Multiple myeloma

 Myeloma is a cancer of plasma cells.
 Plasma cells make antibodies that help to fight infections
and play a key role in bone repair.
 Myeloma cells make too many copies of themselves.
 Myeloma cells make abnormal antibodies called M proteins
that don’t help to fight germs.
 When myeloma cells spread throught the bone marrow, it is
called multiple myeloma.
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 Renal impairment is a common feature of symptomatic
multiple myeloma (MM).
 It is not rare for a patient with myeloma to present to the
nephrology clinic for evaluation of renal impairment, which is
usually of recent onset, or to be hospitalized because of acute
kidney injury (AKI).
Conversely, in a patient with MM, development of RI may
provide a clue to the diagnosis of the disease and may cause major
management problems.

https://seer.cancer.gov
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https://seer.cancer.gov
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https://seer.cancer.gov12/11/2019 7

 Monoclonal gammopathy of undetermined significance
 Multiple Myeloma
 Symptomatic
 Asymptomatic (Smoldering)
 Nonsecretory
 PlasmaCell Leukemia
 Plasmacytoma
 Solitary plasmacytoma of bone
 Extra medullary plasmacytoma
 Deposition Disease
 Primary Amyloidosis,
 Systemic Heavy and Light Chain Disease
 Osteosclerotic Myeloma (POEMS Syndrome)
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Kyle et al, NEJM, Volume 356:2582-2590, June 21, 2007

 MGUS: up to 2 percent of persons 50 years of age or older and about 3
percent of those older than 70 years
 For SMM, maximum risk in the ﬁrst 5 years
 Risk factors: Higher M spike, higher plasma cell burden, type of M protein,
Abnormal free light chain ratio, circulating plasma cells.
Kyle et al, NEJM, Volume 356:2582-2590, June 21, 200712/11/2019 13

●Anemia – 73 %
●Bone pain – 58 %
●Elevated creatinine – 48 %
●Fatigue/generalized weakness – 32 %
●Hypercalcemia – 28 %
●Weight loss – 24 percent, one-half of whom had lost ≥9 kg
Kyle RA, Gertz MA, WitzigTE, et al. Review of 1027 patients with newly diagnosed multiple
myeloma. Mayo Clin Proc 2003; 78:21.12/11/2019 15

Symptoms and signs present in 5 percent or less included:
• Paresthesias (5 percent),
• Hepatomegaly (4 percent),
• Splenomegaly (1 percent),
• Lymphadenopathy (1 percent), and
• Fever (0.7 percent).
Pleural effusion and diffuse pulmonary involvement : Rare
Extramedullary plasmacytomas : 7%.
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1. Bone marrow infiltration.
2. Suppression by cytokines :TNF alfa, IL1.
3. Erythroid apoptosis by fas ligand.
4. Decreased erythropoietin production.
5. Bleeding.
6. Infections.
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• Most common symptom.
• Aggravated on movement
• Sites : vertebral column> ribs > skull > pelvis > femur >
clavicle > scapula.
• Persistent pain is s/o patjological fracture.
• Hypercalcemia
• Spinal cord compression
• Palpable mass lesion
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Glomerular
Primary amyloidosis
LCDD/HCDD/LHCDD
Monoclonal
cryoglobulinemia
Proliferative GN
Tubular
Cast nephropathy/
myeloma kidney
Fancony syndrome
Distal tubular
dysfunction
Interstitial
Plasma cell
infiltration
Interstitial nephritis

 Additional factors exacerbating renal failure in MM
 Volume depletion
 NSAIDS
 Hyperuricemia
 Nephrotoxic chemotherapeutic agents
 IV contrast
 Bisphosphonates
 Calcium
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 The diagnostic criteria that is currently accepted and
followed is the International Myeloma Working Group
Classification published in 2003.
 IMWG revised the diagnostic criteria in 2014.
 The International Myeloma Working Group recommends
these criteria for routine practice and future clinical trials.
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Bone marrow plasma cells ≥10% or bony or biopsy proven
extramedullary plasmacytoma and any one or more of myeloma
defining evens including:
• Myeloma defining events: (CRAB)
• HyperCalcemia: >1 mg/dl higher than upper limit or >11 mg/dl
• Renal insufficiency: serum cretinine >2mg/dl or cretinin clearance <40 ml/min
• Anemia: Hb<10 gm/dl or >2gm/dl below the lower limit of normal
• Bone lesion: one or more osteolytic lesions skeletal radiography, CT or PET-CT
• ••Any one or more biomarker of malignancy including:
• Clonal bone marrow plasma cells ≥ 60%
• Free light chain ratio ≥ 100
• >1 focal lesions on MRI
Criteria for the classification of monoclonal
gammopathies, multiple myeloma and related
disorders: a report of the International Myeloma
Working Group. Br. J. Haematol. 2003
Jun;121(5):749–57.

