Sashim
Shah, MD
BACKGROUND
Multiple
Myeloma is a rare oncologic malignancy accounting for 1-2 percent
of adult cancers. It has an annual incidence of 14,000 people in
the U.S. and a prevalence of approximately 45,000 people.
It usually occurs in persons older than 55 years and the ratio of
men: women is 3:2.(1) This article will present a case review of
a man who has multiple myeloma and was initially treated with radiation,
dexamethasone and then thalidomide, which failed treatment and subsequently
began chemotherapy. This article will review the current treatment
of multiple myeloma and discuss new potential therapies.
CASE
PRESENTATION
This
is a 62 year old white male who was diagnosed with multiple myeloma
in spring of 2000 following an evaluation of L hip pain that occurred
after skiing. Plain films of the hip revealed multiple osteolytic
lesions consistent with multiple myeloma. Subsequent skeletal survey
showed multiple lesions throughout the body. The patient's painful
left hip was subsequently irradiated and the patient was started
on dexamethasone monthly for four months and bisphosphonates monthly.
Repeat bone marrow aspirates showed a decrease in plasma cell infiltration
from 70% to 15%. The patient was then maintained on thalidomide
from the summer of 2001 to the onset of this hospitalization. He
had refused any form of chemotherapy or bone marrow transplantation
at this point. His chief presenting complaint in January of 2002
was left rib pain. A repeat bone marrow aspirate at this time showed
90% plasma cell infiltration, indicating refractory multiple myeloma.
Hospital Course
The
patient decided to receive chemotherapy and underwent (VAD) vincristine,
adriamcyin and dexamethasone regimen. The patient then received
radiation to the L lower ribs for palliation of painful osteolytic
lesions. The patient also had a MRI and bone scan which confirmed
multiple compression fractures and myeloma invasion of the lumbar
spine. These lumbar lesions were to be irradiated as an outpatient.
Discussion
Multiple
myeloma is a plasma cell disorder in which there is a monoclonal
proliferation of plasma cells that produce whole monoclonal antibodies
or fragments. The monoclonal antibodies are most often IgG, then
IgA or light, then heavy chains. In nearly 50 % of cases, serum
protein electrophoresis analysis reveals a monoclonal antibody spike,
in which the 'M' (monoclonal) protein consists of the whole immune
globulin, most notably IgG. In 20% of cases, light chain 'M' proteins
are produced. These proteins are found only in the urine due to
their small size, and therefore inability to maintain high/ detectable
levels in the blood. This is known as bence jones proteinuria and
can be detected by urine protein electrophoresis. (2) In fact this
is what was detected in our patient.
Common
symptoms of the disease include sweats, myalgias, anemia, bone pain
and fevers.
The
most frequent complications are painful pathologic fractures, anemia,
hypercalcemia, and recurrent bacterial infections. (3) The importance
of assessing for complications is the foundation of treatment.
Pathologic
fractures occur in multiple myeloma due to proliferation of plasma
cells in the bone and secondarily to activation of osteoclasts.
Proliferation is dependent on interleukin 6 (IL-6). Osteoclasts
are activated by osteoclast activating factors (OAF) which is made
by myeloma cells. These OAFs are mediated by various other cytokines
including IL -1, lymphotoxin and tumor necrosis factor (TNF). (B).
The lesions produced are lytic as opposed to blastic lesions. This
destruction of bone can lead to hypercalcemia and should be suspected
if a patient presents with bone pain, nausea, fatigue, constipation,
polyuria or confusion. (2)
Treatment
of multiple myeloma is divided into symptomatic relief and systemic
chemotherapy. Our patient initially refused chemotherapy, and was
treated symptomatically. His treatment for bone pain consisted
of steroids (such as dexamethasone), hydration, bisphosphonates
and radiation. The mechanism for steroids in multiple myleoma is
not different from that in other cancers. Namely steroids cause
suppression in the humoral immune system and inhibition of cytokines,
mediators of the inflammatory response. Interestingly, Alexanin
et al. has shown that high dose dexamethasone is the most active
single agent for treatment of myeloma and in inducing remission
(4)
Pamidronate
is a bisphosphonate for which the mechanism of action is to inhibit
osteoclastic activity and reduce bone resorption. Berenson
et al have shown the efficacy of pamidronate in reducing skeletal
events in patients with advanced multiple myeloma. In a study involving
392 patients, all of who were receiving chemotherapy; 196 of who
received pamidronate and the remaining receiving a placebo, those
in the pamidronate group had significantly lower skeletal events
24% vs. 41%. Those that received pamidronate also had less bone
pain and improved performance status and quality of life. (5)
The
patient had been treated with dexamethasone for 4 months and he
continued pamidronate.
