Multiple myeloma is a plasma cell neoplasm characterized by the proliferation of monoclonal plasma cells and overproduction of monoclonal immunoglobulins. It can present with bone pain, renal insufficiency, anemia, and hypercalcemia. Diagnosis requires the presence of a monoclonal protein in serum or urine along with >10% clonal plasma cells in bone marrow and associated organ or tissue impairment. Workup involves complete blood count, serum protein electrophoresis with immunofixation, urine protein electrophoresis, and bone marrow biopsy. Cytogenetic abnormalities like deletion 17p confer a poor prognosis.
This presentation is about chronic lymphocytic leukemia (CLL), its epidemiology and incidence, staging, molecular characteristics, clinical features and management.
This presentation is about chronic lymphocytic leukemia (CLL), its epidemiology and incidence, staging, molecular characteristics, clinical features and management.
Multiple myeloma is the most common primary malignant bone tumor in the world. It is usually seen in elderly individuals of >40 years. In this presentation, all the important aspects of Multiple myeloma have been discussed extensively and in brief..
Plasma cell disorders is a difficult topic where most residents and students confuse with regarding to differentiating between various types of para-proteinemias or plasma cell dyscrasias. This simple presentation will highlight the key points in differentiating, diagnosing these orders. Initial management principles are discussed as well.
multiple myeloma
Pathophysiology
Malignant proliferation of plasma cells in the bone marrow.
Causes bone marrow destruction via infiltration, and bone destruction via ↑RANKL activity (causing ↑osteoclast activity).
A single clone of plasma cells produce large amounts of identical immunoglobulin (a 'paraprotein' or 'monoclonal band'), as well as free κ or λ light chains (also a 'paraprotein', or 'Bence Jones protein' if in the urine).
Classified by Ig class, with prevalence reflecting prevalence in normal blood: IgG (⅔), IgA (⅓), remainder IgM or IgD.
Immunoglobulin classes other than that of the proliferating clone are relatively low ('immunoparesis').
Epidemiology
Lifetime risk: 1/140.
Incidence steadily increases with age. Rare <55.
Slightly commoner in men.
2x commoner in blacks vs. whites.
Challenges in interpreting serum protein electrophoresis. Requires an approach to recognize pattern within the various protein fractions & differentiate systemic inflammatory response from abnormal antibody production due to neoplastic disorders.Presence of M-band does not always correlate with plasma cell disorders but can be seen some lymphomas, chronic leukaemias, systemic amyloidosis hence need further ancillary tests for diagnosis of aetiology for the M-band.
Two cases of Waldenstrӧm macroglobulinemia along with brief disease pathology. Waldenstrӧm macroglobulinemia is a rare B cell lymphoma involving bone marrow with IgM monoclonal gammopathy of any concentration
multiple myloma
By: Nader Amir Al-assadi
Supervised by : Dr/ Ghazi Alariqe
taiz university
Multiple myeloma (MM) is a plasma cell malignancy in which monoclonal plasma cells proliferate in bone marrow, resulting in an over abundance of monoclonal para protein (M protein), destruction of bone, and displacement of other hematopoietic cell lines.
The precise etiology of MM has not yet been established.
Roles have been suggested for a variety of factors, including genetic causes, environmental or occupational causes,radiation, chronic inflammation, and infection .
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
3. HISTORY of Plasma Cell Neoplasm
1850 : 1st Clinical description reported in England by Dr. William Macintrye
a patient named Thomas Alexander presented to him with fatigue , diffuse bone
pain and increased frequency of urination.
1873 : The term Multiple Myeloma by Rustizky (1873) by independent observation with
similar complaints.
1899 : Ellinger described increased serum protein & E.S.R in MM.
1900 : Wright described involvement of Plasma cells in MM & for the 1st time
He used Xray to described patient’s C/F.
1929 : Development of BM aspiration technique.
1937 : Serum protein electrophoresis .
1953 : Graber described heavy & light chain monoclonal protein.
1958 : 1st use of chemotherapeutic agent (d & l mixture of phenylalanine mustard) by Blokin.
1962 : Bergsagel , reported remission in MM by using Melphalan.
4. Group of lymphoid neoplasms of terminally
differentiated B - cells that have in common the
expansion of a single clone of immunoglobulin (Ig)
- secreting plasma cells and a resultant increase in
serum levels of a single homogeneous
(monoclonal) Ig or it’s fragments.
