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 1
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 2
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! Steroids Prednisone Dexamethasone Conventional Chemo Melphalan Cyclophosphamide Doxil IMiDs Thalomid (thalidomide) Revlimid (lenalidomide) Pomalyst (pomalidomide) Proteasome Inhibitors Velcade (bortezomib) Kyprolis (carfilzomib, [low/high dose]) Ninlaro (ixazomib) HDAC inhibitors Farydak (panobinostat) Monoclonal antibodies Darzalex (daratumumab: anti CD38) Empliciti (elotuzumab: anti CS1/SLAMF7) DCEP/D-PACE BCNU Bendamustine Overcome resistance: Keytruda Viracept (nelfinavir) (pembrolizumab) Venclexta (venetoclax) 3
Options at First Relapse Proteasome Inhibitor: Kyprolis (carfilzomib) In combination with dex or with Revlimid + dex for the treatment of patients with relapsed or refractory MM who have received one to three lines of therapy 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 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) History of previous neuropathy Safe for patients with reduced kidney function Standard: Kyprolis used alone or in combination with dex or in combination with Revlimid and dex 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) 4
Proteasome Inhibitor: Kyprolis (carfilzomib) How is Kyprolis administered? Intravenous Given on two consecutive days each week for three weeks (that is, days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17 28) What are the possible side effects? What are important additional medications to take? Common side effects include: Fatigue Anemia Nausea Low platelet count Shortness of breath Diarrhea Fever Shingles prevention pills Proteasome Inhibitor: Ninlaro (ixazomib) In combination with Revlimid and dex for the treatment of patients with MM who have received at least one prior therapy 78% overall response rate (PR or better) Relapsed or relapsed/refractory following at least one prior therapy Standard: With Revlimid and dex Under investigation: with Treanda or Pomalyst in RR patients or with Revlimid in newly diagnosed patients 5
Proteasome Inhibitor: Ninlaro (ixazomib) How is Ninlaro administered? Oral Days 1, 8, and 15 of a 28-day cycle What are the possible side effects? What are important additional medications to take? Common side effects include: Diarrhea Constipation Thrombocytopenia Peripheral neuropathy Nausea Peripheral edema Vomiting Back pain Shingles prevention pills Monoclonal Antibody: Empliciti (elotuzumab) In combination with Revlimid and dex for the treatment of patients with MM who have received one to three prior therapies 78.5% overall response rate (PR or better) Relapsed or relapsed/refractory following at least one to three prior therapies Standard: with Revlimid and dex Under investigation: with Revlimid and Velcade in newly diagnosed patients; with Pomalyst and nivolumab or Pomalyst and Velcade in RR patients 6
Monoclonal Antibody: Empliciti (elotuzumab) How is Empliciti administered? IV Every week for the first two cycles and every 2 weeks thereafter What are the possible side effects? Common side effects include: Fatigue Diarrhea Pyrexia Constipation Cough Peripheral neuropathy Nasopharyngitis Upper respiratory tract infection Decreased appetite Pneumonia Monoclonal Antibody: Daratumumab Combinations Treatment of patients with MM who have received at least one prior therapy in combination with bortezomib and dex (DVd) or in combination with lenalidomide and dex (DRd) 83% overall response rate in combination with bortezomib and dex 93% overall response rate in combination with lenalidomide and dex Relapsed or relapsed/refractory following at least prior line of therapy Standard: with Velcade and dex or with Revlimid and dex Under investigation: with Kyprolis 7
Monoclonal Antibody: Darzalex (daratumumab) How is Darzalex administered? IV Weekly for weeks 1 to 8 then every 2 weeks for weeks 9 to 24 and then every 4 weeks for weeks 25 onwards What are the possible side effects? Common side effects include: Infusion reactions Fatigue Nausea Back pain Pyrexia Cough Upper respiratory tract infection Special consideration What are important additional medications to take? Can affect blood typing; carry a card that lists your blood type and indicates that you are on dara Shingles prevention Options at Second Relapse and Beyond 8
IMiD: Pomalyst (pomalidomide) For MM patients who have received at least two prior therapies including Revlimid and Velcade and have demonstrated disease progression on or within 60 days of completion of the last therapy 23.5% overall response rate in patients who received two or more prior 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 indicates effectiveness in 17p13del Safe for patients with reduced kidney function Patients of all ages Standard: Pomalyst + dex Under investigation: combinations with Vel-dex, Kyprolis-dex; experimental drugs (for example, SAR650984, Filanesib, Ixazomib) IMiD: Pomalyst (pomalidomide) How is Pomalyst administered? What are the possible side effects? What are important additional medications to take? Capsule taken once daily for 21 days out of a 28-day cycle (3 weeks on, 1 week off) 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 Gastrointestinal effects (constipation, nausea, or diarrhea) Shortness of breath Upper respiratory infection Back pain Fever Blood clots* Blood thinners *Reduced risk when taken with blood thinners 9
Histone Deacetylase Inhibitor: Farydak (panobinostat) In combination with Velcade and dex, treatment of MM patients who have received at least two prior regimens including Velcade and an IMiD (for example, Thalomid, Revlimid) 58.5% overall response rate (PR or better) Relapsed or relapsed/refractory following at least two prior regimens including Velcade and an IMiD Standard: with Velcade and dex Under investigation: with Kyprolis and experimental drugs (for example, Ninlaro) Histone Deacetylase Inhibitor: Farydak (panobinostat) How is Farydak administered? Oral Taken once every other day for three doses per week of weeks 1 and 2 of a 4-week cycle (that is, on days 1, 3, 5, 8, and 12) What are the possible side effects? What are important additional medications to take? Common side effects include: Diarrhea Peripheral neuropathy Asthenia/fatigue Nausea Peripheral edema Decreased appetite Vomiting Anti-diarrheal medication 10
Monoclonal Antibody: Darzalex (daratumumab) Treatment of patients with MM 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 (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 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 including a PI and an immunomodulatory agent or who are doublerefractory to a PI and an immunomodulatory agent Under investigation: with Pomalyst and dex Phase 3 Clinical Studies for Relapsed/Refractory Patients Monoclonal Antibodies Revlimid + dex ± Empliciti Velcade + dex ± Darzalex Revlimid + dex ± Darzalex Pomalyst + dex ± Pembrolizumab* Empliciti + Pomalyst Nivolumab* + dex Currently Available Agents Revlimid* + dex ± Ninlaro* Kyprolis* + dex vs Velcade* + dex Pomalyst* + Velcade* + low-dose dex Kyprolis* (oncevs twice-weekly) + 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 11
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 Velcadebased regimen: Darzalex, Velcade, and dexamethasone. Her pain promptly disappeared and she achieved a very good partial response after four cycles. 12
Making Anti-Myeloma Agents Patient Friendly Steroids Prednisone Dexamethasone Oral or IV Conventional Chemo Melphalan Oral or IV In or Outpt SCT Cyclophosphamide Oral or IV Doxil IMiDs Thalomid (thalidomide) Bedtime Revlimid (lenalidomide) Welchol or Prednisone Pomalyst (pomalidomide) 2 or 4 mg Proteasome Inhibitors Velcade (bortezomib) Skin or IV Weekly Kyprolis (carfilzomib, [low/high dose]) Weekly Ninlaro (ixazomib) HDAC Inhibitors Farydak (panobinostat) Every other week Monoclonal Antibodies Darzalex (daratumumab: anti CD38) Skin formulation Empliciti (elotuzumab: anti CS1/SLAMF7) Monthly 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 13