MMRF Patient Summit West Palm Beach, FL 2/11/2017
Management of Multiple Myeloma: The Changing Paradigm
Relapsed/Refractory Disease Kenneth H. Shain, MD, PhD Assistant Member H. Lee Moffitt Cancer Center Assistant Professor University of South Florida College of Medicine Tampa, Florida
Patient Case and Question
A 65-year-old violinist is diagnosed with myeloma and receives Revlimid, Velcade, and dexamethasone (RVD) followed by high-dose melphalan and stem cell transplantation and Revlimid maintenance. 2½ years later, her myeloma markers are increased and, in light of persistent left leg pain, a PET-CT is performed and reveals a new lesion there and in a few other areas. Which of the following factors is NOT a consideration for her treatment at this point? A. The amount of neuropathy she has or could develop B. Her travel schedule C. The genetics of her myeloma at the time of her diagnosis D. The presence of bone disease E. None of the above
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What is relapsed/refractory disease? • Relapsed: recurrence after a response to therapy • Refractory: progression despite ongoing therapy
Options for Relapsed/Refractory Disease Continue to Increase
When did you relapse from your initial therapy?
≤6 months >6 months
Repeat initial therapy
Different therapy Different therapy
Stem cell transplant Stem cell transplant
Clinical trial
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Factors to Consider in Treatment Selection
DISEASE-RELATED • Amount of disease – CRAB symptoms, rate of progression • Duration of response to initial therapy • FISH/cytogenetics/genomics profile
PRIOR TREATMENT–RELATED • Prior drug exposure • Toxicity of regimen • Mode of administration • Previous SCT
PATIENT-RELATED • Pre-existing toxicity • Presence of other medical conditions • Age/frailty • General health • Personal lifestyle and preferences
FISH, fluorescence in situ hybridization; SCT, stem cell transplant Lonial S. Hematology Am Soc Hematol Educ Program. 2010;303.
Available Anti-Myeloma Agents: So Many Choices!
Conventional Proteasome HDAC Monoclonal Steroids Chemo IMiDs Inhibitors inhibitors antibodies Darzalex Thalomid Velcade Farydak Prednisone Melphalan (daratumumab: (thalidomide) (bortezomib) (panobinostat) anti CD38) Kyprolis Empliciti Revlimid Dexamethasone Cyclophosphamide (carfilzomib, (elotuzumab: (lenalidomide) [low/high dose]) anti CS1/SLAMF7) Pomalyst Ninlaro Doxil (pomalidomide) (ixazomib)
DCEP/D-PACE
BCNU
Bendamustine
Overcome resistance: Keytruda Viracept (nelfinavir) (pembrolizumab) Venclexta (venetoclax)
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Options at First Relapse
Proteasome Inhibitor: Kyprolis (carfilzomib)
• In combination with dex or with Revlimid + dex for the treatment of patients with FDA-approved relapsed or refractory MM who have received one to three lines of therapy indication • As a single agent for the treatment of patients with relapsed or refractory MM who have received one or more lines of therapy • 87% overall response rate when combined with Rev/dex • 77% overall response rate when combined with dex • Overall response rates as monotherapy How effective is it?* • 50% in patients who had two or more lines of prior therapy • 23% in patients with at least two or more lines of prior therapy • 50% in patients who were Velcade-naïve and had one to three prior lines of therapy
• High-risk features (for example, t(4;14) or 17p13 del or elevated β2-microglobulin) Who should take it? • History of previous neuropathy • Safe for patients with reduced kidney function
• Standard: Kyprolis used alone or in combination with dex or in combination with What combinations Revlimid and dex are used? • Under investigation: combinations with Farydak, IMiDs such as Revlimid and Pomalyst, experimental therapies (for example, SAR650984, filanesib) Overall response rate = complete response (CR) + very good partial response (VGPR) + partial response (PR) + minimal response (MR)
*Based on clinical studies for FDA approval.
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Proteasome Inhibitor: Kyprolis (carfilzomib)
How is Kyprolis • Intravenous • Given on two consecutive days each week for three weeks (that is, days 1, administered? 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17–28)
• Common side effects include: − Fatigue − Anemia What are the − Nausea possible side − Low platelet count effects? − Shortness of breath − Diarrhea − Fever
What are important additional • Shingles prevention pills medications to take?
Proteasome Inhibitor: Ninlaro (ixazomib)
FDA-approved • In combination with Revlimid and dex for the treatment of patients with MM indication who have received at least one prior therapy
How effective is it?* • 78% overall response rate (PR or better)
Who should take it? • Relapsed or relapsed/refractory following at least one prior therapy
What combinations • Standard: With Revlimid and dex • Under investigation: with Treanda or Pomalyst in RR patients or with are used? Revlimid in newly diagnosed patients
*Based on clinical studies for FDA approval.
