Considerations for Optimizing Transplant in Multiple Myeloma Patient Management The first 68 slides of this library should be considered a sample presentation.

Considerations for Optimizing Transplant in Multiple Myeloma Patient Management
The first 68 slides of this library should be considered a sample presentation only. You should customize your presentation using the slides in the library, keeping in mind that the learning objectives must be met.

Considerations for Optimizing Transplant in Multiple Myeloma Patient Management

Learning Objectives After completing this program, participants should be able to: Identify factors that might determine eligibility for and timing of high-dose chemotherapy (HDT) followed by autologous stem cell transplant (ASCT) in patients with multiple myeloma (MM) Differentiate treatment strategies for patients with newly diagnosed multiple myeloma who are eligible for HDT/ASCT Identify barriers in access to HDT/ASCT for MM Review the rationale for conditioning regimens in patients with multiple myeloma who are eligible for HDT/ASCT Compare and contrast pertinent data regarding a new formulation of melphalan

Myeloma Overview

Hallmarks of MM MULTIPLE MYELOMA Lytic lesions, Pathologic fractures,
Hypercalcemia Bone destruction MULTIPLE MYELOMA Monoclonal globulins Urine: Renal failure Blood: Hyperviscosity, Cryoglobulins, Neuropathy Tissue: Amyloidosis Reduced globulins Infection Anemia Marrow infiltration Plasma cell Carr et al, 1999.

Incidence and Mortality by Race/Ethnicity and Gender
Male Female Age,[1] years (range) Incidence*[2] Mortality*[2] All Races 7.9 4.2 5.1 2.7 White 70 (61-78) 7.5 4.0 72 (62-81) 4.5 2.4 Black 65 (57-74) 15.1 7.6 67 (57-76) 11.2 5.3 Asian/Pacific Islander 69 (60-77) 4.6 2.2 70 (59-78) 3.0 1.4 American Indian/Alaska Native 3.2 2.3 Hispanic 65 (55-74) 7.3 3.5 66 (56-76) 4.8 Blacks have twice the incidence of whites [SEER] *Age-adjusted rates per 100,000 [1] Costa et al. Biol Blood Marrow Transplant Apr;21: [2] SEER Stat Fact Sheets: Myeloma. Available at Accessed August 2015.

Revised International Staging System (R-ISS) for MM
R-ISS I (n = 871) Including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL) No high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)] Normal LDH level (less than the upper limit of normal range) R-ISS III (n = 295) Including ISS stage III (serum β2-microglobulin level > 5.5 mg/L) High-risk CA or high LDH level R-ISS II (n = 1,894) Including all the other possible combinations Combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM). Clinical and laboratory data from 4,445 patients with NDMM enrolled onto 11 international trials were pooled together. The K-adaptive partitioning algorithm was used to define the most appropriate subgroups with homogeneous survival. ISS, CA, and LDH data were simultaneously available in 3,060 of 4,445 patients. We defined the following three groups: revised ISS (R-ISS) I (n = 871), including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)], and normal LDH level (less than the upper limit of normal range); R-ISS III (n = 295), including ISS stage III (serum β2-microglobulin level > 5.5 mg/L) and high-risk CA or high LDH level; and R-ISS II (n = 1,894), including all the other possible combinations. At a median follow-up of 46 months, the 5-year OS rate was 82% in the R-ISS I, 62% in the R-ISS II, and 40% in the R-ISS III groups; the 5-year PFS rates were 55%, 36%, and 24%, respectively. 5-Year OS* 5-Year PFS* R-ISS I 82% 55% R-ISS II 62% 36% R-ISS III 40% 24% Palumbo, et al. JCO. 2015;33(26): *At a median follow-up of 46 months

Indications for Considering Treatment (IMWG Consensus Guidelines)
At least one of the CRAB Criteria (evidence of end organ damage) CRAB Criteria Hypercalcemia Serum calcium >2.75 mmol/L (>11 mg/dL) Renal Failure Serum creatinine ≥ 2 mg/dL or creatinine clearance <40 mL per min Anemia Hemoglobin >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L Bone Lytic lesions, pathologic fractures, or severe osteopenia ≥60% clonal bone marrow plasma cells Serum involved/uninvolved free light chain ratio ≥100 >1 Focal bone lesion (≥5mm) on MRI Clinical judgement Rajkumar, et al. Lancet Oncology. 2014;15(12):e

Available Therapies and Phases of Treatment for MM
Treatment Options Conventional chemotherapy (e.g., alkylating agents) Steroids (corticosteroids) Autologous stem cell transplant (ASCT) Newer therapies Proteasome inhibitors Immunomodulatory agents Monoclonal antibodies HDAC inhibitors Many therapies are available for MM and the choice of therapy is individualized based on disease and patient factors. Transplant eligible patients should receive non-melphalan-containing (stem cell sparing) regimens, while transplant-ineligible patients can receive either melphalan-containing or non-melphalan-containing regimens [Rajkumar ASCO 2012 education session, slide 12] Age is no longer an absolute barrier to transplant. Key factors are performance status and comorbidities [Krishnan ASCO 2012 education session slides 6-7] For patients in which ASCT is planned or a possible future option, the aim of induction treatment is to induce high remission rates rapidly and with minimal toxicity, using regimens that preserve hematopoietic stem cell function to ensure successful mobilization [Bird Br J Haematol 2011] Timing of transplant is a currently debated issue, with questions including whether induction therapy should continue to best response, with transplant acting as a part of consolidation therapy, or whether induction therapy should be given for a fixed number of cycles to minimize toxicity [Krishnan ASCO 2012 education session slides 6-7] There is some confusion about whether post-transplant strategies should be referred to as “consolidation” or “maintenance”. The distinctions are semantic and the questions to be addressed are simply whether post-transplant therapy should be administered, who should receive it [Rajkumar Am J Hematol 2012] Supportive care is required throughout the treatment continuum Initial Therapy Consolidation / Maintenance Treatment of Relapsed Disease ASCT if eligible* Supportive Care *Transplant eligibility may impact initial treatment decisions

Treatment Goals for MM Disease Response and Survival Symptom Control
Rapid cytoreduction to relieve symptoms Minimize treatment-related toxicity Prolong survival – Overall Survival Symptom Control Ameliorate pain and other disease-related symptoms Prevent further organ damage Preserve performance status and quality of life MM is an incurable disease, with the goals of treatment focused on disease and symptom control

Assessing and Monitoring Response to Therapy

MRD Assessment in MM Remains a research tool
Indications are that lower levels of MRD predict for better outcomes Can contribute to better definition of response Potential to monitor efficacy of therapy Best, easily exportable method Optimal time point is still under investigation Even patients who achieve MRD state can relapse, so all may not be able to stop therapy Unsure if changing therapy based on depth of response alters survival outcomes Unsure of next steps for MRD MRD, minimal residual disease. Sherrod, et al. Bone Marrow Transplant. 2015;Jul 20. [Epub ahead of print]

Imaging of Residual Disease in MM
PET/CT[1,2] PET may be useful for some, but not all, patients Variability in PET approaches across different studies and institutions PFS (CR Pts After First-line Therapy) Mos 12 24 36 48 60 72 1.0 0.8 0.6 0.4 0.2 P = .010 PET CR median: 90 mos NO PET CR median: 50 mos PFS (Proportion) [1] Zamagni E, et al. Blood. 2011;118: [2] Zamagni E, et al. ASH Abstract 1936.

New Molecular MRD Tests Under Development for MM
ASO-PCR VDJ Sequencing Exome Sequencing Mass Spectrometry Universal Assay No (patient specific primers) Yes “Yes/No” Sensitivity 10-5 10-6 Unknown Sample Analyzed Bone marrow aspirates Bone marrow aspirates or plasma Urine or serum Inter-observer Variation Likely Likely low Study Clonal Evolution No detection Limited detection Can Overcome Sampling Error Maybe overcome with plasma samples Mailankody, et al. Nature Reviews Clinical Oncology. 2015;12:286–295.

AUTOLOGOUS transplant When and How?

Barriers to Autologous Transplant Access
HEALTH CARE SYSTEM Limited number of HCT centers Workforce shortage Capacity limitations Infrastructure issues ACCESS TO TRANSPLANT SOCIAL Age Ethnicity and race Language Culture Health literacy Patient/family attitudes Caregiver availability ECONOMIC Socioeconomic status Education Number of wage earners Employment status Insurance coverage Place of residence Transportation PROVIDER Physician referral Provider attitudes/biases Provider expertise Provider diversity Majhail NS, et al. Biol Blood Marrow Transplant. 2010;16(8): Disparity in cancer care, including HCT, has been identified for certain high-risk populations, including elderly patients, patients of black or Hispanic race/ethnicity, and women. Barriers to receiving optimal health care may include demographics, cultural differences, lack of culturally sensitive resources, cost concerns, logistical problems, and insurance coverage. Some of these factors may overlap; for example, white patients are more likely than racial minorities to have insurance coverage. With respect to HCT for hematologic malignancy specifically, additional barriers may exist, given the expense of the procedure and the high level of interaction that typically occurs between patients and HCPs before, during, and after the procedure. Reference Majhail NS, Omondi NA, Denzen E, et al. Access to hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2010;16(8): Adapted from: Majhail NS, et al. Biol Blood Marrow Transplant. 2010;16(8):