 This is an intermediate stage during the transition from MGUS to
frank symptomatic MM.
 The monoclonal plasmacytosis and gammopathy has increased to
MM levels but the end organ damage that defines MM has not yet
occurred.
 Serum monoclonal protein (IgG or IgA) ≥ 3gm/dl or 24 hr urinary
monoclonal protein ≥500 mg and/or bone marrow plasma cells
10-60%.
 Absence of myeloma defining event or amyloidosis.
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 In almost all cases multiple myeloma is preceded by a
premalignant asymptomatic stage termed as MGUS.
 In population over the age of 50 year MGUS is present in 3-
4% cases.
 MGUS can progress to multiple myeloma at the rate of 1%
per year.
 Diagnosis of MGUS requires the absence of end organ
involvement.
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 All three criteria must be met:
 Serum monoclonal protein <3 gm/dL
 Clonal bone marrow plasma cells <10%,
 Absence of end-organ damage
 Considering this high risk of plasma cell disorder, persons
found to have MGUS should be monitored stringently
lifelong.
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 Occurs around a decade younger than MM.
 More common in males.
 The sites commonly affected are the axial skeleton more
than the appendicular skeleton.
 Rate of progression to multiple myeloma is 10% in 3 years.
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Solitary plasmacytoma is diagnosed by:
1) Biopsy-proven solitary lesion of bone or soft tissue
with evidence of clonal plasma cells
2) Normal bone marrow with no evidence of clonal
plasma cells
3) Normal skeletal survey and MRI (or CT) of spine and
pelvis (except for the primary solitary lesion)
4) Absence of end-organ damage.

 The common sites of involvement are the nasal cavity,
nasopharynx, larynx and sinuses. It can happen in any location in
the body and is commonly of the IgA subtype.
 Other evidence of systemic MM should not be present.
 The diagnostic criteria is:
 No M-protein in serum and/or urine
 Extramedullary tumour of clonal plasma cells
 Normal bone marrow
 Normal skeletal survey
 No end organ damage including bone lesions.
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 This entity constitutes less than 5% of all PCDs.
 The diagnostic criteria for this entity are as follows:
 No M-protein in serum and/or urine
 More than one localized area of bone destruction or extramedullary
tumour of clonal plasma cells which may be recurrent
 Normal bone marrow
 Normal skeletal survey and MRI of spine and pelvis if done
 No end organ damage other than the localized bone lesions.
* Small elevation of M protein may be seen.
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 PCL occurs when there is more than 20% abnormal plasma
cells in the differential WBC lineage or if there is an absolute
number of more than 2x10^9/L of plasma cells.
 This might be primary or secondary.
 Primary (approx. 60%), if the patient presents with PCL and
secondary is if the patients progresses to PCL from MM.
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Aim Of Investigation
Confirming and quantifying
monoclonal protein and
establishing the
monoclonality of the
plasma cells.
Differentiating MGUS,
SMM and symptomatic
MM
Prognosticating, and
assessing the tumour
burden.
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 The gold standard : SIFE & UIFE.
 In practice it is prudent to start with SPEP & UPEP
 As further follow ups require only a SPEP.
 80% of MM patients will have a positive SPEP.
 With SIFE being added this increases to 93%.
 By adding UIFE the success rate of identifying a monoclonal
gammopathy increased to 97%.
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Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report
of the International Myeloma Working Group. Br. J. Haematol. 2003 Jun;121(5):749–57.

