The ß2M level was increased (6.56 mg/L). Serum
C-reactive protein concentration was 2.98 mg/dl.
A skeletal survey revealed multiple lytic bone lesions in
ribs 4, 7, and 8. The adjusted serum calcium concentration was
2.69 mmol/L. Both cytogenetic and FISH analysis indicated a
normal karyotype (46, XX ). Both ras and p53 gene mutations
were detected in the bone marrow mononuclear cells by
reverse transcription-polymerase chain reaction.
A diagnosis of multiple myeloma (IgA κ) was given
(Durie–Salmon Clinical staging IIIA, ISS stage III). The patient
was then treated with one cycle of "VDZ" (1.3 mg/m2
bortezomib, d 1, 4, 8, and 11; 40/m2 dexamethasone, d1, 8, 15,
and 22; and 4 mg/m2 zoledronic acid, d1) for chemotherapy.
CBC was normal. Bone marrow aspiration and biopsy showed
3% plasma cell. Serum protein electrophoresis and immunofixation
indicated the presence of IgA κ monoclonal protein.
Bence–Jones proteinuria was again detected (806 mg/dl IgA,
1080 mg/dl κ light chain, and 7.1:1 κ/λ ratio), and good partial
remission was achieved based on the evaluation. The patient
further received two regular cycles of "VDZ" chemotherapy (every cycle per month) and consistently showed good partial response. After the second and third cycles of consolidation
chemotherapy, the percentages of plasma cells were separately
3% and 1%. Concentrations of IgA were 173 and 82 mg/dl,
those of κ light chains were 567 and 255 mg/dl, and κ/λ ratios
were 4.2:1 and 1.7:1. Bence–Jones proteinuria test results were
consistently oppositive. B-scan ultrasound did not show any
lesion in the bladder during follow up. The patient was advised
to discontinue bortezomib treatment because of grade 3 toxicity
(bortezomib-induced peripheral neuropathy) and refused
to receive other therapy. Numbness of extremities gradually
In June 2013, the patient presented with severe anemia
(Hb, 52 g/L) and gross hematuria. B-scan ultrasound and cystoscopic
examination confirmed the relapse of bladder cancer.
A pathological examination revealed high-grade invasive
urothelial carcinoma with invasion of the epithelial lamina
propria. Bone marrow aspiration revealed 50% plasma cells.
The patient received two cycles of the "VDZ" regimen, and the
aforementioned symptoms were relieved. Very good partial
remission was again achieved. However, the patient refused to
receive further treatment and was discharged against doctor's
MM following other malignancies is a rare clinical entity. To
our knowledge, only 23 cases of this condition have been reported
in the literature: four cases involved MM following solitary
tumors, such as those in lung cancer, colon adenocarcinoma,
prostate adenocarcinoma, gastrointestinal stromal tumor,
and penile myeloid sarcoma; four involved lymphoma; and 15
were incidences of MPNs, such as essential thrombocythemia,
chronic lymphocytic leukemia, chronic myeloid leukemia, and
chronic neutrophilic leukemia [1-24].
The etiopathogenetic factors of MM following other
malignancies remain undetermined. Whether the development
of MM is spontaneous or is accelerated by the treatment
of other malignancies is difficult to prove. The occurrence of
this type of MM can be explained by a number of factors .
Our patient, who has no history of alcohol or tobacco use,
developed MM after 18 months of treatment with Pharmorubicin
RD. In addition, the patient has no family history of cancer.
Both ras and p53 gene mutations were detected in the bone
marrow mononuclear cells by PCR at the time of MM diagnosis;
no chromosomal abnormality was found. The MM in our
patient may have resulted from treatment with anti-carcinoma
drugs. Anthracyclines inhibit DNA synthesis, block DNA
replication, and create free oxygen radicals that damage the
DNA. Anthracyclines can cause chromosomal abnormality,
with toxicity accumulation being dose dependent. Other secondary
malignancies were estimated at less than 2% within 10
years after anthracycline treatment. No case of MM induction
by anthracyclines has been reported. This case is the first reported
incidence of MM development after exposure to Pharmorubicin
RD alone. However, our patient received localized
intravesical Pharmorubicin RD instillation with no systemic
chemotherapy for four cycles (total accumulated dose of 200
mg) without receiving any prior treatment for bladder cancer.