Transplant Ineligible vs Transplant Eligible
Poor performance status Elderly and frail Unable to perform activities of daily living Decompensated comorbidity Social economic factors Patient choice Very low-risk disease Asymptomatic myeloma Solitary plasmacytoma Age should not be considered an absolute contraindication for SCT Good performance status Adequate organ function Compensated comorbidities Social economic factors Adequate care givers Adequate support for transport to and from transplant center Ability to comply with peritransplant follow-up care Willing to proceed Transplant Ineligible -Poor performance status Elderly and frail Unable to perform activities of daily living. Decompensated comorbidity Congestive heart failure Uncontrolled diabetes Unstable angina Social economic factors Lack of caregiver Distance from transplant center Inability to comply with peritransplant follow up care. Patient choice Very low risk disease Asymptomatic myeloma Solitary plasmacytoma Transplant Eligible Good performance status Adequate organ function Compensated comorbidities No active congestive heart failure (CHF) Renal failure stable on dialyses are appropriate candidates No active uncontrolled infections No acute bleeding or recent thromboembolic events Social Economic Factors Adequate care givers Adequate support for transport to and from transplant center Ability to comply with peritransplant follow up care Willing to proceed Rajkumar SV, et al. Mayo Clin Proc. 2005;80(10): Harousseau JL, et al. N Engl J Med. 2009;360(25):

Indications for Hematopoietic Stem Cell Transplants in the US, 2012
Indications for HSCTs in the US—2012 Indications for Hematopoietic Stem Cell Transplants in the US, 2012 The most common indications for HCT in the US in 2012 were multiple myeloma and lymphoma, accounting for 57% of all HCTs. AML and myelodysplasia are the most common indications for allogeneic transplants accounting for 51% of allogeneic HCTs. PCD, Plasma Cell Dyscrasias; AML, acute myelongenous leukemia; ALL , acute lymphocyte leukemia; CML , chronic myelogenous leukemia; NHL, non-Hodgkins lymphoma; HD, Hodgkin’s disease; MDS/MPD, myelodysplastic syndrome/myelopodiferative disorder; CLL , Chronic lymphocytic leukemia. Pasquini MC, Zhu X CIBMTR Summary Slides. Available at:

Conditioning Regimens for MM
Anti Myeloma activity Standard Melphalan; TBI (total body radiation) Investigational TOXICITY Mortality (TRM) – very low for MEL 200 mg/m2 GI toxicity – dose limiting toxicity Pulmonary Syndrome Arrhythmias COST Days in Hospital Cost of procurement Timely availability – e.g TBI / Thiotepa in the USA

High-dose Melphalan (200 mg/m2) is the Best Conditioning Regimen for MM Survival
100 90 80 70 60 50 40 30 20 10 Overall Survival Rate Months MEL 200 TBI + MEL 140 P = 0.05 Moreau, P. et al. Blood;2002;99:

Bifunctional Alkylator
Melphalan Bifunctional Alkylator PK issues L – Phenyl Alanine Mustard Initially synthesized in the 1950s Forms adducts and crosslinks DNA CSF penetration ?? Rapidly disappears from plasma T ½ – less than 8hrs Unstable in aqueous media Eliminated by spontaneous degradation (1% / 10 min) Clearance is independent of creatinine clearance ? Maybe RENAL IMPAIRMENT and MEL - controversial

Risk-adapted Melphalan Dosing
Suggested Melphalan Dose-adjustment for Patients with Renal Impairment[1] CrCl >15 < 60 mL/min CrCl < 15 mL/min or the patient is on hemodialysis High-dose Melphalan 140 mg/m2 Suggested Age-adjusted Dosing of Melphalan[2] Age <65 years Dose level 0 Age 65–75 years Dose level −1 Age >75 years Dose level −2 Melphalan 0·25 mg/kg days 1–4 every 4–6 weeks 0·18 mg/kg 0·13 mg/kg Melphalan dose may also be adjusted due to comorbidities [1] Dimopoulos, et al. JCO. 2010;28: [2] Palumbo A, Anderson K. N Engl J Med. 2011;364:

Risk-adapted Melphalan Dosing
Dose-Reductions in Obese Patients Median MEL Normal Overweight Obese Severe Obese MEL 200 cases Total MEL 340 370 376 Dose / m2 198 193 167 172 MEL TBI cases 245 250 276 272 Dose/m2 140 137 131 125 Vogl, et al. ASH Abstract 3333.

Intensification of MEL
MEL 220 mg/m2 (French single arm study)[1] Escalating MEL to 300 mg/m2 [2] Cardiac toxicity reported No obvious superiority over MEL 200 (historical) At least 2 other MEL 280 studies in progress or completed Amifostine for protection MTD was MEL 280 mg/m2 At higher MEL doses Atrial Fibrillation Hepatic Necrosis Cardiac Death Severe Mucositis Increased deaths [1] Moreau, et al. Bone Marrow Transplant. 1999;23: [2] Philips, et al. Biol Blood Marrow Transplant. 2004;10:

Comparison of Results with Previous Studies
MEL 280 mg/m2 MCW Study Comparison of Results with Previous Studies Study OS (years) EFS (years) IFM 90 4.5 2.5 IFM 94* 4.3 2.3 IFM 99-04* 3.9 2.0 S9321 4.0 1.9 TT1* 5.7 2.6 MRC 7 MEL 280 /m2 5.6 1.8 *Median OS and EFS similar to prior tandem ASCT studies TT1 and IFM94 from the pre-novel drug era Randhawa, et al. ASMBT BMT Tandem Meetings Abstract 42.

Current Variations for High-dose MEL
Fractionated Melphalan 50 mg/m2 days 1-4 NO prospective or retrospective comparison to standard Melphalan dosing is available Rationale – Reduce Toxicity Fractionated MEL 100 mg/m2 x 2 days

2-Day Dosing Melphalan (n=185) 1-Day Dosing Melphalan (n=93)
MEL-100 x2 vs MEL-200 X1 Response Category 2-Day Dosing Melphalan (n=185) 1-Day Dosing Melphalan (n=93) P-value sCR 23 (12%) 8 (8%) .3 CR 55 (30%) 21 (23%) VGPR 41 (22%) PR 45 (24%) 35 (38%) sCR+CR 78 (42%) 29 (31%) .09 ORR 164 (89%) 85 (91%) .5 Parmar, et al. Bone Marrow Transplantation. 2014;49:761–766.

MEL 200 vs. Bortezomib MEL – Matched pair
Response BOR-MEL (n = 46) MEL 200 (n = 115) P CR 35% 11% .001 VGPR 43% PR 26% CR+VGPR 70% 54% .078 Mucositis Grade 3-4 47% Median duration Mucositis 9 days (2-13) GI – diarrhea G1-2 72% Skin Reactions G1-2 34% Neuropathy 8% Headache 28% Blood Jan 7;115(1):32-7. doi: /blood Epub 2009 Nov 2. Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Roussel M1, Moreau P, Huynh A, Mary JY, Danho C, Caillot D, Hulin C, Fruchart C, Marit G, Pégourié B, Lenain P, Araujo C, Kolb B, Randriamalala E, Royer B, Stoppa AM, Dib M, Dorvaux V, Garderet L, Mathiot C, Avet-Loiseau H, Harousseau JL, Attal M; Intergroupe Francophone du Myélome (IFM). Roussel, et al. Blood. 2010;115:32-37.

Other Conditioning Regimens Currently in Use
Classic Busulfan Cyclophosphamide Busulfan – Melphalan Busulfan – Cyclophosphamide – Thiotepa Variations of MEL Escalated doses Fractionated MEL Newer Targeted Marrow Radiation + MEL MEL + Bortezomib MEL + Arsenic Trioxide MEL + Carfilzomib

Promising Investigational Preparative Regimens
# of Patients Year(s) CR/VGPR Overall Response Survival Toxicity Type of Study Intravenous BUMEL 102 CR: 17% 58% 2-year: 82% Day 100 treatment related mortality: 1% Phase 1 BEAM vs MEL 179 NA 5-year OS: 59% BEAM vs 46% Mel (NS) Retrospective Bortezomib and MEL 54 2007 CR: 32% ≥VGPR: 70% 94% Estimated 2-yr: 96% ≥Grade 3 mucositis of upper and lower digestive tract: 47% 1 case of grade 3 peripheral neuropathy Phase 2 Bortezomib given before or after MEL 39 CR: 21% ≥VGPR: 51% 87% Median OS: 36.7 months ≥Grade 3 mucositis: 31% ≥Grade 3 neutropenic fever: 56% Phase 1/2 Bortezomib with iv BUMEL 20 2010 ≥VGPR: 77% Near CR or better: 54% 100% ≥Grade 3 neutropenic fever: 58% ≥Grade 3 mucositis: 47% ≥Grade 3 hypo-phosphatemia: 37% MEL280 with Palifermin 19 100 days: ≥VGPR: 27% 100 days: 53% Grade 3-4 mucositis: 44% Asymptomatic atrial fibrillation: 17% No treatment related deaths PG-free MEL 15 No unexpected toxicity Phase 2a Modified from: Aljitawi, et al. J Comp Eff Res. 2012;1:57-70.