The remaining 3% is conventionally termed as the Non-secretory myelomas.
This number again drops when Serum Free Light Chain is also added to the investigations.
Thus it’s always imperative to do both Serum as well as Urine IFE at baseline.
Up to 20% of patients are considered as Light Chain Disease (LCD) who does not secrete the heavy
chain part.
They will be missed if only the SPEP is done.
In the diagnosis of MM with SPEP it is prudent to differentiate the Monoclonal M spike from
polyclonal gammopathy which can be present in various benign conditions.
The M spike of MM is usually present in gamma region but at times may be present in the beta 2
region also.
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It detects the levels of κ and l light chains in the serum.
The FLC assay measures free k (reference range, 0.33 - 1.94 mg/dL) and free l (reference range, 0.57 - 2.63 mg/dL) light
chains.
These might together be elevated in polyclonal gammopathy conditions.
Hence to prove the monoclonality of the LC, the ratio of k to l is taken.
The normal ratio is 0.26 to 1.65.
Values < 0.26 indicates a l LC disease whereas >1.65 indicates a k LC disease.
SFLC is also to be normal in order to claim a StringentComplete Response.
Thus it is prudent to consider SPEP, SIFE and SFLC as investigations with increasing sensitivity to detect monoclonal
gammopathy.
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Are also another way to quantify monoclonal gammopathy.
This also helps in monitoring the follow up.
In around 90% of MM patients corresponding to the increase in a specific monoclonal Ig,
there will be a reduction or suppression of levels of the other proteins.
So to summarize, among 100 patients of MM, 50-60% will be if IgG subtype, 20% of IgA,
2% of IgD and <1% of IgM subtypes.
Around 15-20% will be having FLC only.
The LC component in total is almost equal or k might have a slight preponderance, but k
is more common in IgG type (1.7:1) whereas l is more common in IgD (1.9:1).
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Bone marrow plasmacytosis is to be proven by BM aspiration and Biopsy from
both iliac crests.
Bilateral BM Biopsy is recommended as it is proven that MM can have a patchy
affection of the BM.
BM involvement is found in about 95% patients.
In around 40% patients the levels might be below 10%.
• Hence in the presence of end organ damage, the absolute percentage of BM plasmacytosis is not
significant, rather it only needs to be demonstrated that they are malignant, either
morphologically or by flowcytometry.
Monoclonality of these plasma cells can be proven by Immuno Histochemistry
(IHC) using stains against k and l LC.
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 Anaemia is present at initial presentation in around two thirds of patients while
during the course of the disease almost everyone will have this.
 The cut-off level of Hb for diagnosis of MM is <10gm% or 2gm% less than the
normal.
 The anaemia is usually normocytic, normochromic in nature.
 Hypercalcemia is present in around 10-15% patients at presentation and is a
major cause of reversible
 Renal insufficiency at presentation, usually responding to hydration and
steroids.
 Serum Creatinine elevations above normal values are found in about one third
of patients at presentation but requirement of dialysis is much lesser, most of
them responding to correction of dehydration and hypercalcemia.
 Bone lesions.
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Skeletal abnormalities in conventional skeletal
survey in MM can manifest in various ways like
osteopenia, osteoporosis, lytic lesions and
collapse fractures.
In around 70-80% patients there will be some
bone changes evident in baseline and another
15-20% will develop it during the course of the
disease.
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Bone scan is not a preferred modality for assessing skeletal
lesions in MM since it shows areas of bone formation only.
The drawbacks with conventional radiology are that it has a high
false positivity of around 30-70%, and it can’t distinguish age
related osteopenia from MM related osteopenia or osteoporosis.
Whole body CT scans have a better sensitivity than x-rays, but the
drawback is the excessive amount of radiation exposure and poor
visualisation of the marrow.
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This is better in detecting spinal lesions more accurately where urgent local
treatment is required to save impending neurological complications.
MRI also gives a better understanding of the marrow and soft tissue
components and also helps in prognostication.
Hazard of radiation is not present with MRI.
PET might be helpful in detecting active lesions from inactive ones and thus
differentiate between MGUS and MM.
It is also helpful in the follow-up of non-secretory MM.
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Whole Body Skeletal survey is imperative in the initial workup of MM.
For localised lesions or if only single lesions (like solitary plasmacytomas) are
present or if some form of local therapy like Radiotherapy or surgery is urgently
required, a better imaging modality like MRI of PET CT or CT scan can be used.
Routine use of PET CT is not recommended.
Again bone scan is not a recommended modality for work up of MM.
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 Serum β2 microglobulins:
 This is one of the back bones of the International Staging
System (ISS) and is a marker of tumor burden.
 Serum LDH:
 Has an independent prognostic significance in various studies.
 ESR :
 Elevated in most cases of MM but the values correlate neither
with tumor burden nor with treatment response.
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 C-Reactive proteins :
 Elevated in MM and might be of value when infections are a
presenting feature of MM.
 Molecular testing :
 Conventional cytogenetics and Fluorescent In situ Hybridisation
(FISH) are being used recently.
 As per the available data researchers from MayoClinic have devised a
stratification system based on cytogenetics which is as follows,
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Complete blood count and differential; peripheral blood smear, ESR
Kidney function tests and Liver function tests including calcium and LDH levels
SPEP, IFE
Routine urinalysis, 24-hour urine collection for UPEP, UIFE.
Bone marrow aspirate and/or biopsy
Radiologic skeletal bone survey
Serum beta 2-microglobulin
Measurement of serum-free light chains.
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If SPEP was positive, then monitoring the same is only required, there is
no need to repeat SIFE and UIFE.
In non-secretory MM, if SFLC was positive, it has to be used for
monitoring.
Bone marrow need not be repeated routinely, but needs to be done to
document what response has been attained at the end of treatment.
Repeating a skeletal survey is not required unless there is new onset of
skeletal symptoms.
Similarly molecular tests need not be repeated.
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Bone marrow Plasmacytoma Peripheral blood
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10
1
100
1000
10000
100000
0.1 1000 10000 1000001 10 100
Serum Kappa (mg/L)
SerumLambda(mg/L)
Normal sera
Kappa LCMM
Lambda LCMM
Renal impairment
Serum or Urine
Protein Electrophoresis
Serum or Urine
Immunofixation
0.1
Serum Free Light Chain Assay
FLC reference range:
 3.3 – 19.4 mg/L
 5.7 – 26.3 mg/L
 ratio 0.26 - 1.65
FLC reference range:
In Renal Impairement
 ratio : 0.37 – 3.1