Plasma Cell Neoplasm
7. • Terminally differentiated B-cells
• Not normally found in peripheral blood
• Account for less than 3.5% of nucleated
cells in the bone marrow
• Oval cells with low N:C ratio.
Cytoplasm is basophilic blue. Nucleus
(30-40% of the cell) is oval or round
and typically placed eccentrically (to
one side) of the cell.
• A clear, colorless area adjacent to the
nucleus contains Golgi apparatus
• Russell bodies : Globules (2-3 μm) of
accumulated immunoglobulins in the
cytoplasm of plasma cells. Usually
round. Russell bodies may be found in
normal bone marrow.
Plasma Cell
Plasma Cells
8. There is increased production of
immunoglobulin(Ig)
These immunoglobulins are monoclonal in nature.
Immunoglobulin secreted may be heavy chain or
light chain.
Plasma Cell Neoplasm
9. Epidemiology
As per most recent data of SEER (Surveillance
epidemiology & End Result Programme )
Males are affected more than Females
1% of all Malignancy
10% of all Haematological malignancy
2nd common after NHL among haematological malignancy
Median age of diagnosis -70 yrs
Median age of death -75 yrs
Blacks are affected more than Whites.
10. Classification of Plasma Cell Neoplasm
Monoclonal Gammopathy of Undetermined Significance (MGUS) ( 62%)
Malignant Monoclonal Gammopathies
•Multiple Myeloma (18%)
•Variants : Smoldering Myeloma (3%) , Non Secretory Multiple Myeloma, Light Chain Myeloma
•Plasmacytoma (2.5%) : Solitary Plasmacytoma of the bone, Extramedullary Plasmacytoma
•Plasma cell leukemia
•IgD myeloma
•POEMS syndrome ( Osteosclerotic Myeloma)
•Waldenstrom’s Macroglobulinemia (Lymphoplasmacytic Lymphoma )
Malignant Lymphoproliferative disorders
Heavy Chain disease ( Gamma HCD, Mu HCD, Alpha HCD)
Immunoglobulin Deposition diseases : Primary Amyloidosis, Systemic light chain and Heavy
chain deposition diseases
11. Investigations
• Complete Blood Count ( look for anemia)
• Comprehensive Metabolic panel
• Look for renal insufficiency(RFT), hypercalcemia and subtle clues
like decreased anion gap
• Total protein and albumin level. Determine Globulin component. Too
low globulin ( < 2gm%) or Elevated Globulin ( > 3.5gm%) is
concerning : Determine if Polyclonal vs. Monoclonal. Evaluate
further with :
• Quantitative Immunoglobulins : Increase in all components usually,
polyclonal. Increase in single component with reciprocal decrease of
uninvolved globulin usually, may suggest monoclonal .
• Serum Protein Electrophoresis with immunofixation if monoclonal
gammopathy is suspected.
• 24HR-Urine protein electrophoresis with urine immunofixation (
Serum Free Light Chain assay (κ/λ ratio) may be used in place of
UPEP}
• Bone marrow biopsy to evaluate % plasma cells if there is
monoclonal protein or abnormal UPEP or Light chain assay or if
strong clinical picture of myeloma.
• Skeletal survey if monoclonal gammopathy has been established (
Bone scans are usually, negative in MM)
• Beta-2 microglobulin and Albumin for staging and prognosis in MM
( once diagnosis is made).
Investigationsinanysuspected
onoclonalGammopathyshouldinclude,
toaccuratelyclassifythedisorder:
12. Serum is placed on special paper
treated with agarose gel and exposed
to an electric current. This separates
the serum protein components into
five classifications by size and
electrical charge : serum albumin,
alpha-1 globulins, alpha-2 globulins,
beta globulins, and gamma globulins.
Immunoglobulins ( IgG, IgM, IgA)
usually migrate to gamma region but
may sometimes extend to beta region.
SPEP should always be performed in
combination with serum
immunofixation in order to determine
clonality.
Serum Protein Electrophoresis(SPEP)
13. SPEP showing Monoclonal
Gammopathy
• Shows a tall “narrow” band in
gamma region – “M-Spike”
• Also, note reduction in the
normal polyclonal gamma band
SPEP
14. SPEP showing Polyclonal
Gammopathy
• Shows a broad based peak in
gamma region .
• Seen in chronic infections,
inflammation, connective
tissue disease,
lymphoproliferative disease.