High-dose Melphalan is the Most Frequently Used Conditioning Regimen
Frequency of Use MEL 88% MEL + others (TBI) 8% BU-MEL 1% BU-CY 2.5% CIMBTR 2010

>18 mos after prior ASCT Melphalan 200mg/m2 IV + ASCT
Myeloma X: High-dose Melphalan + Salvage ASCT vs Cyclophosphamide in R/R MM PAD induction 2-4 cycles R/R MM; >18 mos after prior ASCT (N = 293) Randomized 1:1 Melphalan 200mg/m2 IV + ASCT (n = 89) Cyclophosphamide 400mg/m2 PO/wk x12 cycles (n = 85) PAD induction therapy: Bortezomib + Doxorubicin + Dexamethasone 2-4 cycles PBSC mobilization and harvesting if applicable Removed from study if PD or CD34+ cells <2x106/kg Primary endpoint: time to disease progression Secondary endpoints: OR, PFS, OS, toxicity, safety, pain, QoL Cook G, et al. Lancel Oncol. 2014;15:

Myeloma X: Response Rates with High-dose Melphalan/2nd ASCT vs Cyclophosphamide
PFS 39.3% 22.4% P = .012 ≥ VGPR rate: 59.5% after salvage ASCT vs 47.1% after cyclophosphamide (OR: 0.38 [95% CI: ]; P = .0036) Cook G, et al. Lancet Oncol. 2014;15:

Melphalan Challenges PK Variability Propylene Glycol Special Issues

MEL Pharmacokinetics Inter-individual variability
Creatinine Clearance Fat free mass Hematocrit Higher MEL exposure—increased toxicity and efficacy Unbound MEL—sensitive predictor of toxicity and efficacy Nath, et al. Br J Clin Pharmacol. 2010;69:

Special Issues with Melphalan: Renal Impairment
Up to 50% of newly diagnosed patients have a decrease in creatine clearance and ∼9% require dialysis because of severe renal impairment [1] No change in the pharmacokinetics of high-dose melphalan in patients with renal failure[2,3] Outcome similar to patients with preserved renal function Similar results observed in a series of 81 MM patients with renal failure (38 patients on dialysis)[4] Renal failure did not affect the quality of stem cell collections or engraftment Median OS >52 months (similar to patients with normal renal function) CR rate was not significantly affected by dialysis dependence (37% in dialysis patients vs 33% in the non-dialysis group; P=.07) No change in the pharmacokinetics of high-dose melphalan in patients with renal failure2,3 Received standard melphalan at a dose of 200 mg/m2, including patients on hemodialysis Outcome similar to patients with preserved renal function Early mortality remained below 5% Similar results observed in a series of 81 MM patients with renal failure (38 patients on dialysis)4 Transplant-related mortality was 6% (single ASCT) and 13% (tandem ASCT) Renal failure did not affect the quality of stem cell collections or engraftment Median OS >52 months (similar to patients with normal renal function) CR rate was not significantly affected by dialysis dependence (37% in dialysis patients vs 33% in the non-dialysis group; P=.07) [1] Knudsen L, et al. Eur J Haematol.1994; 53: 207–212. [2] Tricot, et al. Clin Cancer Res. 1996;2: [3] Jagannath, et al. Blood. 1995;86:205a. [4] Badros A, et al. Br J Haematol. 2001; 114:822–829.

Melphalan 140 mg/m2 as effective as melphalan 200 mg/m2 with less toxicity in patients with renal impairment[1] Mucositis: 93% (MEL-200) vs 67% (MEL-140); P= .04 Pulmonary complications 57% (MEL-200) vs 17% (MEL-140); P=.007 53% (dialysis-dependent) vs 19%; P= .02 Cardiac complications Atrial dysrhythmias significantly more common in MEL-200 group 21% (MEL-200) vs 0 (MEL-140); P = .07 Neurological complications More common in MEL -200 group (36% vs 27%, P = .6) Significantly more common in dialysis group (47% vs 6%; P = .005) 1. Badros A, et al. Br J Haematol. 2001; 114:822–829.

Pharmacokinetics of MEL are no different in renal-impaired patients BUT More leukopenia noted in patients with renal impairment in early studies MEL-200 poorly tolerated by patients with renal dysfunction 60% MEL can be recovered from urine Auto-SCT should be performed early in the disease course before renal failure becomes irreversible1 MEL-140 is associated with less toxicity and equal efficacy to MEL- 200 in patients with renal failure Renal failure patients with low albumin had a higher treatment-related mortality and may do better with even lower doses of MEL (70 ± 100 mg/m2) 1. Badros A, et al. Br J Haematol. 2001; 114:822–829.

Special Issues with Melphalan: Mucositis
MEL-ASCT is associated with severe oral mucositis (OM) OM develops in 45%-75% of patients[1,2] Predictors of severe OM[1] High serum creatinine High mg/kg melphalan Severe OM risk and/or duration was significantly associated with:[2] Higher chemotherapy dose/kg of body weight Poor performance status NOT related to age [1] Grazziutti ML,et al. Bone Marrow Transplant. 2006;38(7): [2] Blijlevens N, et al. J Clin Oncol. 2008;26(9):

Cryotherapy Prevents OM in MM Patients Receiving High-dose Melphalan
117 MM patients randomized to receive cryotherapy (CT) + saline solution (SS) mouth rinse, SS alone, or supersaturated calcium phosphate rinses[1] No OM: 90% of patients in the CT group vs 36% (supersaturated calcium phosphate rinse) and 34% (SS) (P < .0001) No grade 3-4 OM in the CT group Meta analysis of 7 RCTs including 458 patients with hematological malignancies undergoing HSCT[2] Oral cryotherapy significantly reduced The incidence of severe OM OM severity The duration of total parenteral nutrition use The length of hospitalization [1] Toro, et al. BBMT ;20 :S204 - S205. [2] Wang, et al. PLoS One. 2015; 10(5): e

Special Issues with Melphalan: Administration
When reconstituted, Melphalan rapidly hydrolyzes ~1% every 10 minutes Manufacturer recommendations: Dilute dose in NS to </= 0.45 mg/mL and infuse over at least 15 minutes Complete the infusion within 60 minutes of reconstitution of the vial BMT programs should verify that infusions have ended before the Melphalan expiration time/date

Special Issues with Melphalan: Administration
Example: Patient 2.1 m2 ordered 200 mg/m2 A dose of 420 mg diluted in 933 mL NS (0.45 mg/mL) must 1867 mL/h administer the dose over 30 minutes The dose is prepared as 2 bags (466.5 mL each) to infuse simultaneously with each 933 mL/h A typical infusion pump has a maximum infusion rate of 999 mL/h

Special Issues with Melphalan: Stability
Highly unstable in solution 10% per loss of activity/ hr Propylene Glycol (PG) Additive to MEL Toxic in the ICU setting when given as continuous infusion Rate of PG infusion exceeds FDA guidelines when MEL bolus given currently

CE-Melphalan (Propylene Glycol-free)
FDA Approved March 2016 1st drug to gain FDA approval for the high-dose conditioning indication in MM Captisol-enabled melphalan (CE-melphalan) approved for two indications in MM High-dose conditioning treatment prior to HSCT for patients with MM Palliative treatment for MM patients who are not candidates for oral therapy Approval based on multicenter, open-label, phase 2b study of 61 patients (5 relapsed prior to HSCT; 56 with newly diagnosed disease)1 200 mg/m² CE-melphalan, administered in 100 mg/m² doses on day 3 and day 2 before transplantation ORR:95%; CR: 31% (16% stringent CRs) [as determined by investigator assessment] No treatment-related mortality; no new safety signals 1. Hari, et al. Biol Blood Marrow Transplant. 2015;21:

CE-Melphalan (Propylene Glycol-free): Phase 2a Pharmacokinetic Study
Results from the Phase 2a study (N=24) CE-Melphalan is bioequivalent to standard Melphalan Propylene glycol-free More stable following reconstitution Longer infusion times / higher doses possible with CE-Melphalan (propylene glycol-free) could improve response to treatment The efficacy and safety profile were consistent with that already established for high-dose Melphalan conditioning with ASCT for MM 100% of patients achieved myeloablation and engraftment Most frequent AEs included fatigue, nausea, and hypokalemia Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.

CE-Melphalan HCl Melphalan Concentration (ng/mL) Melphalan Plasma Concentration Bioequivalence demonstrated Cmax: % AUC 0-t: 110% AUC-inf: 110% Successful myeloablation (Day +3) Successful engraftment (Day +11) No additional toxicities: Treatment-emergent AEs (100%) Common AEs: nausea, vomiting, hypokalemia, fatigue, decreased appetite, dizziness, and thrombocytopenia Treatment-emergent SAEs (29%) Febrile neutropenia, mucosal inflammation, sepsis and extreme fatigue Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.

Propylene Glycol-free Melphalan: New IV Formulation for MM Patients Undergoing HSCT
Patients received 200 mg/m2 of i.v. melphalan as 2 doses of 100 mg/m2 each on days −3 and −2 followed by a day of rest before ASCT was performed on day 0 Patients were evaluated for safety and response through day +100 Hari, et al. Biol Blood Marrow Transplant Aug 29. [Epub ahead of print]

MM Response Assessment*
Propylene Glycol-free Melphalan: New IV Formulation for MM Patients Undergoing HSCT MM Response Assessment* Value Overall response (sCR, CR, VGPR, or PR) 61 (100%) sCR 8 (13%) CR 5 (8%) VGPR 37 (61%) PR 11 (18%) Stable disease 0 (0%) Progressive disease Myeloablation (day 5) and engraftment (day 13) were achieved with no mortality (day 100) Low grade 3 mucositis and stomatitis incidence No grade 4 mucositis or stomatitis *Independent Reviewer Assessment of response at day +100 after ASCT Figure from: Hari, et al. Biol Blood Marrow Transplant Aug 29. [Epub ahead of print]