Conventional skeletal surveys reveal punched-out lytic lesions, diffuse
osteopenia, or fractures in nearly 80 percent of patients with MM at the
time of diagnosis.
Focal lytic lesions are found in nearly 60 percent; osteoporosis, pathologic
fractures, or compression fractures of the spine each occur in
approximately 20 percent of patients.
The most frequent sites of involvement include areas with active
hematopoiesis, such as the vertebral bodies, skull, thoracic cage, pelvis,
and proximal humeri and femora.
Osteosclerotic lesions (ie, areas of intense increased bone density) are
rare.
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Given the importance of the renal lesion, renal biopsy
plays a vital role in the diagnosis and study of MM
patients with AKI.
Renal biopsy is recommended in patients with a high
degree of albuminuria to rule out immunoglobulin light-
chain (AL) amyloidosis or MIDD.
Patients with sFLC levels <500 mg/L should also
undergo a kidney biopsy as MCN is unlikely.
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 Significant portion of patients had secondary renal
pathologies.
 Eight cases of coexisting MIDD, three cases of AL amyloidosis and
nine cases of focal segmental glomerulosclerosis, which occurred at a
rate much higher than previously thought.
 Renal biopsy had prognostic importance.
 The benefits must be balanced by the cost, the risk and the
added benefits.
Ecotière et al. Prognostic value of kidney biopsy in myeloma cast nephropathy: a
retrospective study of 70 patients. Nephrol DialTransplant 2016; 31: 64–72.)