SPEP
15. More sensitive than SPEP
Immunofixation is performed when SPEP shows a
sharp “peak” or a plasma cell disorder is
suspected despite a normal SPEP
Immunofixation always done to confirm the presence
of M-Protein and to determine the type (IgM or IgG
etc and the light chain restriction : k or λ)
Why do both SPEP and IF ? Why not just IF in
initial diagnosis ?
•Unlike SPEP, immunofixation does not give an estimate of the
size of the M protein (ie, its serum concentration), and thus
should be done in conjunction with electrophoresis.
Immunofixation
16. 18F-Fluoro-Deoxyglucose
Positron Emission Tomography (FDG-PET)
• Advantages
– Higher sensitivity vs
conventional radiography
– Detects 46% to 63% more
lesions than WBXR
– Normalization of scans after
treatment corresponds with a ≥
90% decrease in M-protein
• Disadvantages
– Less sensitive than MRI
• Especially for diffuse disease
MRI
BASELINE POST TREATMENT
18. Monoclonal Gammopathy of
Undetermined Significance ( MGUS)
Denotes presence of an M-protein in a patient without a plasma cell or
lymphoproliferative disorder i.e; Undetermined Significance
M-protein <3 g/dL
<10% Plasma cells in Bone Marrow
No or small amount of M-protein in urine
Absence of lytic bony lesions , anaemia , hypercalcemia or renal
insuffciency.
No evidence of lymphoproliferative disorder
Stability of M-protein over time.
19. Monoclonal Gammopathy of
Undetermined Significance ( MGUS)
Incidence of MGUS increases with age :
1% of adults in US
3% of adults over age 70 years
11% of adults over age 80 years
14% of adults over age 90 years
Significance : Can progress to monoclonal Disease
IgG or IgA MGUS Ig M MGUS
Multiple Myeloma
Primary Amyloidosis
Related Plasma cell
disorder
NHL
CLL
Waldenstrom’s
Macroglobulinemia
20. MGUS - Progression
Predictors of Progression :
• Size of the M-protein at the time of recognition of MGUS - most
important predictor of progression
• IgM & IgA monoclonal proteins have a greater risk of progression
than an IgG M-protein.
• Risk of progression does not go away with time!
• Risk of progression 1% per year
CUMULATIVE RISK
10% at 10 years, 25% at 25 years from diagnosis
• So, Management :
Periodic monitoring of serum protein electrophoresis
Interval of monitoring based on initial M-Protein level
Monitoring should be at least annually LIFELONG
21. Pathogenesis
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)
22. Pathogenesis
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)
23. Pathogenesis
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)
24. Pathogenesis
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)
IL-6
Ig
Ck
25. Pathogenesis Aberrent Expression of TLR by Plasma cells
TLR + Specific ligand = Abnormal reaction to
Infection
Increased expression of IL-6
MGUS(abnormal plasma cells)
contains CD126(IL-6 receptor α chain)
In compare to normal plasma cells
Increased production of Ig due
to activation or proliferation of MGUS
Proliferation may acquire
Cytogenetic abnormality
Normally human B-cells expresses
TLRs
These are essential for B-cells to
recognise
Infectious agent & PAMP
(Pathogen Associated Molecular
Pattern)
Then initiates host defence (Ig
production)
28. Smoldering Myeloma
• Both criteria should be met :
• Serum monoclonal protein ≥3 g/dL and/or bone marrow
plasma cells ≥10 percent
• No end organ damage related to plasma cell dyscrasia (see
CRAB)
• Management :
• Does not require any intervention
• Close surveillanace is necessary to ensure stability of the disease (
SPEP, CBC, Creatinine and calcium every 3 to 4 month and Skeletal
Survey annually to pick up asymptomatic bone lesions)
29. Non-Secretory Myeloma
• Rare variant : About 1% of Myelomas
• May present with Bone lesions ( most common presenting symptom
bone pain)
• No serum or urine monoclonal protein ( diagnosis can be missed if
one is not aware of this entity, NSMM).
• Renal failure and hypercalcemia are generally lacking
• Anemia may be present
• Bone marrow biopsy must be performed in suspected cases:
Immunostaining for a monoclonal protein on bone marrow sections
may establish the diagnosis, Clonal plasma cell population in marrow.
• Must rule out IgD and IgE myeloma
30. Solitary Plasmacytoma
• No M protein in serum / urine
• Single area of bone destruction due to clonal plasma cell .