AUTOLOGOUS TRANSPLANTATION Transplant Vs Conventional Therapy

Prospective, Randomized Studies Evaluating HSCT for the Treatment of MM
Study Treatment n OS Benefit EFS Benefit Barlogie 2006[1] Chemotherapy 255 NS NS* HDT + HSCT 261 Bladé 2005[2] 83 81 Fermand 2005[3] 96 94 Palumbo 2004[4] 99 Yes 95 Child 2003[5] 196 Yes* 197 Segeren 2003[6] 129 132 Attal 2003[7] Single HSCT 199 Double HSCT 200 Attal 1996[8] 100 A number of randomized studies have been performed comparing outcomes with high-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (autoHSCT) with conventional chemotherapy (CC)1-11 All studies shown were prospective, randomized clinical studies published between 1996 and 2006 evaluating the use of HDT with autoHSCT compared with CC1-6 All studies demonstrated survival outcomes that were at least as good, if not better, for patients receiving HDT + autoHSCT vs CC1-6 Although survival outcomes were not different between the two arms, the study by Segeren et al6 demonstrated significantly better rates of complete remission for the melphalan + autoHSCT group compared to the CC group6 The study by Attal et al7 demonstrates the benefits of double versus single HSCT in patient with multiple myeloma Currently there are no published randomized comparisons for HDT + autoHSCT against newer agents such as lenalidomide or bortezomib, although these studies are ongoing and have been presented at national and international meetings9-11 The Phase III GIMEMA trial comparing melphalan/prednisone/lenalidomide (MPR) to high dose melphalan and autologous HSCT (MEL200) in newly diagnosed multiple patients demonstrated:11 No difference in overall survival between arms, at 24 months Improved progression-free survival in the MEL200 arm at 24 months More toxicity was observed in the MEL200 arm References: Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol ;24: Bladé J, Rosinol L, Sureda A, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long- term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106: Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long- term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23: Palumbo A, Bringhen S, Petrucci MT, et al. Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: results of a randomized controlled trial. Blood. 2004;104: Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348: Segeren CM, Sonneveld P, van der Holt B, et al. Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood. 2003;101: Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349: Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996;335:91-97. Accessed February 19th, 2012. Palumbo AP, Cavallo F, Di Raimondo F, et al. A phase III trial of melphalan/prednisone/lenalidomide (MPR) versus melphalan (200 mg/m2) and autologous transplantation (MEL200) in newly diagnosed myeloma patients. J Clin Oncol. 2010; 28: 15s. Abstract 8015 Boccadoro M, Cavallo F, Nagler A, et al. Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) in newly diagnosed multiple myeloma (MM) patients: A phase III trial. J Clin Oncol ;29. Abstract 8020 [oral presentation]. *Progression-free survival. All studies included were published between 1996 and 2006. OS, overall survival; EFS, event-free survival HDT, high-dose chemotherapy; HSCT, haematopoietic stem cell transplant; NS, not significant. [1] Barlogie B, et al. J Clin Oncol 2006;24:929–936. [2] Bladé J, et al. Blood 2005;106:3755–3759. [3] Fermand JP, et al. J Clin Oncol 2005;23:9227– [4] Palumbo A, et al. Blood 2004;104:3052–3057. [5] Child. JA, et al. N Engl J Med 2003;348:1875–1883. [6] Segeren CM, et al. Blood 2003;101:2144– Attal M, et al. N Engl J Med. 2003;349:2495–2502. [8] Attal M, et al. N Engl J Med. 1996;335:91–97.

Meta-analysis of PFS: Standard Chemotherapy vs Autologous SCT
Favors HDT Favors SDT PFS (95%CI) IFM90 MAG90* MAG91 MRC7 S9321 PETHEMA* HOVON* M97G* IFM9906*† Combined Sensitivity/Sub-group Analyses Excluding Non-Standard RCTs RCTs preferring PBSCs RCTs with Longer Follow- up RCTs with Lower Crossover ‡ 0.61 (0.42, 0.89) 0.42 (0.30, 0.58) 0.76 (0.57, 1.02) 0.68 (0.54, 0.85) 0.87 (0.72, 1.06) 0.85 (0.60, 1.22) 0.85 (0.63, 1.14) 0.48 (0.34, 0.66) 1.80 (1.30, 2.50) 0.75 (0.59, 0.96) Event-free survival and progression-free survival (PFS) outcomes were grouped together as they both represent time from randomization to death, progression, or relapse1 High-dose therapy followed by autologous hematopoietic stem cell transplantation is associated with a PFS benefit1 The benefit is not restricted to chemosensitive disease1 Reference: Koreth J, Cutler CS, Djulbegovic B, et al. High-dose therapy with single autologous transplantation versus chemotherapy for newly diagnosed multiple myeloma: A systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant. 2007;13: 0.75 (0.65, 0.87) 0.77 (0.59, 1.00) 0.70 (0.51, 0.96) 0.72 (0.62, 0.83) . 1 . 5 1 5 10 Hazard Ratio of Progression *Nonstandard study † Patients aged >65 years ‡ Two negative studies (HOVON, IFM9906) with missing crossover information were omitted from this analysis. Figure from: Koreth J, et al. Biol Blood Marrow Transplant. 2007;13:

Bortezomib-based vs Non-bortezomib—based Induction Treatment Before ASCT
Median TTP 37.5 months vs 31.3 months; P< A Meta-Analysis of Phase III Randomized, Controlled Trials Median TTP was 37.5 months versus 31.3 months (HR, 0.76; 95% CI,0.66 to 0.88; P.0001). After median follow-up periods of 37.0 and 36.8 months in the bortezomib-based and nonbortezomib-based induction groups, respectively, 207 patients (26%) and 175 patients (22%) died, and median OS had not been reached in either group (Appendix Figure A2B). There was a significant improvement in OS in the bortezomib-based induction group (HR, 0.81; 95% CI, 0.66 to 0.99; P ); 3-year OS rates were 79.7% and 74.7%, respectively. HRs for OS were consistent across studies (Appendix Figure A3). Sonneveld, et al. J Clin Oncol. 2013;31:

Outcomes with/without Pre-ASCT Salvage
Years 2 4 10 8 6 100 20 40 60 80 90 30 50 70 SALVAGE (n=324) NO SALVAGE (n=251) PFS Years 2 4 10 8 6 100 20 40 60 80 90 30 50 70 SALVAGE (n=324) NO SALVAGE (n=251) OS P = .3470 P = .2622 Median follow-up Salvage No Salvage Months ( ) 61 (9-181) P = NS P = NS Vij, et al. Blood. 2012;120(21): Abstract 597

Influence of Response After Induction: Superior Outcome When CR is Achieved Before ASCT
CR vs nCR: P = .1 CR vs PR: P = .07 CR vs SD: P = .02 nCR vs PR vs SD: P = .9 CR vs nCR: P = .1 CR vs PR: P = .05 nCR vs PR: P = .9 1.0 0.2 0.4 0.6 0.8 1.0 0.1 0.3 0.5 0.7 0.9 0.9 0.8 0.7 0.6 EFS (Probability) 0.5 OS (Probability) 0.4 0.3 0.2 0.1 ASCT, autologous stem cell transplantation; CR, complete remission; EFS, event-free survival; nCR, near complete remission; OS, overall survival; PD, progressive disease; PR, partial response; SD, stable disease. It may be possible to further increase the level of CR by continuing treatment after CR is achieved. This study showed that it is important to achieve a CR at different stages of the treatment. The left graph shows that patients achieving a CR before ASCT in this study had a better outcome than patients achieving CR only after ASCT. Spanish trial 752 pts VBMCP induction BUL MEL or MEL sct ultimately 632 underwent only 1 sct and were evaluable Med f/u 45 months 16% CR after induction THE BETTER THE RESPONSE POST INDUCTION THE BETTER THE CR RATE POST SCT 12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96 Mos Mos CR (n = 101) nCR (n = 96) PR (n = 346) SD (n = 63) PD (n = 26) Lahuerta JJ, et al. J Clin Oncol. 2008;26:

Pts Achieving ≥ VGPR (%)
Earlier Phase Studies: Induction Regimens for Transplantation-Eligible Pts Regimens Survival Bortezomib/lenalidomide/ dexamethasone (RVD)[1] 18-mo PFS: 75% 18-mo OS: 97% Carfilzomib/lenalidomide/ dexamethasone (KRd)[2,3] 12-mo PFS: 97%[2] 24-mo PFS: 92%[2] 3-yr PFS: 79%[3] 3-yr OS: 96%[3] Carfilzomib/thalidomide/ dexamethasone (KTd)[4] 3-yr PFS: 72% Bortezomib/ cyclophosphamide/ dexamethasone (CyBorD)[5] 5-yr PFS: 42%[6] 5-yr OS: 70%[6] Ixazomib/lenalidomide/ dexamethasone[7] 12-mo PFS: 88% 12-mo OS: 94% 100 80 60 40 20 81 67 68 60 58 Pts Achieving ≥ VGPR (%) RVD[1] KRd[2] KTd[4]] CyBorD[5] Ixazomib/RD[7] [1] Richardson, PG et al. Blood. 2010;116: [2] Jakubowiak A, et al. Blood. 2012;120: [3] Jasielec J, et al. ASH Abstract [4] Sonneveld P, et al. Blood. 2015;125: [5] Reeder CB, et al. Blood. 2010;115: [6] Reeder CB, et al. ASH Abstract [7] Kumar SK, et al. Lancet Oncol. 2014;15:

