MEDINA, Miguel Andrei C.

2016-00448
FINAL EXAM – OS 216 Hematology
We have as our patient PN, a 65-year old retired elementary school teacher Filipino female,
consulting to our institution with a chief complaint of lower back pain. On history, the patient
first experienced the lower back pain, described as “parang ngalay,” VAS 4-5/10, 3 months PTC.
The pain was associated with prolonged periods of sitting down, and was relieved by ibuprofen,
paracetamol, and warm compress. There were no other symptoms. 2 months PTC, there was an
increase in frequency of the lower back pain, but this was still mildly relieved by the
aforementioned drugs. 1 month PTC, the patient reported decreasing efficacy of the drugs and
reported that the lower back pain had become severe with impairment of some activities of
daily living such as getting out of her bed. She consulted with her family physician who
prescribed diclofenac 50mg 1tab/8h for a week and who instructed her to have ancillary tests
done. The patient’s symptoms were relieved by diclofenac so she delayed having her tests and
continued taking diclofenac. 2 weeks PTC, patient reported decreasing relief with diclofenac
and started to have vague abdominal discomfort. She had her tests done at this time.
CBC showed a microcytic normochromic anemia with anisocytosis, neutrophilia, and
thrombocytopenia. Other blood tests also revealed an elevated fasting blood sugar, elevated
serum creatinine (2.70 mg/dL; eGFR=19mL/min/1.73m 2 indicating severely reduced kidney
function), hyperuricemia, lowered cholesterol and direct HDL, elevated total protein,
hypoalbuminemia, hyperglobulinemia, elevated lactate dehydrogenase, and hypercalcemia.
Other blood tests were within normal ranges. An x-ray of the chest revealed a small lytic lesion
on the 4th right rib, with cardiomegaly, an atherosclerotic aorta, and thoracic spondylosis. An x-
ray of the lumbosacral region revealed mild disc narrowing and lytic lesions at the L4-L5
vertebral bodies, along with beginning degenerative changes in the sacroiliac joints. On return
to her family physician she was advised hematology consult which led to her current referral.
On review of systems, there was no headache, weakness, easy fatigability, chest pain, or
palpitations, but there was note of unquantified weight loss, low-grade afternoon fever, dark-
colored stools, frothy dark yellow urine, nocturia, urinary frequency, polydipsia, and
polyphagia.
Patient is a known hypertensive controlled using losartan 50mg 1tab/day and aspirin 80mg
1tab/day. There were no other co-morbids. She reports that 10 years prior she had severe low
back and bilateral knee pain after moderate exertion, resolved after being given unrecalled IV
pain medications and physical therapy. Ancillary tests were unremarkable at the time. Patient
reported no use of vices. Patient is G4P4 (4-0-0-4) with all pregnancies delivered via
spontaneous vaginal delivery. Menopause was at age 52.
On physical exam, the patient was awake, coherent, and in distress. PN had a normal pulse rate,
was normotensive and afebrile, but tachypneic (RR 21). PE revealed pale palpebral conjunctiva,
anicteric sclerae, and no palpable CLAD. There was symmetric chest expansion, and clear
breath sounds. There was an adynamic precordium, NRRR, with no murmurs. Abdomen was
flat, soft, and nontender with normoactive bowel sounds. There were pale nail beds and
bipedal edema with no limitations in motion along the extremities. Neurologic exam was
unremarkable.
The patient’s clinical picture is highly suspicious for multiple myeloma (MM), because the
patient exhibits the tetrad of hypercalcemia, renal insufficiency (elevated creatinine), anemia,
and bone lytic lesions. This is also in the context of elevated total protein and
hypergammoglobulinemia, which could be related to the production of abnormal
immunoglobulins (“M proteins”) and free light chains (FLC) by malignant MM plasma cells. The
patient’s age and complaint of lower back pain is also compatible with a diagnosis of multiple
myeloma; however, this condition usually affects males more than females. Furthermore, the
patient exhibits a microcytic normochromic anemia, when 80% of multiple myeloma patients
experience a normocytic normochromic anemia. Nevertheless, multiple myeloma seems to
encapsulate a lot of the salient points of this patient, and explains the lower back pain, so this is
our primary working impression. Because of the elevated FBS of the patient, a diagnosis of
diabetes mellitus may also be made.