Many eosinophilic, often fractured casts (medullary portion of the
distal nephron predominantly)
Intratubular and interstitial macrophages and giant cells in response
to casts
Interstitial inflammation, fibrosis, tubular atrophy, crystalline
inclusions
Minimal glomerular abnormality
Minimal or no vascular changes.
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Supportive care
Mechanical means
• Plasma exchange
• Free light chain removal with HCO dialysis
RRT
Specific antimyeloma therapy
Stem cell transplantation
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 Adequate hydration is a key component.
 Treatment of anemia
 Prompt treatment of infections.
 Management of hypercalcaemia is crucial.
 Avoidance of agents that contribute to renal damage,
such as NSAIDS, aminoglycoside antibiotics, and
contrast dyes.
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A therapeutic trial of ESA can be considered in cases where significant anemia (Hb<10g/L)
is attributed to renal disease/ myeloma.
Doses : Recommended are lowest possible to cause a rise in hemoglobin sufficient to
avoid transfusions.
150 U/kg three times a week SC.
• If no response after 4 weeks can escalate to 300 U/kg three times a week.
Darbepoetin 6.25 mcg/kg three weekly.
Target Hb = 12g/L.
Stop if Hb>12 or no response within 6-8 weeks of trial.
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1.Vaccination
• May be useful in patients with recurrent, severe infections.
2. Prophylactic Immunoglobulins
3. ProphylacticAcyclovir
4. Co-trimoxozole / Azole prophylaxis
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Patients >1 risk factor require therapeutic anticoagulation, while those
with 1 or no risk factor can do with Ecosprin (Low dose).
Most Indian patients have more than 1 risk factor for thrombosis (newly
diagnosed, have comorbidities, Immobile due to pain, and are on
combination therapy or high dose steroids for treatment of myeloma).
All such patients on thalidomide or Lenalidomide based chemotherapy
need to be started on LMWH 1mg/kg OD or Low dose UFH (5000 U SC
BD) orWarfarin dose adjusted to a target INR of 2-3.
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 WHO ladder that can be used are
1. Paracetomol (Max 1 gm QID)
2.Tramadol (max 50mg QID or BD sustained release forms)
3. Fentanyl patches (25-50 mcg patch/ 48 hrs)
4. Morphine can be used for severe pain (patients on palliative care for
advanced myeloma may be given max morphine upto 120 mg/day)
5. Neuropathic pain: Gabapentin/ Pregabalin/ Amitryptyline
 All patients receiving opioid analgesics to be given laxatives. Avoid
using NSAIDS
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 PN can be due to myeloma disease per se (M-protein
associated), POEMS, AL-amyloidosis, chemotherapy
induced (CIPN) or associated with comorbidities e.g. type2
diabetes mellitus, CIDP, CKD or nutritional deficiency.
 The prevalence of PN in newly diagnosed MM is to the tune
of 62%.
 NCS is not always necessary in the diagnosis as they do not
co-relate with the clinical findings.
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Clin J Am Soc Nephrol 7: 1722–1729, 2012. doi: 10.2215/CJN.02470312

When?They are recommended for all patients with symptomatic
myeloma irrespective of bone lesions on radiology.
• However, evidence is insufficient in asymptomatic myeloma patients.
Which? Zolendronate or Pamidronate are the preferred drugs.
• Zolendronate is the drug of choice.
Precautions before starting: Dental evaluation, Renal function.
• Avoid invasive dental procedures.
How frequently? 4 weekly.
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How long? Generally these are given for 2-
years.
Oral calcium and vitamin D supplementation is
recommended.
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Clin J Am Soc Nephrol 7: 1722–1729, 2012. doi: 10.2215/CJN.02470312

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Future Oncol. (2015) 11(21), 2865–2871

 Denosumab is a fully human monoclonal antibody that binds
to RANKL and inhibits osteoclast maturation, activation, and
function.
 Denosumab is well tolerated, with arthralgias as the most
common side effect.
 The FDA has reported only a slightly increased incidence of
serious infections (4.1% for denosumab and 3.3% for
placebo), with no increase in opportunistic infections.
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 Denosumab has been associated with a similar incidence of
osteonecrosis of the jaw as zoledronic acid.
 The median response time is 9 days with duration of response
sustained for up to 104 days.
 Phase III multicenter randomized double-blinded trial comparing
efficacy of denosumab with zoledronic acid showed a statistically
significant delay in time with first on-study HCM, and recurrence of
HCM in patients treated with denosumab compared with zoledronic
acid.
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Denosumab can lead to hypocalcemia in patients with vitamin D deficiency,
renal impairment (glomerular filtration rate ≤30 ml/min or hemodialysis) and in
patients with history of hypoparathyroidism.
Gastrointestinal side effects (nausea, vomiting, diarrhea and constipation),
peripheral edema, dyspnea and anemia were reported in >20% of patients
receiving treatment.
Atypical femoral fractures and osteonecrosis of the jaw have been reported in
similar rates of occurrence as with intravenous bisphosphonate therapy.
Monitor serum calcium levels during the first weeks of initiating therapy and
treat underlying vitamin D deficiency.
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Cost Around 28000/-