Modern Induction + AHCT
>VGPR (%) Post AHCT >VGPR (%) Median PFS and OS HOVON-50 Lokhorst et al. TAD 37 66 34 months / 73 months VAD 18 54 25 months / 60 months IFM Harousseau et al. Vel/Dex 38 36 months/ 3-year OS: 81 15 30 months / 77% @ 3 yrs GIMEMA MMY-3006 Cavo et al. VTD 62 87 2yr PFS: 85% / OS: 96% TD 31 69 2yr PFS 75% / OS: 91% HOVON65 / HD4 Sonneveld et al. PAD 42 PFS 35 mo 14 36 PFS 28 mo IFM Moreau et al. 58 PFS 30 mo VtD 49 74 PFS 26 mo Zimmerman et al CFZ, LEN, and DEX 78 97 52 of 53 pts progression free after a median of 9.7 months Carf data from Sonneveld et al ASH 2012 – Carf TD indn , ASCT and CTD consolidation. >VGPR rate 53  63 70 PFS -- 97% at 12 months, overall survival was 100% at a median follow-up of 10.4 months Similar data available for Carfilzomib Thalidomide Combination Hari P and McCarthy. BBMT. 2013;19(1 Suppl):S20-5. Zimmerman, et al. ASCO Abstract 8510,

High-dose Melphalan + ASCT vs Chemotherapy + Lenalidomide Followed by Lenalidomide + Prednisone vs Lenalidomide Maintenance in MM Induction Four 28-day cycles of lenalidomide (25 mg on days 1–21) and dexamethasone (40 mg on days 1, 8, 15, and 22) Induction CY (3g/m2) MOBILIZATION CY (3g/m2) MOBILIZATION Collection Cyclophosphamide, Lenalidomide, Dexamethasone High-dose Melphalan + ASCT Consolidation Lenalidomide Lenalidomide + Prednisone Lenalidomide Lenalidomide+ Prednisone Maintenance Gay, et al. Lancet Oncol. 2015;16: 57

Longer PFS with High-dose Melphalan + ASCT vs Chemotherapy + Lenalidomide
Median follow-up was 52.0 months Median PFS with consolidation therapy High-dose melphalan + ASCT: 43.3 months Chemotherapy + lenalidomide: 28.6 months (HR for the first 24 months = 2.51, P < .0001) Median PFS with maintenance therapy Lenalidomide + prednisone: 37.5 months Lenalidomide: 28.5 months (HR = 0.84, P = .34). 4-year OS High-dose melphalan + ASCT: 86% Chemotherapy + lenalidomide: 73% (HR = 2.40, P = .004). Gay, et al. Lancet Oncol. 2015;16:

Phase 3 MPR Consolidation vs Tandem MEL200
Lenalidomide + low-dose Dexamethasone Induction 4 cycles (N = 402) MPR 6 cycles (n = 202) MEL 200 (n = 200) Lenalidomide Maintenance 10 mg, d 1-21 (n = 98) No Maintenance (n = 104) Lenalidomide Maintenance 10 mg, d 1-21 (n = 100) No Maintenance (n = 100) MPR: melphalan, prednisone, lenalidomide Palumbo, et al. N Engl J Med. 2014;371:

Tandem MEL-200 Improves OS
CR Rates Post Consolidation Post Maintenance Tandem MEL 15.7% 35.7% MPR Consolidation 20% 33.8% Progression Free Survival Survival Tandem Transplant + Len Tandem Transplant, NO Len NO Transplant + NO Len Tandem Transplant + Len 63% of relapsed non transplant pts received ASCT Palumbo, et al. N Engl J Med. 2014;371:

Autologous transplantation Early vs Late HCT

Upfront vs Delayed Transplant
Months 10 20 30 40 50 60 70 Median OS Median EFS TWSTT PSCT (early) PSCT (late) PSCT = peripheral stem cell transplant; TWISTT = time without symptoms, treatment, and treatment toxicity. Fermand J, et al. Blood. 1998;92:

Early vs Late SCT: Ongoing Phase 3 Study in Newly Diagnosed MM SCT Candidates (IFM/DFCI 2009)
Randomize RVDx3 Induction RVDx3 CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg Collection VGPR pre Maintenance translates into PFS? Powered to detect ≥ 9 months improved PFS Melphalan 200 AHCT + RVD x 2 Consolidation RVD x 5 Lenalidomide Maintenance Lenalidomide RVD: lenalidomide, bortezomib and dexamethasone AHCT at relapse ClinicalTrials.gov Identifier: NCT 63

Ongoing Phase 3 Upfront Transplant Study: BMT CTN 0702
Lenalidomide Maintenance Register and Randomize MEL 200mg/m2 Lenalidomide Maintenance RVD x 4 MEL 200mg/m2 Lenalidomide Maintenance Primary End Point PFS RVD: lenalidomide, bortezomib and dexamethasone ClinicalTrials.gov Identifier: NCT

Allogeneic transplantation

ASCT vs Allogeneic SCT Trial Type of SCT N Median EFS (months) P Value Median OS (months) Garban et al, 2006 IFM & 99-04 Auto-Auto or Auto-Allo 284 35 31.7 NS 47.2 .07 Bruno et al, 2007 162 29 .02 54 80 .01 Rosinol et al, 2008* PETHEMA/GEM 2000 110 26 19 .40 58 NR .90 Kirshnan et al, 2011 BMT CTN 0102 710 46% PFS at 3-years survival 43% PFS at 3-years survival .671 80% at 3-years survival 7% at 3-years survival .191 Bjorkstrand et al, 2011 357 19% PFS at 60 months 39% PFS at 60 months .004 60% at 60 months 63% at 60 months .753 *Only patients with suboptimal response (<nCR) first ASCT were considered for a second transplantation. NR = not reached. Garban F, et al. Blood. 2006;107: Bruno B, et al. N Engl J Med. 2007;356: Rosinol L, et al. Blood. 2008;112: Krishnan A, et al. Lancet Oncol. 2011;12: Bjorkstrand B, et al. J Clin Oncol. 2011;29:

High-Risk or Early-Relapse MM: BMT CTN 1302
Ages 18-65; Upfront High Risk MM, or Early Failures; 8/8 match donor Fludarabine/Melphalan/Bortezomib Allo HCT R 60-120 days Primary end point: 18 months PFS Sample size: 138 patients Ixazomib Placebo 12 cycles ClinicalTrials.gov Identifier:NCT

Conclusions

Are all Relapses the same?
“Improving the Modern Triple Sequence” Induction AutoHCT and Maintenance INITIAL 3 Drug Induction CONSOLIDATE Consolidation w/Transplant ONGOING THERAPY Maintain with Lenalidomide or Bortezomib RELAPSE MONITORING Second AHCT ALLO HCT Other Immune MRD directed ? When to stop ? Implications of prolonged therapy Better Induction VGPR before ASCT TREATMENT of RELAPSE Biochemical or Clinical Are all Relapses the same? Randomized trials – Achievement of VGPR/CR or better Emerging data – PCR or Multicolor Flow based remissions

Multiple Myeloma: US Cooperative Group Trials—Feb 2015
CALGB Len vs Pl CTN 0702 Phase 3 E1A11: CRd vs VRd S1211: VRd vs. VRd Elo BMTCTN 1302: High-risk Allo E1A11 R 2 yrs vs PD BMT CTN 1401 Len vs Len DC Vaccine post Auto Extension of R 0702 S:R vs RI post Auto? A: R Dara vs R post HSCT? E3A06 R vs. Obs A061202 Plasmacytoma Z vs ZI Induction Rx Asymptomatic & Early Maintenance Stem Cell Transplant Non Consolidation Relapse S1304: K high and low dose PDI vs PD RRMM: no prior BMT PDI vs HSCT? Relapse after ASCT PDI vs no PDI consolidation P and I maintenance? DETERMINATION: RVD Early vs Late HSCT A:Rd vs Rd Dara for HSCT Eligible & ineligible Correlative sciences for HSCT ineligible S0777- Rd vs VRd E1A06 - MPT vs. MPR E3A06 Phase 2

Appendix of additional slides for customizing presentations

Myeloma Overview

Multiple Myeloma: A Plasma Cell Malignancy
Multiple myeloma is a B-cell malignancy derived from antibody- producing plasma cells in the bone marrow Myeloma cells crowd out and interfere with the development and function of normal cells in the bone marrow The abnormal accumulation of myeloma cells in the bone marrow and production of M-protein have direct and indirect effects on the blood, skeleton, and kidneys MM is a blood cancer arising from the bone marrow from abnormal plasma cells that undergo malignant transformation and secrete large quantities of monoclonal protein into the blood and/or urine. Normally, plasma cells make up less than 1% of the bone marrow but in MM, myeloma cells crowd out and interfere with the development and function of normal blood cells, leading to effects on the bone, blood, and kidneys [Durie 2011/12; MMRF 2011] Kufe DW, Bast RC, Hait WN, Hong WK, Pollock RE, Weichselbaum RR, Holland JF, Frei E, eds. Cancer Medicine 7. Hamilton, Ontario: BC Decker, Inc.;2006:770−785. © Mayo Foundation for Medical Education and Research (MFMER). All rights reserved. A single copy of these materials may be reprinted for noncommercial personal use only. "Mayo," "Mayo Clinic," "MayoClinic.com," "EmbodyHealth," "Enhance your life," and the triple-shield Mayo Clinic logo are trademarks of Mayo Foundation for Medical Education and Research. Durie. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition; Multiple Myeloma Research Foundation. Multiple Myeloma Disease Overview

What Is Multiple Myeloma?
Cancer of the plasma cells in bone marrow Growth of myeloma cells Disrupts normal bone marrow function Reduces normal immune function Results in abnormal production and release of monoclonal protein into blood and/or urine Destroys and invades surrounding bone Bone marrow Myeloma is a disease of neoplastic B lymphocytes that mature into plasma cells and synthesize abnormal amounts of immunoglobulin (Ig) or Ig fragments and belongs to a spectrum of disorders referred to as plasma cell dyscrasias Multiple myeloma is a cancer of the plasma cells of the bone marrow As malignant myeloma cells grow and accumulate in the bone marrow, the surrounding bone is invaded and destroyed The abnormal myeloma cells produce and release monoclonal protein (M protein) into the blood and urine, which contributes to immunosuppression References: Barlogie B, Shaughnessy J, Epstein J, et al. Plasma cell myeloma. In: Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology. 7th ed. New York, NY: McGraw-Hill; 2006: Durie BGM. Multiple myeloma: cancer of the bone marrow. Concise review of the disease and treatment options. North Hollywood, CA: International Myeloma Foundation; Available at: id=13&menu_id=0&id=941Accessed January 8, 2008. Barlogie et al. In: Williams Hematology. 7th ed. 2006:1501. Durie. International Myeloma Foundation

Incidence Patterns of MM by Race and Age: 1973-2005 (SEER-9)
Age Distribution by Race Age-Specific Incidence Incidence patterns of MM by race and age, (SEER-9). Figures from: Waxman, et al. Blood. 2010;116:

Incidence of MM according to Gender, Race/Ethnicity, and Age
Figure courtesy of Drs. Costa and Hari.