Furthermore, no chromosomal abnormality was found in our
patient. Therefore, evidence to prove that anti-bladder cancer
therapy could possibly cause myeloma development was insufficient
in this case.
The development of MM and bladder cancer involves
genomic instability. Therefore, the patient may have possessed
a genetic defect predisposing the development of frequent neoplasia.
Both ras and p53 genes are carcinogenic genes that are
closely related to MM and bladder cancer. Mutations of these
genes were also detected in our patient. These two genetic mutations
may have triggered the occurrence of the two distinct
malignancies. Another possible explanation for the biological
mechanism of MM is that one genetic mutation (ras or p53)
occurred at the onset of bladder cancer in the first stage, consequently
creating a possible preneoplastic state for MM. The
other gene (p53 or ras) mutated in the second stage under
immune-deficient conditions and resulted in overt MM. This
condition is a called a "two-hit phenomenon." However, the
genetic mutations in bone marrow were undetected during biopsy
and diagnosis of bladder cancer. However, the most likely
explanation for the development of MM is predisposition to
The treatment process for this patient is also notable.
The different progressive biological activities of both
neoplasms, including the markedly divergent responses to
therapies, contributed to a significant clinical dilemma. The
presence of two neoplasms in one patient is a therapeutic
challenge. A review of the literature showed that no standard
treatment has been established for MM following other malignancies.
Most cases in the literature temporarily received
divergent treatment regimens for different cancers. This condition
may have been caused by the superposition of side effects,
particularly severe bone marrow failure, sepsis, and major organ
failure caused by various antineoplastic agents, which may
eventually result in death. MM following other malignancies
has a relatively poor prognosis. Median disease-free survival
was less than 10 months, even if the patients received regular
chemotherapy without bortezomib.
In this report, our patient received bortezomib treatment.
Bortezomib reversibly inhibits the 26S proteasome,
which disrupts various cell signaling pathways and leads to
cell cycle arrest, apoptosis, and inhibition of angiogenesis.
Bortezomib has been approved and widely used as the first
therapeutic proteasome inhibitor for patients with relapsed
or refractory MM and mantle cell lymphoma . Successful
treatment of simultaneous MM and bladder cancer by bortezomib
has not yet been reported. Nevertheless, in vitro and
in vivo data from cell cultures and clinical trials support the
hypothesis that bortezomib induces bladder cancer cell death
and inhibits angiogenesis [27-30]. Bladder cancer rapidly relapsed
and progressed because of the absence of a sensitive
therapy, including TURBT and Pharmorubicin RD, at the
early stage. Therefore, bortezomib was administered to our
patient with MM and bladder cancer. Good clinical response
was achieved for 20 months. Relapse of MM and bladder cancer
occurred after discontinuation of bortezomib therapy.
Complete remission was again achieved after three cycles of bortezomib. Although direct evidence of the efficacy of bortezomib as a targeted therapy for bladder cancer is currently
lacking, administration of bortezomib may be feasible because
this drug is cytochrome independent. Further studies are required
to improve the management of this rare case of coexisting
To the best of our knowledge, this study is the first to
report on an MM case following bladder cancer treated with
Pharmorubicin RD alone. Genetic mutations may have been
involved in the development of MM. The successful treatment
of the condition with bortezomib may be used as a clinical basis
for future treatment of concomitant MM and other malignancies.
YH. Wang and FP. Peng have contributed equally to this work.
This study was partly supported by Tianjin Bureau of Public
Health (No. 2010KZ105), Tianjin Medical University
(No. 2010ky20), and Natural Science Foundation of Tianjin
Municipal Science and Technology commission (No.
The authors do not have any conflict of interest.