NEWER AGENTS IN

PLASMA CELL DISORDERS

Dr Venkata Pradeep Babu K,

DNB Resident, Medical Oncology

■ 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.

Pathogenesis of myeloma in brief

Cumulative Genetic and Epigenetic changes

Giada Bianchi, and Nikhil C. Munshi Blood 2015;125:3049-3058

©2015 by American Society of Hematology

BONE LESIONS IN MYELOMA ARE DIFFERENT• Major Morbidity in Myeloma

• Seen on Xray, MRI,PET-CT • Bone scan not useful

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

Why End organ failure ??

Clinical Manifestations

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

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 Myeloma Therapies

High-dose melphalan

1962 1983 1984 1986 1996 1999 2000+

Thalidomide

ABMT

Treatment approach to Myeloma

Natural History of Multiple Myeloma:

Nearly All Pts Experience Relapse

MGUS or smoldering myeloma

Asymptomatic Symptomatic

ACTIVE MYELOMA

M P

rote

in (g

/L)

20

50

100

1. RELAPSE

2. RELAPSEREFRACTORYRELAPSE

First-line therapy

Plateau remission

Second-line Third-line

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.

RECENT ADVANCES IN RX OF MYELOMA

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.

T TO PUT IT SIMPLY…..

ACCUMULATION OF PROTEINS ER STRESS APOPTOSIS

PROTEASOME INHIBITORS

■ What are the drugs already in use ??

■ Bortezomib

■ What are newly approved drugs in this group ??

■ CARFILZOMIB■ IXAZOMIB

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 , Hepatic Toxicity and Hepatic Failure

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 OF ADMINISTRATION :■ 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

afterfood

■ ADVERSE EVENTS :■ In ≥ 20% , Diarrhoea, constipation, thrombocytopenia, peripheral

neuropathy, nausea, peripheral oedema, vomiting, and back pain.

■ WARNINGS :■ Thrombocytopenia , Hepatotoxicity , Peripheral Neuropathy

MULTIPLE MYELOMA INDUCED IMMUNOPARESIS:: Role of Immunomodulators

Immunomodulatory drugs (IMiDS) in multiple myeloma

■ What are the drugs already in use ??

■ Thalidomide, Lenalidomide

■ What are newly approved drugs in this group ??

■ Pomalidomide

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 :■ Hematologic Toxicity: Neutropenia was the most frequently

reported Grade 3/4 adverse event.

Histone Deacetylation in Multiple Myeloma

HDAC inhibitors in multiple myeloma

■ What are the drugs already in use ??

■ None . Several drugs like Vorinostat failed in clinical trials.

■ What are newly approved drugs in this group ??

■ Panabinostat.

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) of Weeks 1 and 2 of each 21-day cycle for 8 cycles

■ ADVERSE EVENTS :■ In ≥40%, H ypophosphatemia, hypokalemia, hyponatremia, and

increasedcreatinine and Netropenia

■In ≥ 20% patients :: Diarrhea, fatigue, nausea, peripheral edema, decreased appetite.

■ WARNINGS :■ Gastrointestinal and pulmonary haemorrhage & Hepatotoxicity:

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

DARATUMUMAB

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 OF ADMINISTRATION :■ 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

ELOTUZUMAB

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 OF ADMINISTRATION :

■ 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

INVESTIGATIONAL DRUGS WITH SINGLE

AGENT ACTIVITY

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

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.

■ 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.

■ 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. "