Age at Diagnosis of MM According to Gender and Race/Ethnicity
Black women, 67 White men, 70 Black men, 65 White women, 71 Cumulative percentage of cases Years Figure courtesy of Drs. Costa and Hari.

AHPCT Utilization in MM According to Gender and Race/Ethnicity
Number of Newly Diagnosed Cases Number of First AHPCT Black men Black women White men White women Figure courtesy of Drs. Costa and Hari.

MM Risk Categories Risk Factors Standard Risk (80%)
(Expected OS: 6-7 Yrs) High Risk (20%) (Expected OS: 2-3 Yrs) FISH t(11;14), t(6;14) del(17p), t(4;14)* t(14;16), +1q21 Cytogenetics Hyperdiploidy Hypodiploidy del(13q) β2-microglobulin* Low (< 3.5 mg/L) High (≥ 5.5 mg/L) PCLI < 3% High (≥ 3%) Gene expression profile Good risk High risk FISH, fluorescence in situ hybridization; Hb, hemoglobin; MM, multiple myeloma; OS, overall survival; PCLI, plasma cell labeling index. *Patients with t(4;14), β2-microglobulin < 4 mg/L, and Hb ≥ 10 g/dL may have intermediate-risk disease. Dispenzieri A, et al. Mayo Clin Proc. 2007;82: Kumar SK, et al. Mayo Clin Proc. 2009;84: Mikhael JR, et al. Mayo Clin Proc. 2013;88: NCCN. Clinical practice guidelines in oncology: multiple myeloma. v Chng WJ, et al. Leukemia. 2014;28:

Light chains types (later termed kappa and lambda) recognized
History of MM 1928 First large case series of MM 1844 First documented case 1845 Abnormal urine protein, later termed Bence Jones protein 1895 Description of plasma cells 1939 Serum protein spike identified 1956 Light chains types (later termed kappa and lambda) recognized 1975 Durie-Salmon staging system 2005 International Staging System Cytogenetic classification Rhubarb and orange peel Steel and quinine 1947 Urethane 1958 Melphalan 1962 Corticosteroids 1983 ASCT 1999 Thalidomide 2002 Bortezomib Lenalidomide 2013 Pomalidomide Novel agents in development 2012 Carfilzomib 2015 Panobinostat 2015 Elotuzumab Daratumumab Ixazomib Kyle. Blood. 2008;111:2962; Durie. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation; 2011/2012 edition; KYPROLIS [package insert]. Onyx Pharmaceuticals, Inc. July 2012; POMALYST [package insert]. Celgene Corporation. February 2012.

MM is Characterized by a Pattern of Remission and Relapse
Disease Burden MGUS or Indolent Myeloma Active Myeloma Remission Relapse Front-line Therapy 2nd or 3rd-line Therapy Remission duration decreases with each line of therapy // Asymptomatic Symptomatic Relapsing Refractory MM can remain asymptomatic for many years [Durie ] In the symptomatic phase, the most common presenting complaint is bone pain [Durie ] Serum and/or uring M-protein is elevated and usually rising at the time of diagnosis [Durie ] Pattern of disease can include multiple periods of remission and relapse. The duration of response typically decreases with each successive treatment regimen [Kumar 2004] Durie. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation; 2011/2012 edition; Kumar. Mayo Clin Proc. 2004;79:867.

Diagnostic Workup for MM
Test Blood Serum protein electrophoresis and immunofixation Serum immunoglobulins quantitative Serum free light chain assay Total serum protein, serum albumin, creatinine, calcium, electrolytes, lactate dehydrogenase, β2-microglobulin Hemoglobin, white blood cell count, differential count, platelet count Urine Urine protein electrophoresis and immunofixation 24 h urine for total protein, light chains Bone marrow Aspirate and biopsy for plasma cell count, morphology, amyloid* Cytogenetic evaluation and fluorescence in-situ hybridisation for the detection of del 13, del 17p13, t(4;14), t(11;14), t(14;16), 1q+ Bones Skeletal survey (conventional x-ray) or low-dose CT scan without contrast Whole body MRI*, PET-CT*, CT* Tissue biopsy for solitary or extraosseous plasmacytoma* Additional Tests Heavy light chains Gene expression profile *Useful under some circumstances. Röllig, et al. Lancet. 2015;385:

Overview of MM MGUS Smoldering MM Symptomatic MM No routine treatment
Clonal protein in serum or urine Clonal protein in serum or urine, and Plasmocytosis (10%-60%) in BM or M spike ≥ 3g/dL in serum or ≥ 500 mg/24h in urine Clonal protein in serum or urine Clonal plasmocytosis in BM or tissue Morbidity or Imminent threat of morbidity Hypercalcemia Renal insufficiency Anemia Bone lesions Clonal PC in marrow ≥60%. Involved:uninvolved SFLC >100 >1 focal lesions on MRI No routine treatment Treatment usually indicated Slide courtesy of Dr. Costa.

Treatment Paradigm and Goals

Common Approach to Initial Treatment of MM
Patients with Newly Diagnosed MM Needing Systemic Therapy Transplant-eligible Patient Transplant-ineligible Patient Three-drug Regimen Bortezomib, cyclophosphamide, dexamethasone Bortezomib, doxorubicin, dexamethasone* Bortezomib, lenalidomide, dexamethasone* Bortezomib, thalidomide, dexamethasone* Two-drug Regimen Lenalidomide, dexamethasone* Bortezomib, dexamethasone* Three-drug Regimen Melphalan, prednisone, bortezomib* Melphalan, prednisone, thalidomide* Two-drug Regimen Lenalidomide, dexamethasone* Bortezomib, dexamethasone* Melphalan, prednisone*† Bendamustine, prednisone*† Dexamethasone† The listed therapy combinations are selected and not inclusive of all regimens Single Autologous SCT‡ Consider Maintenance . *Treatment combinations with evidence from randomized-controlled trials †Melphalan + prednisone, bendamustine + prednisone, or dexamethasone can be used if novel drugs are not available or contraindicated ‡Consider allogeneic stem-cell transplantation in young patients with deletion 17p and HLA-identical siblings. Röllig, et al. Lancet. 2015;385:

Common Approach to Treatment of Relapsed/Progressive MM
Patients with Relapsed or Progressive MM Transplant-eligible Patient Transplant-ineligible Patient Previous SCT >12-18 months ago Previous SCT <12-18 months ago Previous treatment without novel drugs Previous treatment with novel drugs <6-9 months ago >6-9 months ago Consider re-induction and Autologous SCT Change regimen Consider repeating previous regimen The listed therapy combinations are selected and not inclusive of all regimens Novel drug +/- steroid and +/- alkylator or anthracycline *Available clinical trial applicable to all patients Röllig, et al. Lancet. 2015;385:

Indications for Hematopoietic Stem Cell Transplants in the US, 2012
Indications for Hematopoietic SCT in the US, 2012 Indications for Hematopoietic Stem Cell Transplants in the US, 2012 The most common indications for HCT in the US in 2012 were multiple myeloma and lymphoma, accounting for 57% of all HCTs. AML and myelodysplasia are the most common indications for allogeneic transplants accounting for 51% of allogeneic HCTs. Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: 2014 CIBMTR Summary Slides. Available at:

MM Treatment Lines for Transplant Eligible Patients
Initial SCT/ Consolidation First-line Treatment Maintenance Rescue Relapsed IMID:Thal-Len Proteasome Inhibitor: Bor-Car Steroids: Dex-Pred Alkylator: Cyclo-Mel Anthracycline: LipoDnr-Adr SCT or non-SCT consolidation Observation Proteasome Inh-Bor Steroids:Dex-Pred IMID:Thal-Len-Pom Proteasome Inh:Bor-Car Alkylators:Mel-Cy-Benda HDACi: Panobinostat Anthracycline Investigational SCT at relapse / Second SCT . Bor/Dex = bortezomib, dexamethasone; Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin; Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone; Len/Dex = lenalidomide, dexamethasone; SCT = stem-cell transplant; Thal/pred = thalidomide, prednsione; Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin; HDACi= histone deacetylase inhibitor NCCN, 2015 89

NCCN Guidelines for Initial Therapy of Transplant Candidates
Preferred Regimens Other Regimens Bortezomib/dexamethasone Bortezomib/cyclophosphamide/ dexamethasone Bortezomib/doxorubicin/ dexamethasone Bortezomib/lenalidomide/ dexamethasone Bortezomib/thalidomide/ dexamethasone Lenalidomide/dexamethasone Carfilzomib/lenalidomide/ dexamethasone Dexamethasone Liposomal doxorubicin/ vincristine/dexamethasone Thalidomide/dexamethasone NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V