• Bone marrow not consistent with M.M.
• Normal skeletal survey.
• No end organ damage(other than solitary bone lesion)
Younger median Age at Presentation (55yrs)
50-60% will convert to Multiple Myeloma within 10 yrs
Treatment : Radiation(40-50Gy) to the site of Solitary
Plasmacytoma
31. Extramedullary Plasmacytoma
•No M protein in serum / urine
•Extramedullary tumor of clonal plasma cells
•Normal bone marrow
•Normal skeletal survey
•No end organ damage(including bone lesions)
32. Extramedullary Plasmacytoma
• Plasma cell tumors that arise outside the bone
marrow and no features of Multiple Myeloma
• Most Common Primary Sites - Head and
Neck region: Upper air passages and
oropharynx (May involve draining lymph
nodes.
• Less Common Sites – Lymph nodes (primary),
salivary glands, spleen, liver, etc.
• 25% have small monoclonal spike
• Rare dissemination, rarer evolution to myeloma
• Management :
• If completely resected during biopsy, no
further therapy
• If incompletely resected, radiation therapy
locally(40-50Gy)
33. All three criteria must be met
Presence of a serum or urinary monoclonal protein
Presence of 10 percent or more clonal plasma cells in the
bone marrow or a plasmacytoma
Presence of end organ damage felt related to the plasma cell
dyscrasia, such as: CRAB : Hypercalcemia (calcium >
11.5gm%), Renal Insufficiency, Anemia (Hb < 10gm%) or
Lytic bone lesions
Multiple Myeloma
37. •Complete Blood Count ( look for anemia)
•Comprehensive Metabolic panel
•Look for renal insufficiency(RFT), hypercalcemia and subtle clues like decreased
anion gap
•Total protein and albumin level. Determine Globulin component. Too low globulin ( <
2gm%) or Elevated Globulin ( > 3.5gm%) is concerning :
Determine if Polyclonal vs. Monoclonal. Evaluate further with :
•Quantitative Immunoglobulins : Increase in all components usually,
polyclonal. Increase in single component with reciprocal decrease of
uninvolved globulin usually, may suggest monoclonal .
•Serum Protein Electrophoresis with immunofixation if monoclonal
gammopathy is suspected.
•24HR-Urine protein electrophoresis with urine immunofixation ( Serum
Free Light Chain assay (κ/λ ratio) may be used in place of UPEP}
•Bone marrow biopsy to evaluate % plasma cells if there is monoclonal
protein or abnormal UPEP or Light chain assay or if strong clinical picture
of myeloma.
•Skeletal survey if monoclonal gammopathy has been established ( Bone
scans are usually, negative in MM)
•Beta-2 microglobulin and Albumin for staging and prognosis in MM (
once diagnosis is made).
Investigations:
39. Multiple Myeloma
STAGE PARAMETER MEDIAN SURVIVAL
Stage Í Serum β2-microglobulin<3.5mg/L 62 months
Stage ÍÍ Not fitting stage Í & ÍÍ 44 months
Stage ÍÍÍ Serum β2-microglobulin>5.5mg/L 29 months
40. *High lactate dehydrogenase and plasma cell leukemia are also considered high-risk myeloma.
RISK STRTIFICATION OF MULTIPLE MYELOMA
(MYO CLINIC)
Standard Risk
• Hyperdiploidy
• t(11;14)
• t(6;14)
Intermediate Risk
• t(4;14)
High Risk*
•17p deletion
• t(14;16)
• t(14;20)
41.
42. More effective, less toxic mechanism-based TXs
Paradigm Shift in Oncology
1960-1990 2000
EMPERICAL
APPROACH
NON SPECIFIC
CYTOTOXIC
AGENT
MOLECULAR
BASED
APPROACH
TARGETED AND
SELECTED
BIOLOGICAL
APPROACH
43. Clearly not transplantation
candidate based on age, performance
score, and comorbidity
MPT, MPV, Len/dex
or clinical trial*
Potential transplantation
candidate
Nonalkylator-based
induction x 4 cycles
Stem cell harvest
*Thal/dex or dex are additional
options especially if immediate
response is needed.