Amyloid light chain (AL) amyloidosis may also be another differential. This results from a
monoclonal proliferation of plasma cells secreting light chains, which may then deposit as
amyloid fibrils in tissues, leading to nephrotic syndrome, cardiac and hepatic insults, and
neurological symptoms such as peripheral neuropathy or autonomic dysfunction. Patients may
also complain of easy bruising due to deposition of amyloid in capillaries or clotting factor X
deficiency due to binding with amyloid fibrils. These are not seen in pure, classical MM.
However, it is of note that AL amyloidosis may occur with multiple myeloma because MM cells
may secrete free light chains, hence the need to probe more for symptoms of AL amyloidosis in
this patient. Of note is the (+) bipedal edema, and hypoalbuminemia of this patient, which are
some of the symptoms of nephrotic syndrome. However, nephrotic syndrome presents with
hypercholesterolemia, which the patient’s labs failed to demonstrate. Nevertheless, checking
for albumin in the urine may show if the patient has damage to the glomeruli, which MM
usually spares (damage is by deposition of light chains in the tubules in MM).
Other possible differentials include other plasma cell dyscrasias such as Waldenstrom
macroglobulinemia (WM). Patients with WM also exhibit anemia but are characterized by
symptoms due to excessive production of IgM, a pentamer, which is present in the blood and
causes increased viscosity. Multiple myeloma may rarely present similarly to WM because MM
cells may also produce excessive IgM (IgM myeloma), mimicking WM. The hyperviscosity
syndrome in WM causes complaints such as headache, vertigo, dizziness, deafness, confusion,
or stupor due to sluggish blood flow in the blood vessels. Our patient experiences no
headaches. Our patient’s neurological exam was unremarkable, but in WM, peripheral
neuropathy is common. Visual disturbances may also be present. Fundoscopy may reveal
dilated retinal vessels also related to hyperviscosity. Macroglobulins in WM may also
precipitate in the cold producing Raynaud’s phenomenon. Hepatosplenomegaly is present in
WM, but is not present in MM. Lymphoplasmacytic lymphoma may also occur in association
with WM, resulting in enlarged lymph nodes which are not seen in MM. In WM, renal and
gastrointestinal insults may also arise from deposition of IgM. The size of the IgM paraprotein
causes it to not be excreted however, and only 20% of patients excrete light chains, so renal
disease is not as common as in MM. Notably, bone lytic lesions are not seen both in WM and in
lymphoplasmacytic lymphoma.
Monoclonal gammopathy of undetermined significance (MGUS) is another possibility, which
may represent a premalignant form of multiple myeloma. However, by definition, the tetrad of
hypercalcemia, renal insufficiency, anemia, and bone lytic lesions is absent in MGUS. MGUS
may progress to MM at a risk of 1% per year. Similarly, Smoldering Multiple Myeloma (SMM)
represents a middle ground between MGUS and MM. Patients with SMM are also likewise
asymptomatic, but 75% of patients with SMM progress to MM within 15 years. The difference
between the two is that MGUS has a serum M-protein level of <3 gm/dL and SMM has a serum
M-protein level of greater than 3gm/dL. Another related differential is non-secretory myeloma,
which presents with a normal serum and urine immunofixation and normal serum free light
chains. This presents with the usual symptoms of MM such as osteolytic lesions, but without
the renal insufficiency (because the renal damage is secondary to secreted paraproteins). This
patient already presented with hypergammaglobulinemia so non-secretory myeloma is unlikely.
Another important consideration is metastatic carcinoma. Particularly, renal CA may explain the
renal insufficiency and anemia of PN. Renal CA may also metastasize and produce osteolytic
lesions, which would lead to hypercalcemia. To rule this out, measurement of clonal plasma
cells in the bone marrow must be done. Renal CA also presents with smaller M-component on
SPEP.
Another possible differential is diabetic or hypertensive nephropathy, which may explain the
renal insufficiency and anemia in the patient. This could also be in the setting of osteoarthritis
which could explain the lower back pain. However, imaging has already shown lytic lesions
which are not seen in OA. This diagnosis is too complex, and we should follow the principle of
parsimony and choose a diagnosis which encapsulates most, if not all, of the salient points of
our patient.