NCCN Guidelines for Initial Therapy of Non-Transplant Candidates
Preferred Regimens Other Regimens Bortezomib/dexamethasone Bortezomib/cyclophosphamide/ dexamethasone Bortezomib/lenalidomide/ dexamethasone Lenalidomide/low-dose dexamethasone Melphalan/prednisone/bortezomib Melphalan/prednisone/lenalidomide Melphalan/prednisone/thalidomide Dexamethasone Liposomal doxorubicin/ vincristine/dexamethasone Melphalan/prednisone Thalidomide/dexamethasone Vincristine/doxorubicin/ dexamethasone NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V

NCCN Guidelines for Previously Treated MM
Preferred Regimens Repeat induction regimen if relapse at > 6 months Bortezomib Bortezomib/dexamethasone Bortezomib/cyclophosphamide/ dexamethasone Bortezomib/lenalidomide/ dexamethasone Bortezomib/liposomal doxorubicin Carfilzomib Carfilzomib/dexamethasone Carfilzomib/lenalidomide/ dexamethasone Cyclophosphamide/lenalidomide/dexamethasone Dexamethasone/cyclophosphamide/etoposide/cisplatin Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide± bortezomib High-dose cyclophosphamide Lenalidomide/dexamethasone Panobinostat/bortezomib/dexamethasone Pomalidomide/dexamethasone Thalidomide/dexamethasone Other regimens: Bendamustine Bortezomib/vorinostat Lenalidomide/bendamustine/dexamethasone NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V

NCCN Guidelines for Previously Treated MM
Other Regimens Bendamustine Bortezomib/vorinostat Lenalidomide/bendamustine/dexamethasone NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V

Role of Maintenance Therapy

Maintenance in Myeloma
PFS advantage[1-3] OS improvements?[2] Toxicities of treatment Myelosuppression[3] Second primary malignancies[3,4] Quality of life Unclear whether all patients benefit from maintenance Unclear which agent and duration of therapy [1] Attal M, et al. ASH Abstract 406. [2] McCarthy PL, et al. N Engl J Med. 2012;366: [3] Attal M, et al. N Engl J Med. 2012;366: [4] Palumbo A, et al. Lancet Oncol. 2014;15:

NCCN Guidelines for MM Maintenance Therapy
Preferred Regimens Other Regimens Bortezomib Lenalidomide Thalidomide Bortezomib + prednisone Bortezomib + thalidomide Interferon Steroids Thalidomide + prednisone NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V

Maintenance Therapy in MM: Summary
Median PFS after ASCT has improved without maintenance using better induction Maintenance with novel agents further improves PFS Toxicity issues are critical OS results are improved in some studies of thalidomide, lenalidomide, and bortezomib maintenance Decisions regarding maintenance will be influenced by Incidence of toxicity such as secondary cancers Outcome after myeloma progression Identification of subgroups most likely to benefit

Assessing and Monitoring Response to Therapy

The Deeper the Response, the Longer PFS
Schematic representation to illustrate the paradigm of the deeper the response, the longer the (progression-free) survival (filled lines). However, distinct biological subgroups exist, and their clinical course may differ from the paradigm (dotted lines): a, those patients with a baseline MGUS-like signature and prolonged survival irrespectively of CR; b, those patients with unsustained CR (high-risk cytogenetics and persistent MRD); c, MRD-positive patients who may also experience extended outcomes if small residual clones are quiescent (MGUS-like) or under control (eg, by immune cells); d, an MRD-negative result does not preclude the risk of relapse, and optimization of MRD monitoring together with follow-up MRD studies are likely crucial to predict relapses early on; e, long-term disease control (ie, functional cure) could potentially be achieved if therapy eradicates (detectable) MRD levels. This is a hypothetical model, which does not translate to the real behavior of individual patients. Figure from: Bruno Paiva et al. Blood ;125:

Features of Currently Available Techniques to Monitor MRD in MM
MFC (≥8-color) ASO-PCR NGS PET/CT Applicability ∼100% 60% to 70% ∼90% ∼100%* Reproducibility among centers High Not reported Moderate at MRD Availability in individual laboratories around the world Intermediate Limited Diagnostic sample Important but not mandatory Mandatory Time 2-3 h ≥5 d (follow-up), 3-4 wk (target identification) ≥7 d 2 h Cost per sample ∼350 USD ∼500 USD (follow-up), ∼1500 USD at diagnosis (target identification) ∼700 USD ∼2000 USD Sensitivity 10−5 to 10−6 10−6 High (4 mm) Quantitative Yes (directly; high accuracy) Yes Fresh sample Needed (<36 h) Not needed NA Patchy sample Impacts No impact Global cell characterization No Standardization Ongoing (EuroFlow/IMF) Yes, since 15 y (EuroMRD) EuroFlow, see EuroMRD, see IMF, International Myeloma Foundation; PET/CT, positron emission tomography/computed tomography; USD, US dollars. NA, not appropriate. * Specifically for extramedullary disease. ↵† Costs calculated based on both reagent and personnel costs for a medium-size laboratory receiving ∼150 to 200 MRD samples per year. ↵‡ Defined as minimal percentage of cells detectable within or out of the quantitative range of the method or in size for imaging techniques. Table from: Bruno Paiva et al. Blood ;125:

Methods for Assessing MRD to Predict Outcome
8-color Flow[1] Next Gen Sequencing[2] TTP (%) 100 80 60 40 20 150 50 P = .001 n = 26 n = 36 TTP (CR Patients) MRD – MRD + 1.0 0.8 0.6 0.4 0.2 6 12 18 24 30 36 42 MRD – MRD + Overall Mos PFS (proportion) PFS [1] Roussel M, et al. J Clin Oncol. 2014;32: [2] Martinez-Lopez J, et al. Blood. 2014;123:

Response to Therapy in MM Patients
1 × 1012 At diagnosis Number of Myeloma Cells Partial response – 50% reduction in M protein Near complete remission – immunofixation positive only Complete remission – immunofixation negative Abbrevs: Nonquantitative ASO-PCR 1 × 108 1 × 106 Quantitative ASO-PCR High quality flow cytometry Deep sequencing MRD 1 × 104 Rajkumar, et al (IMWG consensus criteria). Blood. 2011;117:4691–4695.

MM MRD Testing by Flow Cytometry: U.S. in 2014
53 year old female with myeloma Abnormal plasma cells at diagnosis: CD19-, CD45-, CD38 dim, CD20-, CD56+, CD81, CD27 dim Now MRD work-up post therapy 100,000 cells 500,000 cells 1 Million cells 3 Million cells No abnormal plasma cells 6 abnormal plasma cells 12 abnormal plasma cells 30 abnormal plasma cells Mailankody et al. Nature Reviews. 2015;12:286–295

Stem Cell Mobilization

International Myeloma Working Group (IMWG) Consensus Recommendations for Cell Doses
Is there an optimum CD34+ cell dose to be infused? Cell doses > 3 × 106 CD34+ cells/kg associated with better outcomes[1-3] Studies primarily retrospective Recommendation: the issue of optimal CD34+ cell dosing in aHSCT for MM requires a prospective clinical trial Is there an optimal dose of CD34+ cells to be collected? Recommendations[1] Minimum target of 4 × 106 CD34+ cells/kg should be collected If feasible an average of 8-10 × 106 CD34+ cells/kg should be collected These targets allow most patients to undergo at least 2 aHSCT, each with an optimal cell dose The International Myeloma Working Group (IMWG) published a consensus statement/set of guidelines on the status of stem cell collection through The guidelines focus on a number of areas, and specifically addressed the “optimum” CD34+ cell dose to be infused as well as the optimal dose of CD34+ cells to be collected as outlined on the slide1 Current practice is to collect a minimum of 2 x 106 CD34+ cells, and target an optimal dose of 4 – 6 x 106 CD34+ cells/kg or more1 When performing tandem hematopoietic stem cell rescue for multiple myeloma, the optimal dose collected should be 8 – 10 x 106 CD34+ cells/kg1 A prospective study designed to identify factors associated with rapid engraftment (N = 39) found that higher cell doses were associated with faster neutrophil and platelet recovery, less hospitalization, reduced duration of fever, and fewer blood transfusions.2 These results have been corroborated by several retrospective analyses.3-5 Specifically, infusion of cell doses ≥ 5 × 106 CD34+ cells/kg appears to confer the greatest benefits noted above.2,3,5,6 Some studies suggest that higher cell doses may improve engraftment2-6 and patient survival.7,8 The role of higher doses of CD34+ cell doses and improved outcomes still need further evaluation. Reference: Giralt S, Stadtmauer EA, Harrouseau JL, et al. International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia. 2009;23: Sola C, Maroto P, Salazar R, et al. Bone marrow transplantation: prognostic factors of peripheral blood stem cell mobilization with cyclophosphamide and filgrastim (r-metHuG-CSF): the CD34+ cell dose positively affects the time to hematopoietic recovery and supportive requirements after high-dose chemotherapy. Hematology. 1999;4: Weaver CH, Hazelton B, Birch R, et al. An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. Blood. 1995;86: Siena S, Schiavo R, Pedrazzoli P, Carlo-Stella C. Therapeutic relevance of CD34 cell dose in blood cell transplantation for cancer therapy. J Clin Oncol. 2000;18: Limat S, Woronoff-Lemsi MC, Milpied N, et al. Effect of cell determinant (CD)34+ cell dose on the cost and consequences of peripheral blood stem cell transplantation for non-Hodgkin's lymphoma patients in front-line therapy. Eur J Cancer. 2000;36: Stiff PJ, Micallef I, Nademanee AP, et al. Transplanted CD34(+) cell dose is associated with long-term platelet count recovery following autologous peripheral blood stem cell transplant in patients with non-Hodgkin lymphoma or multiple myeloma. Biol Blood Marrow Transplant. 2011;17: Toor AA, Ayers J, Strupeck J, et al. Favourable results with a single autologous stem cell transplant following conditioning with busulphan and cyclophosphamide in patients with multiple myeloma. Br J Haematol. 2004;124: Bolwell BJ, Pohlman B, Rybicki L, et al. Patients mobilizing large numbers of CD34+ cells ('super mobilizers') have improved survival in autologous stem cell transplantation for lymphoid malignancies. Bone Marrow Transplant. 2007;40: aHSCT, autologous hematopoietic stem cell transplantation; MM, multiple myeloma. [1] Desikan JR, et al. Br J Haematol. 2001;112: [2]Bensinger W, et al. J Clin Oncol. 1995;13: [3] Weaver CH, et al. Blood. 1995;86: [4] Giralt S, et al. Leukemia. 2009;23: 105