Initial Approach to Treatment of MM
44. ELIGIBILITY FOR STEM CELL
TRANSPLANTATION
Autologous Hematopoietic Stem Cell Transplantation
1.Age ≤ 70 years
2.Cardiac Function: ejection fraction ≥ 45%
3.Pulmonary Function: DLCO ≥ 60% predicted
4.Serologies: Patients cannot be HIV + or have active Hepatitis B, Hepatitis C or HTLV-1
5.Renal Function : creatinine clearance ≥ 50 ml/min
6.Liver Function: Bilirubin ≤ 2.0 mg/dl and transaminases ≤ 2x normal,
7.Karnofsky performance status >: 80%
8.No significant co-morbid medical or psychiatric illness which would significantly
compromise the patient's clinical care and chances of survival.
Allogeneic Hematopoietic Stem Cell/Bone Marrow Transplantation
1.Age ≤ 50 years
2.Availability of an HLA-matched sibling donor (six of six or five of six HLA-match).
3.Normal LFT's (unless related to disease).
4.Cardiac function: ejection fraction ≥ 45%.
45. CLINICAL FOLLOW UP
Active Therapy
Pre Transplant
Disease
Assessment
Post Transplant
Disease
Assessment
Surveillance
•quantitative
paraprotein
•CBC
•calcium
•albumin
•creatinine monthly
•paraprotein
assessment
(serum, urine)
•skeletal survey
•CBC
•calcium
•albumin
•creatinine
•B2 microglobulin
•see pre transplant
disease
assessment
•bone marrow
investigation
if absence of
monoclonal
protein to determine
complete remission
status
•Q3 monthly
assessment with
quantitative
paraprotein
measurement
CBC, calcium,
albumin, creatinine
•skeletal survey
annually
•bone marrow
examination as
clinically
indicated
BCSH
46. Primary therapy (transplant candidates)
Relapse after transplant:
*A second (tandem) autologous stem cell transplant is recommended for
patients who relapse more than 12months after the first transplant.
*Patients who relapse within 12 months of the initial transplant are best treated with
agents they have not received before
*Patients who relapse after the second autologous transplant may be candidates
for allogeneic transplant or salvage chemotherapy
Main Component 3 Drug regimen 2 Drug regimen 4 Drug regimen
Bortezomib based PAD, VCD VD
Bortezomib+IMiD based VRD, VTD VRDC, VDTC
Lenalidomide based LD, Ld
Thalidomide based TAD, CTD TD
If none of Novel drug
available
VAD
48. Disease category Response criteria7
sCR, stringent complete response *Normal free light chain (FLC) and absence of
clonal cells in bone marrow by
immunohistochemistry / immunofluorescence
CR, complete response *Negative immunofixation on the serum and
urine and disappearance of any soft tissue
plasmacytomas and ≤ 5% plasma cells in bone
marrow
VGPR, very good partial response *Serum and urine M-protein detectable by
immunofixation but not on electrophoresis
PR, partial response *≥50% reduction of serum M-protein AND
reduction 24h urinary M-protein by ≥90% OR
to <200mg per 24hour
SD, stable disease *Not meeting criteria for CR, VGPR, PR or
progressive disease
49. Primary treatment (non-transplant candidates)
Once the best remission has been achieved, maintenance
therapy with lenalidomide or thalidomide, with or
without steroids, can prolong remission, although not survival
Main Component 3 Drug regimen 2 Drug
regimen
4 Drug
regimen
Thalidomide MPT, CTD TD
Bortezomib MPV, VCD VD, vD VMPT
Thalidomide +Bortezomib VTD
Lenalidomide LD, lD
If none of Novel drugs available MP, BP
50. Treatment recommendations for
salvage therapy
Salvage therapy is used in patients who have relapse following allogeneic or
autologous stem cell transplant or in patients with primary progressive disease
following initial autologous or allogeneic stem cell transplant
Salvage therapy can also be used in patients who are ineligible for stem cell
transplant with progressive or relapsing disease after initial induction therapy
Salvage therapy includes the regimens, that were not previously selected
51. Therapy for relapse / refractory myeloma
Thalidomide*
Lenalidomide*
Bortezomib*
Liposomal doxorubicin*
*All of the drugs mentioned above can be used with or without Dexamethasone
Newer agents
•Pomalidomide(Thalidomde analogue)
•Carfilzomib(2nd generation Proteosome inhibitor)
•Vorinostat , Panobinostat (HDAC Inhibitor)
•Perifosine (AKT Inhibitor)
•Elotozumab(Anti CS-1 cell surface molecule)
52. Comparative trials of high-dose therapy (HDT) versus standard-dose chemotherapy (SDT). IFM-
90 (Intergroupe Francais de Myelome) randomized trial with 100 patients accrued to each arm
comparing SDT with VMCP-VBAP and HDT with melphalan 140 mg/m2 plus total-body
irradiation (8 Gy). Higher complete remission rates and significantly longer event-free and
overall survival were noted with HDT
High dose with TBI Vs Standard Dose
53. HDT versus conventional therapy also showed a superior CR
rate in the HDT arm, with a trend for prolonged EFS and OS in
the HDT arm
55. Thalidomide:
Proposed Mechanism of Action
Inhibition of TNF- synthesis.