 Approved for the treatment of malignancy related hypercalcemia.
 Reduction in osteoclast activity and bone remodeling.
 Administered by a continuous infusion at a dosage of 200 mg/m2
per day over 5 consecutive days.
 Reports comparing gallium to bisphosphonates and calcitonin have
shown equal or perhaps even superior efficacy in decreasing
calcium levels.
 Adverse effects: Hypocalcemia & Hypophosphatemia.
 The latter being observed in nearly 80% of patients.
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 Renal impairment has been reported.
 Not recommended for use when the serum creatinine concentration > 2.5
mg/dl.
 Adequate fluid resuscitation is essential before initiation of
treatmentwith gallium.
 BUN and creatinine must be followed closely during treatment.
 Patients receiving gallium have reported nausea, vomiting,
lethargy, altered mental status, and both diarrhea and
constipation.
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 Inhibits osteoclast bone resorption and increases urinary calcium
excretion.
 Synthetic calcitonin (derived from salmon) is administered as 4–8
U/kg intramuscularly or subcutaneously every 6–8
 hours.
 Rapid onset of effect, leading to reductions in serum calcium within
2–6 hours after dosing.
 Effect is modest and transient, with a mean duration of effect of 2–4
days.
 Repeated administration :Tachyphylaxis.
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 Overall, its efficacy is poor, inducing normocalcemia in just one
third of patients.
 Calcitonin’s major role may be as an adjunctive agent with
bisphosphonates in the treatment of severe, symptomatic
hypercalcemia when calcium levels must be reduced rapidly.
 Side effects are minimal; nausea, vomiting, and injection site
pain are the most common.
 Davidson TG: Conventional treatment of hypercalcemia of malignancy
Am J Health Syst Pharm 58[Suppl 3]: S8–S15, 2001.
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 Inhibiting 1a-hydroxylase conversion of 25-hydroxyvitamin D to
calcitriol.
 The efficacy of corticosteroids is based on case reports and thus
the dosing guidelines are uncertain;
 Reasonable regimen is IV hydrocortisone, 200–300 mg/d, for 3–5 days.
 Typically, calcium levels are slow to decrease with corticosteroid
treatment alone.
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Mathur M, Sykes JA, Saxena VR, et al:Treatment of acute lymphoblastic leukemia-induced extreme
hypercalcemia with pamidronate and calcitonin. Pediatr Crit Care Med 4: 252–255, 2003

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•For patients with acute hypercalcemia and AKI (especially in the
setting of oliguria), SALINE-INDUCED DIURESIS may not be feasible
and may lead to volume overload.
•In these circumstances, hemodialysis using a very-low-calcium
dialysate (#1 mmol/L) is an option.
Argile´s A, Kerr PG, Canaud B, Flavier JL, Mion C: Calcium kinetic and the long-term effects of
lowering dialysate calcium concentration. Kidney Int 43: 630–640, 1993.
•For refractory cases of hypercalcemia, several case reports describe the
use of citrate anticoagulation to chelate calcium along with CVVHDF.
Kindgen-Milles D, KramR, KleinekofortW, Morgera S:Treatment of severe hypercalcemia
using continuous renal replacement therapy with regional citrate anticoagulation. ASAIO
J 54: 442–444, 2008.

 Two studies suggested that plasma exchange was beneficial.
 (Pozzi et al., 1987; Zucchelli et al., 1988).
 Blade and Rosinol (2005) supported that patients with renal failure
severe enough to require dialysis do not benefit from plasma
exchange.
 In a recent report from the Mayo Clinic, plasma exchange in
combination with bortezomib-based chemotherapy, in a limited
number of patients, was associated with high rates of renal recovery.
 (Burnette et al., 2011).
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 In some patients with non-oliguric AKI, early initiation of a
plasma exchange programme and effective chemotherapy may
be of some benefit, but these patients should be carefully
selected (Dimopoulos et al., 2010c; Burnette et al., 2011).
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MPT, melphalan, prednisone, thalidomide;
VMP, bortezomib, melphalan, prednisone;
CTD, cyclophosphamide, thalidomide,dexamethasone;
MP, melphalan, prednisone;
VTD, bortezomib, thalidomide,dexamethasone;
VCD, bortezomib, cyclophosphamide, dexamethasone;
PAD, bortezomib, doxorubicin, dexamethasone;
RVD, lenalidomide, bortezomib, dexamethasone,
BP, bendamustin, prednisolone]

 Thalidomide-Dexamethasone (TD):
▪ Thalidomide : 100-200 mg daily
▪ Dexamethasone : 40 mg on days : 1-4, 9-12, 17-20.
▪ Repeat every 4 weeks
▪ Overall response rate : 60-70%
▪ Progression free survival : 22 months.
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P Gupta. A twelve year study of multiple myeloma at the all india institute of medical sciences, new delhi,
india. Indian Journal of Medical and Paediatric Oncology. 1995 Jun;16(2):108–14.

