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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. "