Suppression of angiogenesis(inhibition of
FGF,VEGF,IL-6)
Increase in cell-mediated cytotoxic effects
Modulation of cell surface adhesion
molecule expression
Dose : 50 – 400 mg/day orally
Toxicity : Somnolence , Constipation , Neuropathy , DVT, SJS , Teratogenic
56. Lenalidomide
Immunomodulatory derivative of thalidomide
More potent than thalidomide .
Dose-dependent decrease in TNF-α and interleukin-6
Directly induces apoptosis, G1 growth arrest
Enhances activity of dexamethasone
More favorable toxicity profile than thalidomide
Difficult to use in renal insufficiency ( dose adjust)
Dose : 25 mg /day oral D1-D21 . 28 day cycle.
57. Renal Impairment (CrCl)
Moderate (30 to < 60 mL/min)
Severe (< 30 mL/min, not requiring
dialysis)
ESRD (< 30 mL/min, requiring
dialysis)
Lenalidomide Dosage
10 mg QD
15 mg Q 48 hrs
5 mg QD
On dialysis days, administer
following dialysis
Lenalidomide Dosing for MM and
Impaired Renal Function
58. Bortezomib:
A Reversible Proteasome Inhibitor
Chymo-
tryptic
Site
Post-
Glutamyl
Site
Tryptic
Site
β1 β2
b3
b4
β5
b6
b7
Cross section of b ring
Bortezomib
H
N B
N
H
O
O
OH
N
N
OH
Interferes with intracellular pathway that
degrades proteins regulating cell cycle,
apoptosis,angiogenesis
59. Mechanism of Action
•Blockade of NFkB activation and related pracrine IL-6 production by BMScs
•Acts directly on MM cells to induce apoptosis through Caspases 8,9 activation
•Reversible inhibitor of 26s proteosome
•Adds to antiMM effects of dexamethasone.
•It inhibits the secretion of Growth Promoting cytokines.
It has been shown to overcome the adverse outcome
associated with chromosome 13 abnormality
Dose : 1.3 mg/m2 I.V. twice weekly for 2 weeks (1,4,8,11 days)
Followed by a 10 day rest period (day 12 to 21 )
Toxicity : fatigue, diarrhoea, impaired LFT , orthostatic
hypotension, reversible thrombocytopenia, peripheral neuoropathy
60. Peripheral Neuropathy Following
Bortezomib Therapy in Advanced MM
Peripheral neuropathy was reported in 90/256 (35%)
patients with MM treated with bortezomib in phase II trials
80% of patients entered these trials with preexisting peripheral
neuropathy
3% patients without vs 16% with baseline peripheral neuropathy
developed grade 3 peripheral neuropathy
61. Treatment of complications:
Anaemia : blood transfusion , supportive management ,
inj. Erythropoietin 40000U/week
Nephropathy : correction of hypercalcaemia , dose reduction of
chemotherapeutic agents . e.g. Lenalidomide.
Hyperviscocity : plasmapheresis.
Infections : antibiotics , IVIG for recurrent life threatnening infections
Prophylaxis :Herpes zooster prophylaxis Before bortezomib therapy ,
antipneumococcal / anti influenza vaccine prophylaxis.
Pain : NSAIDS , Spinal braces
Bone pain & Skeletal complications : Bisphophonates ,
fixation of fracture of bone , +/- RT.
Pal RT for impending pathological fracture or to treat spinal cord compression,
Dose 8 Gy in single fraction / 20 Gy in 5 fractions.