To help lend support to the diagnosis of multiple myeloma, and to help exclude these
differentials, additional points can be elicited in the history and physical exam. Probing for
symptoms of hyperviscosity such as blurred vision or confusion, or the presence of Raynaud’s
phenomenon, may help rule out WM. Probing for issues with bleeding and easy bruising may
help rule out AL amyloidosis. Asking the patient to recall if she has been prone to bacterial
infections may help to establish the presence of decreased immunity, which is seen in MM
(specifically bacterial infections b/c MM is a disorder of B-cells). Probing for other GI symptoms,
such as constipation, nausea, and poor appetite, may help us better understand the effects of
the patient’s hypercalcemia. Asking about symptoms such as shortness of breath may help in
understanding the clinical effects of the patient’s anemia; this could also be a complication due
to cardiac insults secondary from AL amyloidosis. Neurological examination had unremarkable
findings, but imaging has already revealed mild disc narrowing hence it is important to continue
to probe for symptoms such as urinary or fecal incontinence to help exclude spinal cord
damage. Symptoms of peripheral neuropathy and easy bruising, complications of AL
amyloidosis (FLC deposition) should be elicited. Lastly, the history of the bipedal edema should
be taken. This may help us understand if it’s a complication of the multiple myeloma (e.g. due
to deposition of FLC damaging the glomeruli leading to albumin loss) or if it is unrelated (e.g.
cardiac). The onset of the edema is important because ascending edema is more likely cardiac
than renal in etiology.
With regards to the physical examination, checking for signs of hyperviscosity may help exclude
WM. This can be done by fundoscopy and checking retinal vessels for dilation. Additionally,
because the patient’s FBS is elevated, fundoscopy may help to see if the patient has diabetic
retinopathy. The abdominal exam revealed a flat, soft, nontender abdomen but there was no
note if hepatosplenomegaly was present or not. This is important because conditions like MM
characteristically do not present with hepatosplenomegaly. The extremities have already been
examined, but the face should also be checked for peri-orbital edema which may point to a
renal etiology for the bipedal edema. The tongue should be examined for macroglossia,
pathognomonic for AL amyloidosis. Looking for ecchymoses may help rule in AL amyloidosis.
To diagnose MM, a bone marrow biopsy must be done. Bone marrow plasmacytosis of >10%,
combined with a serum or urine M spike found through electrophoresis, in the setting of a
tetrad of hypercalcemia (>11 mg/dL), renal insufficiency (serum Crea > 2 mg/dL), anemia
(hemoglobin <10 g/dL), and bone lytic lesions (>= 5mm in size) will satisfy the diagnostic criteria
for MM. The presence of a biomarker associated with near inevitable progression to end-organ
damage, such as greater than 60% clonal plasma cells in the marrow, may substitute for these
symptoms in the diagnosis of MM. It is important to note that the hemoglobin of PN does not
satisfy the anemia criteria however all lab tests have a margin for error and are not fully
accurate. The overall clinical picture is more important for our assessment of this patient. Other
tests are no longer required to make a diagnosis of MM but may be done to exclude other
differentials.
In MM, serum-protein electrophoresis (SPEP) should show a monoclonal gammopathy (M-
spike). Absence of this M-spike might point towards metastatic cancer to the bone instead, for
example in renal CA which may produce osteolytic lesions. Immunofixation should be done to
qualify the M-spike, because the type of Ig produced affects presentations. E.g., IgD myeloma
may have light chain disease, and IgM myeloma may present similarly to WM with
hyperviscosity syndrome. Both MM and WM will show an M-spike during SPEP, but the most
common M-protein produced in MM is IgG while by definition WM has excess IgM. WM and
IgM myeloma present similarly, but the presence of bone lytic lesions in MM differentiates the
two. Rarely, a patient with suspected MM may not have an M-spike; this points instead to non-
secretory myeloma.
In MM, urine protein electrophoresis may show an M-spike and excess light chains in the urine.
Greater than 10 mg light chains in the urine is pathologic and are known as Bence Jones
proteins. Immunofixation is important to determine the subtype of light chain because lambda
light chains are more likely to cause renal damage than kappa light chains. In contrast, in WM,
only 20% of patients excrete light chains therefore WM has less renal involvement. Urine
electrophoresis with immunofixation may also reveal monoclonal light chains in 90% of AL
amyloidosis patients.
A peripheral blood smear, while not required to diagnose MM, may show the so-called
rouleaux formation because the red blood cells clump in the setting of the increased Ig in the
blood. This, however, is much more common in WM patients. Additionally, WM patients have a
positive Coombs test due to having autoimmune hemolytic anemia, and this is uncommon in
MM.