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Proteasome Inhibitor: Ninlaro (ixazomib)
How is Ninlaro •Oral administered? • Days 1, 8, and 15 of a 28-day cycle
• Common side effects include: − Diarrhea − Constipation What are the − Thrombocytopenia possible side − Peripheral neuropathy effects? − Nausea − Peripheral edema − Vomiting − Back pain What are important additional • Shingles prevention pills medications to take?
Monoclonal Antibody: Empliciti (elotuzumab)
FDA-approved • In combination with Revlimid and dex for the treatment of patients with MM indication who have received one to three prior therapies
How effective is it?* • 78.5% overall response rate (PR or better)
• Relapsed or relapsed/refractory following at least one to three prior Who should take it? therapies
• Standard: with Revlimid and dex What combinations • Under investigation: with Revlimid and Velcade in newly diagnosed are used? patients; with Pomalyst and nivolumab or Pomalyst and Velcade in RR patients
*Based on clinical studies for FDA approval.
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Monoclonal Antibody: Empliciti (elotuzumab)
How is Empliciti •IV administered? • Every week for the first two cycles and every 2 weeks thereafter
• Common side effects include: − Fatigue − Diarrhea − Pyrexia What are the − Constipation possible side − Cough effects? − Peripheral neuropathy − Nasopharyngitis − Upper respiratory tract infection − Decreased appetite − Pneumonia
Monoclonal Antibody: Daratumumab Combinations
FDA-approved • Treatment of patients with MM who have received at least one prior therapy in combination with bortezomib and dex (DVd) or in combination with indication lenalidomide and dex (DRd)
• 83% overall response rate in combination with bortezomib and dex How effective is it?* • 93% overall response rate in combination with lenalidomide and dex
Who should take it? • Relapsed or relapsed/refractory following at least prior line of therapy
What combinations • Standard: with Velcade and dex or with Revlimid and dex are used? • Under investigation: with Kyprolis
*Based on clinical studies for FDA approval.
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Monoclonal Antibody: Darzalex (daratumumab)
How is Darzalex •IV • Weekly for weeks 1 to 8 then every 2 weeks for weeks 9 to 24 and administered? then every 4 weeks for weeks 25 onwards
• Common side effects include: − Infusion reactions − Fatigue What are the − Nausea possible side − Back pain effects? − Pyrexia − Cough − Upper respiratory tract infection
Special • Can affect blood typing; carry a card that lists your blood type and consideration indicates that you are on dara
What are important additional • Shingles prevention medications to take?
Options at Second Relapse and Beyond
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IMiD: Pomalyst (pomalidomide)
FDA-approved • For MM patients who have received at least two prior therapies including Revlimid and Velcade and have demonstrated disease progression on or indication within 60 days of completion of the last therapy
• 23.5% overall response rate in patients who received two or more prior How effective is it?* therapies, including Velcade and Revlimid
• Received two or more prior therapies, including Velcade and Revlimid • High-risk myeloma with DNA alterations, including t(4;14); preliminary data Who should take it? indicates effectiveness in 17p13del • Safe for patients with reduced kidney function • Patients of all ages
What combinations • Standard: Pomalyst + dex • Under investigation: combinations with Vel-dex, Kyprolis-dex; experimental are used? drugs (for example, SAR650984, Filanesib, Ixazomib)
*Based on clinical studies for FDA approval.
IMiD: Pomalyst (pomalidomide)
• Capsule taken once daily for 21 days out of a 28-day cycle (3 weeks on, How is Pomalyst 1 week off) administered? • Blood thinners (for example, aspirin or low-molecule-weight heparin) are given along with Pomalyst to reduce the risk of blood clots
• Common side effects include: − Fatigue and weakness − Low white blood cell counts − Anemia What are the − Gastrointestinal effects (constipation, nausea, or diarrhea) possible side − Shortness of breath effects? − Upper respiratory infection − Back pain − Fever − Blood clots* What are important additional • Blood thinners medications to take?
*Reduced risk when taken with blood thinners
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Histone Deacetylase Inhibitor: Farydak (panobinostat)
FDA-approved • In combination with Velcade and dex, treatment of MM patients who have received at least two prior regimens including Velcade and an IMiD (for indication example, Thalomid, Revlimid)
How effective is it?* • 58.5% overall response rate (PR or better)
• Relapsed or relapsed/refractory following at least two prior regimens Who should take it? including Velcade and an IMiD
What combinations • Standard: with Velcade and dex • Under investigation: with Kyprolis and experimental drugs (for example, are used? Ninlaro)
*Based on clinical studies for FDA approval.