62. MM & Skeletal Complications
~ 80% of patients with
multiple myeloma will have
evidence of skeletal
involvement on skeletal
survey
– Vertebrae: 65%
– Ribs: 45%
– Skull: 40%
– Shoulders: 40%
– Pelvis: 30%
– Long bones: 25%
63. The Central Role of the Osteoclast in
Osteolytic Bone Destruction
Growth
factors
Osteoclast differentiation
Osteolysis
Direct effects on
osteoclast differentiation
Tumor cells
Bone loss
Active
osteoclast
64. Mechanism of Bisphosphonate
Inhibition of Osteoclast Activity
Bisphosphonates
inhibit osteoclast
activity, and promote
osteoclast apoptosis[1]
Bisphosphonates
are released locally
during bone resorption[1]
Bisphosphonates are
concentrated under
osteoclasts[1]
Bisphosphonates may modulate
signaling from osteoblasts
to osteoclasts
New bone
X
Bone
Increased OPG production[2]
Decreased RANKL expression[3]
65. Recommended Doses and Infusion
Times
Drug Dose/Infusion Time Interval
Estimated CrCl > 60 mL/min
Pamidronate
Zoledronic acid
90 mg over 2-3 hrs
4 mg over 15 mins
3-4 wks
3-4 wks
Estimated CrCl 30 to < 60 mL/min
Pamidronate
Zoledronic acid
90 mg over 2-3 hrs*
Reduced dosage†
3-4 wks
3-4 wks
Estimated CrCl < 30 mL/min
Pamidronate
Zoledronic acid
90 mg over 4-6 hrs*
Not recommended
3-4 wks
*Consider dose reduction .
†3.5mg (CrCl 50-60 mL/min); 3.3 mg (CrCl 40-49 mL/min); 3.0 mg (CrCl 30-39
mL/min).
Kyle R, et al. J Clin Oncol. 2007;25:2464-2472.
66. Bisphosphonates and Osteonecrosis
Uncommon complication causing
avascular necrosis of maxilla or
mandible
Suspect with tooth or jaw pain
or exposed bone
May be related to duration of
therapy
True incidence unknown
Always enquire recent dental
therapy or tooth related
problems before starting
bisphosphonates
67. • Transplant-eligible patients
–Bortezomib/Thalidomide/Dexamethasone (VTD) vs Thalidomide/Dexamethasone (TD)
–Bortezomib/dexamethasone
–Lenalidomide/low-dose Dexamethasone (Rd)
• Transplant-ineligible patients
–VISTA: Bortezomib/Melphalan/Prednisone (VMP) vs Melphalan/Prednisone (MP)
–Lenalidomide/low-dose Dexamethasone (Rd)
• New combinations and early studies
–Transplant-eligible patients
• Bortezomib/Lenalidomide/Dexamethasone
• Bortezomib/Lenalidomide/Dexamethasone vs Bortezomib/Dexamethasone
–Transplant-ineligible patients
• MTP vs MPR (Phase III)
• VMP vs Bortezomib/Thalidomide/Prednisone (VTP) (Phase III)
–Early studies
• Bortezomib/Vorinostat (Phase I)
Recent and Ongoing Clinical Studies
68. VTD vs. TD in Patients
Who Are Transplant Eligible
• Study objective
– VTD vs TD in preparation for autologous stem cell
transplantation (ASCT)
• Study design
– Randomized trial
– Three cycles of induction therapy
• Methods
– Pts. randomized to either VDT (n=199) or TD (n=200).
– Stem cells were collected.
– Consolidation therapy with same treatment to pts.
– Results drawn from a final analysis of 399 patients.
Phase III Bortezomib-Thalidomide-Dexamethasone (VTD) vs
Thalidomide-Dexamethasone (TD) Prior to Stem Cell
Transplantation (SCT)
Cavo et al. Blood 2008 112: Abstract 158
69. • Prophylaxis
– Acyclovir prophylaxis against reactivation of VZV.
– TEE prophylaxis with low molecular weight heparin, aspirin,
or warfarin; fixed low-dose warfarin is effective.
• Conclusions:
– In comparison with TD, 3 21-d cycles of VTD as primary
therapy significantly increased CR+nCR rates.
– These response rates translated into significantly higher
CR+nCR after first ASCT in the VTD arm.
– Combinations of novel induction agents, such as VTD, can
have a remarkable impact on both pre- and post-ASCT
clinical outcome.
Conclusions From VTD vs. TD
Cavo et al. Blood 2008 112: Abstract 158
70. Bortezomib and Dexamethasone Prior
to ASCT in Transplant-Eligible Patients
• Phase III, active control, multicenter, open label, randomized
– Objective: compare the CR rate with vincristine/adriamycin/dexamethasone
(VAD) and bortezomib/dexamethasone combinations as induction therapy.
