The document discusses several new agents for the treatment of plasma cell disorders like multiple myeloma. It provides information on newer proteasome inhibitors like carfilzomib and ixazomib, immunomodulatory drugs like pomalidomide, HDAC inhibitors like panobinostat, and monoclonal antibodies like daratumumab and elotuzumab. It also mentions some investigational drugs in development and discusses the importance of combination therapies and addressing issues like cost of these new treatments.

1. NEWER
AGENTS IN
PLASMA CELL
DISORDERS
Dr Venkata Pradeep
Babu K,
DNB Resident,
Medical Oncology

2. ■ Multiple myeloma accounts for 1% of all cancers and approximately
10% of all hematologic malignancies
■ The median age of patients at the time of diagnosis is about 65 years
■ It evolves from asymptomatic pre-malignant stage termed monoclonal
gammopathy of undetermined significance (MGUS) .
■ MGUS :: In 3% of the population above the age of 50,
■ Progresses to multiple myeloma :: 1% per year
■ An intermediate asymptomatic, more advanced premalignant stage::
Smoldering multiple myeloma (SMM) .
■ SMM :: progression to MM at 10% per year over the first 5 years of Dx
■ Rate of progression is influenced by the underlying cytogenetic type of
disease.

3. Pathogenesis of myeloma in brief

4. Cumulative Genetic and Epigenetic changes
Giada Bianchi, and Nikhil C. Munshi Blood 2015;125:3049-
3058
©2015 by American Society of Hematology

5. BONE LESIONS IN MYELOMA ARE DIFFERENT
• Major Morbidity in Myeloma
• Seen on Xray, MRI,PET-CT
• Bone scan not useful

6. Importance of Interaction Between Plasma Cells and Bone
Marrow for Development of Myeloma

7. Why End organ failure ??

8. Clinical Manifestations

11. Prognosis and Risk Stratification
■ The median survival is approximately
6–7 years.
■ In patients eligible for ASCT 4 year
survival rates exceed 80%.
■ However, there is major variation in
survival depending on::
Host factors, tumour burden
(stage), biology (cytogenetic
abnormalities), and response to
therapy

12. 1983
Bisphosphonates
Oral melphalan
and prednisone
VAD
High-dose
dexamethasone
High-dose therapy
with autologous
stem cell support
Proteasome
inhibitors
Other immuno-
modulatory
agents
Historical Perspective of Multiple
MyelomaTherapies
High-dose melphalan
1962 1983 1984 1986 1996 1999 2000+
Thalidomide
ABMT

13. Treatment approach to Myeloma

14. Natural History of Multiple Myeloma:
Nearly All Pts Experience Relapse
MGUS or
smoldering
myeloma
Asymptomatic Symptomatic
ACTIVE
MYELOMA
MProtein(g/L)
20
50
100
1. RELAPSE
2. RELAPSE
REFRACTORY
RELAPSE
First-line therapy
Plateau
remission
Second-line Third-line

15. Treatment of Relapse
DRD, daratumumab, lenalidomide, dexamethasone; DVD, daratumumab, bortezomib, dexamethasone;
ERD, elotuzumab, lenalidomide, dexamethasone; IRD, ixazomib, lenalidomide, dexamethasone; KRD, carfilzomib,
lenalidomide, dexamethasone; PD, pomalidomide plus dexamethasone.

16. RECENT
ADVANCES
IN RX OF
MYELOMA

17. PROTEASOME INHIBITORS
■ PROTEASOME S: Get rids off the unwanted proteins in cell
■ In Multiple myeloma cell , they are much more active to churn out excessive
immunoglobulins.
■ Blocking proteasomes  overburdens and poisons cell  ER stress 
Apoptosis
■ The possibility of targeting the proteasome was initially doubted due to the
essential role the ubiquitin-proteasome pathway plays in critical biological
processes.
■ Bortezomib (Velcade, Millennium Pharmaceuticals ) is the first proteasome
inhibitor approved by the US FDA
■ Proteasome inhibition could promote degradation of anti-apoptotic proteins
and prevent degradation of pro-apoptotic proteins, resulting in programmed
cell death in malignant cells.