A urine dipstick test to check for proteinuria has no use in the diagnosis of multiple myeloma
(doesn’t detect gammaglobulins) but may help rule in the presence of complications such as
nephrotic syndrome, caused by deposition of amyloid in concurrent AL amyloidosis, a common
co-morbid with MM. Nephrotic syndrome presents with albumin in the urine due to glomerular
damage. In classical MM, renal damage is limited to the tubules so albumin will not leak out the
urine. Additionally, an MRI may be ordered. Spinal involvement due to the bony lesions in MM
is an emergency. Finally, serum B2-microglobulin and albumin levels should be measured since
this is useful as a prognostic factor in MM and for staging using the International Staging
System.
The pathophysiology of multiple myeloma can explain the signs and symptoms found in this
patient. MM cells bind via cell-surface adhesion molecules to bone marrow stromal cells and to
the extracellular matrix, triggering adhesion-mediated signaling and the production of
cytokines. This provides for the growth, survival, antiapoptotic, and drug resistant qualities of
MM cells. The proliferation of MM cells activates osteoclasts (through MM-produced osteoclast
activating factors mediated by IL-1, among others) and suppress osteoblasts (through
production of DKK-1 by MM cells) that are responsible for the lytic bone lesions, hypercalcemia,
and subsequent lower back pain. The hypercalcemia may produce gastrointestinal symptoms,
which explains the vague abdominal pain of PN. MM patients also frequently experience
susceptibility to bacterial infections, due to the excess production of only one Ig by malignant
MM cells, at the expense of the others. Viral immunity is not as affected because the MM cells
come from the B-cell lineage, although various abnormalities in T-cell function may also be
observed. The renal insufficiency of this patient may be caused by many factors, including
hypercalcemia, deposition of amyloid, and the excretion of light chains, a product of MM cells.
The excessive excretion of light chains damages the tubules, sparing the glomeruli in MM.
However, deposition of amyloid may damage the glomeruli and lead to hypoalbuminemia,
lowering oncotic pressure which explains the (+) bipedal edema of PN. The anemia can be
explained by the replacement of normal marrow, the inhibition of hematopoiesis by factors
produced by malignant plasma cells, and reduced EPO production due to kidney damage. In
80% of patients it is normocytic normochromic, but PN may be exhibiting microcytic anemia
because iron use is IL-6 mediated, which is also implicated in multiple myeloma.
Thrombocytopenia is rare in MM but this may be explained by the excessive intake of NSAIDs in
this patient. Clotting abnormalities may be present due to the interaction of M-proteins with
clotting factors. Hyperviscosity syndromes may be seen if the MM cells are producing IgM, IgG3,
or IgA. Neurological symptoms are uncommon but may be caused by hyperviscosity, deposition
of amyloid, or due to cord compression from vertebral collapse.
Treatment for MM begins by identifying if the patient is eligible for autologous stem cell
transplant (ASCT). Having a physiologic age of >70 years or having significant cardiopulmonary
problems/co-morbids are criteria for ineligibility. Induction therapy, consisting of lenalidomide,
bortezomib, and dexamethasone, is the regimen of choice in eligible patients. High dose
therapy and ASCT then follows. In ineligible patients, the three aforementioned drugs may also
be used for induction. All patients should then be put on maintenance with lenalidomide.
Supportive treatment of the bone damage, anemia, decreased immunity, renal damage, and
distress should also be done. Bisphosphonates may prevent further bone damage and has been
shown to improve pain and quality of life (QoL). Erythropoietin-stimulating agents may manage
the anemia in the short-term and are associated with a better well-being. TMP/SMX may be
given for the first 2 months of chemo to decrease the frequency and severity of bacterial
infections, a common complication of MM. Fluid intake of at least 3L per day, and oral
replacement of bicarbonates may improve renal function. The symptoms caused by
hypercalcemia should be immediately managed by giving 3-6 L/day IV saline and high doses of
loop diuretics. NSAIDs for pain must be given sparingly. COX-2 inhibitors are less toxic.
Antidepressants as needed may be given. Metformin may be given to lower the PN’s sugar, and
antihypertensives should continue. Emotions should be managed with PN’s family’s help, and
PN’s happiness and quality of life during her elderly years should be paramount. Palliative care
may help improve QoL in MM.
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