• Number of severe AE was similar between the arms:
Post Induction Post ASCT
CR/nCR ≥VGPR ≥PR CR/nCR ≥VGPR ≥PR
VAD 9% 24% 71% 28% 50% 88%
Bortezomib/
Dexamethasone
22% 50% 89% 38% 66% 87%
P-value 0.0085 0.0001 NS 0.127 0.021 NS
Harousseau et al, Blood 2007 110: Abstract 450.
71. • Post-induction complete remission (CR) was
increased by VD compared to VAD.
• One-year PFS and OS rates were 93% and 97%
with VD and 90% and 95% with VAD, respectively.
Conclusions From Bortezomib and
Dexamethasone Prior to ASCT
Harousseau et al, Blood 2007 110: Abstract 450.
72. VISTA Trial: VMP vs MP
in Transplant-Ineligible Patients
A Phase 3 Study Comparing Bortezomib/Melphalan/Prednisone (VMP) With
Melphalan/Prednisone (MP)
• Study objective:
–Define the differences in efficacy and outcome between VMP vs MP
• Study design and method:
–VMP arm (IV Bortezomib in combination with oral prednisone and oral melphalan) vs
MP arm (oral melphalan and prednisone)
• Primary endpoint:
–Time to progression (TTP)
• Secondary endpoints:
–Progression-free survival (PFS), overall survival (OS), overall response rate (ORR),
time to progression (TTP) and duration of response (DOR), and safety
San Miguel et al Blood 2007 110: Abstract 76; San Miguel et al Blood 2008 112: Abstract 650; Harousseau et al Blood 2008 112: Abstract 650
Mateous et al. Haematologica 2008; 93(4), 560-565
73. VISTA Trial: VMP vs. MP
Most Common Adverse Events (in ≥30% Patients)
receiving VMP (n=60)
Adverse Event % Toxicities All Grades % Toxicities Grades 3/4
Anemia 86 10
Thrombocytopenia 93 51
Infection 75 16
Neutropenia 85 43
Asthenia 63 5
Nausea 55 2
Diarrhea 55 16
Peripheral Neuropathy 55 17
Constipation 52 8
Anorexia 38 2
Vomiting 30 2
Mateos, et al. Haematologica 2008; 93(4) 560-565
74. Conclusions
• Adverse events
– 46% with VMP
– 36% with MP
• Patients remained on therapy longer with VMP:
– 46 weeks with VMP
– 39 weeks with MP
• Patients had a longer time to next therapy.
• Patients also had longer treatment-free survival.
VISTA Trial: VMP vs. MP
These results establish VMP as another option for patients
not eligible for SCT.
San Miguel et al Blood 2007 110: Abstract 76; San Miguel et al. Blood 2008 112: Abstract 650.
75. • Randomized multicenter Phase III ECOG
E4A03 study
–RD arm (223 patients)
• Lenalidomide 25 mg (days 1-21)
• Dexamethasone 40 mg (days 1-4,9-12,17-20)
–Rd arm (222 patients)
• Lenalidomide 25 mg (days 1-21)
• Dexamethasone 40 mg (days 1,8,15,22)
–Primary endpoint: response rate at 4 months
Lenalidomide/Dexamethasone (RD)
vs Lenalidomide/Low-Dose
Dexamethasone (Rd) in Transplant-
Ineligible Patients
Rajkumar et al, Blood 2007 110: Abstract 74
77. Results From RD vs Rd
• Rd is associated with superior OS compared to
RD in NDMM patients.
• Increased mortality in RD arm is due to
disease progression as well as increased
toxicity.
– Prevention of venous thrombotic events is a
priority for both combinations.
Rajkumar et al, Blood 2007 110: Abstract 74; Jacobus et al., Blood 2008 112: Abstract 1740
Editor's Notes
Stem cells =CD34+ Pro B-cells =CD10+,CD19+,CD34+,CD79a+ Pre B-cells =CD34-,CD10,CD19,CD79a
Immature B-cells = CD19,CD79a,CD20+,CD21+,CD22+,IgM(surface) Mature B-cells=CD19,CD79a,CD20,CD21,CD22,IgM,IgD
Activated B-cells=CD19,CD79a,CD20,CD21,CD22,CD10+,CD23+ Plasma cells=CD38+,CD138+,CD19-,CD20-,CD21-,CD22-,IgG.