19. T TO PUT IT SIMPLY…..
ACCUMULATION OF PROTEINS  ER STRESS
APOPTOSIS

20. PROTEASOME INHIBITORS
■ What are the drugs already in use ??
■ Bortezomib
■ What are newly approved drugs in this group ??
■ CARFILZOMIB
■ IXAZOMIB

21. CARFILZOMIB
■ INDICATION:
■ For patients who have received at least two prior therapies including
bortezomib and an immunomodulatory agent and have demonstrated disease
progression on or within 60 days of completion of the last therapy.
■ MODE OF ADMINISTRATION :
■ Intravenously over 2 to 10 minutes, on two consecutive days each week for
three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days
17 to 28).
■ ADVERSE EVENTS :
■ In ≥ 30% patients :: Fatigue, anemia, Thrombocytopenia, dyspnea, diarrhea,
and pyrexia.
■ WARNINGS :
■ Cardiac Adverse Reactions including heart failure and ischemia
Pulmonary Hypertension ,Tumor Lysis Syndrome , HepaticToxicity and
Hepatic Failure

22. IXAZOMIB
■ INDICATION:
■ Indicated in combination with lenalidomide and dexamethasone for the
treatment of patients with multiple myeloma who have received at least one
prior therapy.
.
■ MODE OFADMINISTRATION :
■ Recommended starting dose of 4 mg taken orally on Days 1, 8, and 15
of a 28-day cycle.
■ Dose should be taken at least one hour before or at least two hours after
food
■ ADVERSE EVENTS :
■ In ≥ 20% , Diarrhoea, constipation, thrombocytopenia, peripheral neuropathy,
nausea, peripheral oedema, vomiting, and back pain.
■ WARNINGS :
■ Thrombocytopenia , Hepatotoxicity , Peripheral Neuropathy

23. MULTIPLE MYELOMA INDUCED IMMUNOPARESIS::
Role of Immunomodulators

24. Immunomodulatory drugs (IMiDS) in multiple myeloma
■ What are the drugs already in use ??
■ Thalidomide, Lenalidomide
■ What are newly approved drugs in this group ??
■ Pomalidomide

25. POMALIDOMIDE
■ INDICATION:
■ a thalidomide analogue indicated for patients, who have received at least
two prior therapies including lenalidomide and bortezomib and have
demonstrated disease progression on or within 60 days of completion of
the last therapy.
■ MODE OF ADMINISTRATION :
■ 4 mg per day taken orally on days 1-21 of repeated 28-day cycles until
disease progression.
■ ADVERSE EVENTS :
■ In ≥ 30% patients :: Fatigue and asthenia, Neutropenia, anemia,
constipation, nausea, upperrespiratory tract infections, back pain and
pyrexia .
■ WARNINGS :
■ HematologicToxicity: Neutropenia was the most frequently
reported Grade 3/4 adverse event.

26. Histone Deacetylation in Multiple
Myeloma

27. HDAC inhibitors in multiple myeloma
■ What are the drugs already in use ??
■ None . Several drugs likeVorinostat failed in clinical trials.
■ What are newly approved drugs in this group ??
■ Panabinostat.

28. PANABINOSTAT
■ INDICATION:
■ In combination with bortezomib and dexamethasone, is indicated for the
treatment of patients who have received at least 2 prior regimens,
including bortezomib and an immunomodulatory agent.
■ MODE OF ADMINISTRATION :
■ 20 mg, taken orally once every other day for 3 doses per week (on Days 1,
3, 5, 8, 10, and 12) ofWeeks 1 and 2 of each 21-day cycle for 8 cycles
■ ADVERSE EVENTS :
■ In ≥40%, H ypophosphatemia, hypokalemia, hyponatremia, and increased
creatinine and Netropenia
■
In ≥ 20% patients :: Diarrhea, fatigue, nausea, peripheral edema,
decreased appetite.
■ WARNINGS :
■ Gastrointestinal and pulmonary haemorrhage & Hepatotoxicity:

29. MONOCLONAL ANTIBODIES IN
MULTIPLE MYELOMA
■ What are the drugs already in use ??
■ None
■ What are newly approved drugs in this group ??
■ DARATUMUMAB : Anti-CD 38 antibody
■ ELOTUZUMAB : Anti –SLAM7 anibody

30. DARATUMUMAB

31. DARATUMUMAB
■ INDICATION:
■ In combination with lenalidomide and dexamethasone, or bortezomib and
dexamethasone, who have received at least one prior therapy
■ As s monotherapy, for patients who have received at least three prior lines of
therapy including a proteasome inhibitor (PI) and an immunomodulatory agent
or who are double refractory to a PI and an immunomodulatory agent.
■ MODE OFADMINISTRATION :
■ As an intravenous infusion at a dose is 16 mg/kg
■ ADVERSE EVENTS :
■ In ≥40%, infusion reactions, neutropenia, thrombocytopenia, fatigue,
nausea, diarrhea, muscle spasms,
■ WARNINGS :
■ Grade ¾ Neutropenia and thrombocytopenia

32. ELOTUZUMAB

33. ELOTUZUMAB
■ INDICATION:
■ Indicated in combination with lenalidomide and dexamethasone for
the treatment of patients with multiple myeloma who have received
one to three prior therapies.
■ MODE OFADMINISTRATION :
■ 10 mg/kg administered intravenously every week for the frst two
cycles and every 2 weeks thereafter until disease progression or
unacceptable toxicity.
■ ADVERSE EVENTS :
■ In ≥20%, fatigue, diarrhea, , cough, peripheral neuropathy,
nasopharyngitis, upper respiratory tract infection, decreased appetite,
pneumonia.
■ WARNINGS :
■ Second primary malignancies (SPM), hepatotoxicity

34. INVESTIGATIONAL DRUGS
WITH SINGLE AGENT ACTIVITY

35. Finally , the ALTERNATE fact is
…■ Keeping away the appreciation for the research done to unveil the new
drugs, there is another angle of all these new drugs we have to conceive an
idea about.
■ The Pharmaco economic perspective.
■ Leave alone the people with insurance , the US government itself is unable
to bear the expenses of these new drugs, if one has to give combination of
these drugs as per guidelines.
■ These problems are not unique to myeloma, but are commonly
encountered in several other cancers as well.
■ But to some extent these pharmacoeconomic concerns are amplified in
myeloma due to the need for multidrug regimens that combine 2 or more
expensive new drugs, continuous therapy, and the prolonged disease
course in most patients

36. However, We do not lament the advances that have
occurred in myeloma.
We should welcome and embrace them.
They have changed the face of myeloma, and brought
hope and even the prospect of cure to myeloma
patients.

39. ■
After a tiring day, a young lady settled down in her local train seat
and closed her eyes.
■ As the train rolled out of the station, the guy sitting next to her,
pulled out his cell phone and started talking in a loud voice "Hi
Sweetheart, its Vinod, I'm on the Train" "Yes, I know it's Six thirty
and not four thirty, but I had A Long Meeting" I was with the Boss
attending the meet""No Sweetheart,You're the only one in My
life""Yes, I'm sure, Cross my heart".
■ Fifteen minutes later, he was still talking loudly.
■ When the Young Woman sitting next to him had enough, she leaned
over and said into the phone,
■ "Vinod darling, hang up the phone and come back to bed.
■ "Now Vinod is in hospital and doesn't use his cell phone in Public Any
Longer.

40. ■ Once a Chinese man came to Goa for holidays.
■ At Airport he hired a taxi to take him to Panjim.
■ On the way he sees a bus 🚌. He said - "The buses here are so slow and
nois .. In China the buses are very fast."
■ At Cortalim Bridge Chinese sees a train passing by on the railway bridge
the other side...... he says - "The trains here are so slow..... in China the
trains are very fast."
■ All the way driver kept silent and drove to Panjim.
■ Chinese man 👨 gets off the taxi and asked for meter readings.
■ Driver - "₹ 5000."Chinese -" ₹ 5000 ? Are you kidding ?Your buses are so
slow, the trains are so slow... if everything else here is so slow then how
come the meter of your taxi is so fast ?
■ "Driver -" Because the meter is made in China. "