Histone Deacetylase Inhibitor: Farydak (panobinostat)
How is Farydak •Oral • Taken once every other day for three doses per week of weeks 1 and 2 of a administered? 4-week cycle (that is, on days 1, 3, 5, 8, and 12)
• Common side effects include: − Diarrhea − Peripheral neuropathy What are the − Asthenia/fatigue possible side − Nausea effects? − Peripheral edema − Decreased appetite − Vomiting
What are important additional • Anti-diarrheal medication medications to take?
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Monoclonal Antibody: Darzalex (daratumumab)
• Treatment of patients with MM who have received at least three prior lines FDA-approved of therapy including a proteasome inhibitor (PI) and an immunomodulatory indication agent or who are double-refractory to a PI and an immunomodulatory (IMiD) agent
• 29% overall response rate in patients who had at least three prior lines of therapy including PI and IMiD or were double-refractory to a PI and IMiD How effective is it?* • 36% overall response rate in patients with at least two different cytoreductive therapies
• Relapsed or relapsed/refractory following at least three prior lines of therapy Who should take it? including a PI and an immunomodulatory agent or who are double- refractory to a PI and an immunomodulatory agent
What combinations • Under investigation: with Pomalyst and dex are used?
*Based on clinical studies for FDA approval.
Phase 3 Clinical Studies for Relapsed/Refractory Patients
Monoclonal Currently Antibodies Available Agents • Revlimid + dex ± • Revlimid* + dex ± Empliciti Ninlaro* • Velcade + dex ± • Kyprolis* + dex vs Darzalex Velcade* + dex • Revlimid + dex ± • Pomalyst* + Velcade* + Darzalex low-dose dex • Pomalyst + dex ± • Kyprolis* (once- Pembrolizumab* vs twice-weekly) + dex • Empliciti + Pomalyst Nivolumab* + dex
Ask your doctor if you are a candidate for clinical trials. Many phase 1 and 2 trials of new drugs and new combinations
*Experimental therapy not yet FDA approved
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Special Circumstances • High disease burden requiring rapid response: 96-hour continuous IV chemo: – V(DCEP) = Velcade + (dex + Cytoxan + etoposide + platinum) – VDTPACE = VDCEP + thalidomide + doxorubicin • If blood counts low, need a bridge to a clinical trial, and stem cells remaining – Consider second (or salvage) autologous stem cell transplant
Patient Case, Update
• A 65-year-old violinist is diagnosed with myeloma and receives Revlimid, Velcade, and dexamethasone (RVD), followed by high-dose melphalan and stem cell transplantation, and Revlimid maintenance. • 2½ years later, her myeloma markers are increased and, in light of persistent left leg pain, a PET-CT is performed and reveals a new lesion there and in a few other areas. • Because her myeloma had t(4;14) and she had no neuropathy (including when she received Velcade) she and her oncology team decided upon a Velcade- based regimen: Darzalex, Velcade, and dexamethasone. • Her pain promptly disappeared and she achieved a very good partial response after four cycles.
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Making Anti-Myeloma Agents Patient Friendly
Conventional Proteasome HDAC Monoclonal Steroids Chemo IMiDs Inhibitors Inhibitors Antibodies Velcade Darzalex Melphalan Thalomid Farydak (bortezomib) (daratumumab: Prednisone Oral or IV (thalidomide) (panobinostat) Skin or IV anti CD38) In or Outpt SCT Bedtime Every other week Weekly Skin formulation Empliciti Revlimid Kyprolis Cyclophospha- (elotuzumab: Dexamethasone (lenalidomide) (carfilzomib, mide anti Oral or IV Welchol or [low/high dose]) Oral or IV CS1/SLAMF7) Prednisone Weekly Monthly Pomalyst Ninlaro Doxil (pomalidomide) (ixazomib) 2 or 4 mg DCEP/D-PACE In or Outpt
BCNU
Bendamustine Days 1, 2 or 1, 4 Overcome resistance: Keytruda Viracept (nelfinavir) (pembrolizumab) Venclexta (venetoclax)
Ask about co-pay assistance and travel assistance programs!
Relapsed/Refractory Myeloma: Choice Is Good!
Relapsed/refractory multiple myeloma is treatable
Patients typically receive multiple lines of therapy
Treatment may sometimes be continued for an extended period
Six new drugs (Kyprolis, Pomalyst, Farydak, Darzalex, Empliciti, Ninlaro) introduced in last 4 years
With the introduction of each new drug, potential for additional combinations
Many promising new drugs/new combinations in clinical development—consider a clinical trial
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