 Lenalidomide- Dexamethasone (LD) :
▪ Lenalidomide : 25 mg daily from D1 to D21
▪ Dexamethasone : 40 mg on D1, D8, D15, D21
▪ Overall response rate : 70 – 80 %
▪ Progression free survival : 25 months
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Philippe Moreau, Michel Attal, Thierry Facon: Frontline therapy of multiple myeloma. Blood.
2015; 125(20):3076-3084.

 Better response rates with VD(38% vs. 15% VGPR) and a modest
improvement (36 vs. 30months).
 Grade 3 or 4 adverse events were similar in both groups (38% vs.
40%).
 There were more deaths during treatment in VAD arm, (0.8% vs.
2.9%).
 Neuropathy was more with VD arm (35% vs. 22% and Grade 3 or 4
in 10% vs. 3%).
 But to summarise this study showed that VD was superior to VAD
regimen.
12/11/2019 91

 The major drawback of Bortezomib-containing regimens is
the risk of neurotoxicity early in the disease course.
 The neuropathy with Bortezomib can occur abruptly and can
be significantly painful and debilitating in a subset of
patients.
 Recent studies show that the neurotoxicity of Bortezomib
can be greatly diminished by administering Bortezomib
using a once-weekly schedule and by administering the drug
subcutaneously.
 Bortezomib, unlike Lenalidomide, does not affect stem cell
mobilisation.
12/11/2019 92

 Bortezomib : 2 Mg Bolus IV Or SC On D1, D8, D15,
D22.
 Thalidomide : 100 – 200 MG on days D1-D21.
 Dexamethasone : 40 mg on D1,D8,D15,D22.
 4 cycles every 4 weeks
 Overall response rate : 95%
12/11/2019 93

 Bortezomib–Cyclophosphamide–Dexamethasone (VCD)
▪ Cyclophosphamide : 300 mg/m2 orally on :
D1,D8,D15,D22
▪ Bortezomib : 2 mg iv on : D1, D8, D15, D22
▪ Dexamethasone : 40 mg on : D1, D8, D15, D22
▪ Overall response rate : 90 %
12/11/2019 94

 Bortezomib+Lenalidomide+Dexamethasone (VRD)
 Bortezomib : 2 MG IV ON D1, D8, D15
 Lenalidomide : 25 MG ORAL, ON D1-D14
 Dexamethasone : 40 MG ON D1,D8,D15,D22
 Overall Response Rate : 100%
12/11/2019 95

 Autologous stem cell transplantation
 Allogeneic stem cell transplantation
 Stem cell Mobilization
 Plerixafor
 Cyclophosphamide
12/11/2019 96

 Indications
 Pre-transplantation
 Palliation of symptoms (i.e.: pain)
 Plasmacytoma
12/11/2019 97

 Indications
1. Plasmacytoma
2. Pathological fractures
3. Compression fractures
12/11/2019 98

 Stage of disease
 Proliferation rates
 LDH levels
 Treatment availability:Conventional therapy /
TargetedTherapy / High-dose chemotherapy
 M protein concentration
 Age
 Treatment response
 Plasmablastic histology
12/11/2019 99

 High LDH levels
 Hypercalcemia
 Renal impairment
 Large tumor burden
 Bence-Jones proteinuria
 Low hemoglobin value
12/11/2019 100

 Rare due to the nature of the disease:
 Patients with MM die due to their underlying malignancy in a median
of 3–5 years after the diagnosis.
 Furthermore, patients with MM are at high risk for
infections, may experience several relapses in which the
allograft is exposed to toxic light chains, and the use of
immunosuppression may be problematic.
 (De Lima et al., 1981; Walker and Bear, 1983; van Bommel, 1996).
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However, there is an increasing number of patients with MM who attain long-lasting responses,
including several patients who may have a complete response of their underlying myeloma for
several years.
Thus, a renal transplantation could be considered for some patients (Dagher et al., 1996;
Tsakiris et al., 2010; Bansal et al., 2012).
A combination of ASCT with renal transplantation has also been reported (Spitzer et al., 1999,
2011).
Still, there are only limited data about renal transplantation in patients with myeloma and
current information needs to be reviewed carefully, especially in light of the recent
improvements in the outcome of patients with MM (Kumar et al., 2008; Kastritis et al., 2009).
12/11/2019 102

Multiple myeloma

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