He
was then administered thalidomide, which is often used in patients
who are refractory to chemotherapy.
Thalidomide
works as an anti-angiogenic drug therapy by inhibiting fibroblast
growth factor and hence inhibiting vascularity. In myeloma it does
this particularly in the bone marrow (6). This theoretically inhibits
the physical progression of myeloma cells. Thalidomide is also believed
to reduce TNF alpha by accelerating the degradation of TNF alpha
mRNA encoding protein. Singhal et al showed that using thalidomide
in progressively increasing doses in refractory myeloma patients,
led to a serum or urine paraprotein level decrease of 32 percent
overall. These reductions were apparent within two months in nearly
80% of patients. Subsequent bone marrow showed decreased plasma
cells along with increased hemoglobin levels. (7)
Despite
the above treatments, the patient had become refractory and was
admitted for chemotherapy to achieve the goal of systemic remission.
Our patient received VAD for refractory myeloma. Studies by Alexanin
done to assess initial therapy have shown that the response rate
was 15% higher in the VAD groups compared to previous drug combinations
such as melphalan and prednisone. In the VAD treated patients, although
remission was more rapid, VAD neither prolonged remission or survival
over other combinations.
In
relapsing cases, VAD has been shown to be the treatment of choice;
leading to remission in nearly 40% of patients. In patients who
had a response, survival was prolonged by one year. (3)
The future of treatment
Once
remission is achieved with above therapies, the next goal is to
maintain remission
Interferon
alpha has been tested to assess maintenance of remission in multiple
myeloma. In vitro it inhibits growth of plasma cells and in
studies has induced remission in nearly 20% of patients. Studies
however have been unclear and inconclusive regarding its role in
remission. (8)
Stem
cell transplantation is the most promising modality for long term
disease free survival following chemotherapy. One study has shown
greater than 4 years of remission in 7 of 90 patients treated with
allogenic bone marrow transplant following chemotherapy. However
this therapy option is limited to myeloma patients who have an HLA
compatible relative and who are under 50 years old, as the rate
of mortality with BMT can approach 40%.(9)
Autologous
bone marrow transplant is another option. Intuitively it may seem
contradictory to reinfuse cells that may be myeloma cells. The hope
is that following ablative chemotherapy, myeloma cells will no longer
be present and an autologous BMT can lead to remission. This
combination has been shown to induce remission in 60% of patients
with relapsing disease although the period of remission was short,
approximately 3-15 months in 50% of patients (c).
Stem
cell transplantation along with total body irradiation has also
been promising with response rates as high as 85% in some groups.
Future
therapies are targeting the multidrug resistance mechanism. Drugs
such as verapamil and cyclosporin are being used to allow chemotherapeutic
drugs to remain in the cells indefinitely.
REFERENCES
- Kuppers R, Klein et al. New England Journal of Medicine.
Vol 341 No. 20, pg 1520. 1999
- Longo, Dan. Plasma Cell Disorders (Multiple Myeloma).
Harrison's Principles of Internal Medicine 14th ed. chapter
114. Pg. 712-713.
- Alexanian, Dimopoulos et al. The Treatment of Multiple
Myeloma. New England Journal of Medicine. Vol 330:No. 7
pg 484-489. Feb 17, 1994
- Alexanian, R. Dimopoulous et al. Primary dexamethasone
treatment of Multiple Myeloma. Blood. Vol 80: pg 887-890.
1992
- Berenson, JR. et al. Efficacy of Pamidronate in Reducing
Skeletal Events in Patients with Advanced Multiple Myeloma.
New England Journal of Medicine. Vol 334. No 8. pg 488-493.
1996
- Klausner, JD. Freedman VH, et al. Short analytical review
Thalidomide as an anti-TNF -alpha inhibitor: implications for
clinical use. Clinical Immunology Immunopatology. Vol 81:
219-223, 1996.
- Singhal, S. Antitumor Activity of Thalidomide in Refractory
Multiple Myeloma.
New England Journal of Medicine. Vol 341: No 21, pg 1565-1571.
Nov 1999.
- Quesada, JR, et al. Treatment of multiple myeloma with
recombinant alpha-interferon. Blood. vol: 67: pg 275-278,
1986.
- Gahrton, G. Tura et al. Allogenic bone marrow transplantation
in multiple myeloma. New England Journal of Medicine. Vol
325: pg 1267-1273, 1991.
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