Outcomes of Standard Mobilization Regimens
Mobilization failure rate for MM is approximately 5% A more recent retrospective review of the Mayo clinic database from December 2007 to January showed a failure rate of 14% in MM patients Failure was defined as collection of <2 x 106 CD34+ cells/kg A perception in the transplant community exists that mobilization failure is relatively uncommon, despite literature reports suggesting a failure rate of 5%-40%1-3 A retrospective analysis of 1040 patients who underwent autoHSCT at Washington University between 11/1995 and 10/2006 was published.3 In this study, mobilization failure was defined as collection of < 2 × 106 CD34+ cells/kg after up to 5 days of apheresis. The following results were observed3: Non-Hodgkin’s lymphoma (NHL) failure rates G-CSF alone: 26.8% (n = 467) Chemotherapy + G-CSF: 22.9% (n = 35) Multiple myeloma (MM) failure rates G-CSF alone: 6.3% (n = 384) Chemotherapy + G-CSF: 5.9% (n = 17) Chemomobilization resulted in significantly higher CD34+ yields and greater numbers of patients reaching their target cell goal when compared with G-CSF alone3 There were limitations to the study, including: Retrospective analysis only Relatively small patient population received chemotherapy + G-CSF Choice of chemomobilization depended on patient diagnosis, clinical status, and physician preference – potential bias in allocating mobilization strategy A more recent single-center retrospective review of the Mayo Clinic HSCT database identified 1775 patients with a diagnosis of MM and lymphoma undergoing autoHSCT4 There was a total of 93 patients with Hodgkin’s disease (HD), 685 patients with NHL, and 997 patients with MM Patients were grouped into 4 categories based on cell yield at the completion of the mobilization process: Optimal collection (≥ 5 x 106 CD34+ cells/kg): 43% HD, 29% NHL, 70% MM Low collection (≥ 2 - < 5 x 106CD34+ cells/kg): 30% HD, 38% NHL; 16% MM Poor (< 2 x 106 CD34+ cells/kg): 9% HD, 17% NHL, 5% MM Failed (peripheral blood CD34+ count < 10 cells/mcL and apheresis not attempted): 18% HD, 15% NHL, 9% MM Multiple aphereses are often required to obtain sufficient cells for transplantation, which increases the cost associated with these procedures4 References: Bensinger W, DiPersio JF, McCarty JM. Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant. 2009;43: Pavone V, Gaudio F, Console G, et al. Poor mobilization is an independent prognostic factor in patients with malignant lymphomas treated by peripheral blood stem cell transplantation. Bone Marrow Transplant. 2006;37: Pusic I, Jiang SY, Landua S, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14: Gertz MA, Wolff RC, Micallef IN, Gastineau DA. Clinical impact and resource utilization after stem cell mobilization failure in patients with multiple myeloma and lymphoma. Bone Marrow Transplant Jan 11. [Epub ahead of print]. Bensinger W, et al. Bone Marrow Transplant. 2009;43(3): Pavone V, et al. Bone Marrow Transplant. 2006;37: Pusic I, et al. Biol Blood Marrow Transplant. 2008;14: Gertz MA, et al. Bone Marrow Transplant. 2010;45(9):

Mobilization Strategies Used in Clinical Practice
Approved Other Treatment Options Hematopoietic growth factors G-CSF (filgrastim), GM-CSF (sargramostim) Plerixafor injection in combination with G-CSF Approved for used in patients with NHL and MM Hematopoietic growth factors Pegfilgrastim Chemotherapeutic agents Chemotherapy apart from disease treatment Disease-specific regimens Growth factor + CT Currently, G-CSF, GM-CSF, and Mozobil® in combination with G-CSF are approved by the US Food and Drug Administration for the mobilization of peripheral blood progenitor cells for autologous hematopoietic stem cell transplant1-3 The American Society of Clinical Oncology recognizes treatment with growth factor with or without chemotherapy as the current standard of care for peripheral blood stem cell mobilization1 Studies have reported greater stem cell yields with the use of chemotherapeutic agents in combination with G-CSF than with the use of G-CSF alone4-6 Although not currently indicated in this setting, pegfilgrastim has also been shown to mobilize stem cells into the peripheral blood7 A comparative study between G-CSF and GM-CSF demonstrated that G-CSF obtained a greater CD34+ cell yield, fewer apheresis sessions, faster neutrophil recovery, and less resource utilization than did GM-CSF8 References: Neupogen® [prescribing information]. Thousand Oaks, CA: Amgen; 2008. Leukine® [prescribing information]. Seattle, WA: Bayer Healthcare; 2008. Mozobil® [prescribing information]. Cambridge, MA: Genzyme Corp; 2008. Desikan KR, Barlogie B, Jagannath S, et al. Comparable engraftment kinetics following peripheral-blood stem-cell infusion mobilized with granulocyte colony-stimulating factor with or without cyclophosphamide in multiple myeloma. J Clin Oncol. 1998;16: Narayanasami U, Kanteti R, Morelli J, et al. Randomized trial of filgrastim versus chemotherapy and filgrastim mobilization of hematopoietic progenitor cells for rescue in autologous transplantation. Blood. 2001;98: Bensinger W, Appelbaum F, Rowley S, et al. Factors that influence collection and engraftment of autologous peripheral-blood stem cells. J Clin Oncol. 1995;13: Kobbe G, Bruns I, Fenk R, et al. Pegfilgrastim for PBSC mobilization and autologous haematopoietic SCT. Bone Marrow Transplant. 2009;43: Weaver CH, Schulman KA, Wilson-Relyea B, et al. Randomized trial of filgrastim, sargramostim, or sequential sargramostim and filgrastim after myelosuppressive chemotherapy for the harvesting of peripheral-blood stem cells. J Clin Oncol. 2000;18:43-53. KP15 – there are recent clinical trials evaluating the use of Pegfilgrastim for mobilization; however, to my knowledge, pegfilgrastim is NOT FDA approved for stem cell mobilization. In fact, the package insert reads on page 5 (of 17), lines 86-87: Pegfilgrastim “should not be used for PBPC mobilization.” CT = chemotherapy; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony stimulating factor. Smith TJ, et al. J Clin Oncol. 2006;24: Kobbe G, et al. Bone Marrow Transplant. 2009;43: Hicks ML, et al. Transfusion. 2007;47(4): 107 107 107

Known Risk Factors for Suboptimal Mobilization
Poor or failed mobilization is often defined as a collection of < 1-2 x 10 cells/kg Patient characteristics Aged > 60 years Underlying disease Previous radiation therapy and/or chemotherapy Multiple chemotherapy cycles Previous treatment with melphalan or carmustine Novel induction strategies (eg, lenalidomide in MM) There are a number of known patient or treatment characteristics that are associated with poor or suboptimal mobilization and these are outlined in the slide1-8 A retrospective review of 602 patients with non-Hodgkin’s lymphoma and multiple myeloma at the University of Heidelberg identified the total number of prior cycles of chemotherapy and prior treatment with melphalan as risk factors for poor mobilization4 Lenalidomide (Revlimid®, Celgene Corporation, Summit, NJ), a novel immunomodulatory agent that is widely used in the treatment of MM, has been shown to impair the ability to mobilize hematopoietic stem cells as the number of cycles of lenalidomide administered increase5,7,8 References: Goterris R, Hernández-Boluda JC, Teruel A, et al. Impact of different strategies of second-line stem cell harvest on the outcome of autologous transplantation in poor peripheral blood stem cell mobilizers. Bone Marrow Transplant. 2005;36: Micallef IN, Apostolidis J, Rohatiner AZ, et al. Factors which predict unsuccessful mobilisation of peripheral blood progenitor cells following G-CSF alone in patients with non-Hodgkin's lymphoma. Hematol J. 2000;1: Stiff PJ. Management strategies for the hard-to-mobilize patient. Bone Marrow Transplant. 1999;23(suppl 2):S29-S33. Wuchter P, Ran D, Bruckner T, et al. Poor mobilization of hematopoietic stem cells – definitions, incidence, risk factors, and impact on outcome of autologous transtplantation. Biol Blood Marrow Transplant. 2010;16: Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma. Leukemia. 2007;21: Mazumder A, Kaufman J, Niesvizky R, et al. Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia. 2008;22; Paripat H, Stewart AK, Cabou S, et al. Compromised stem cell mobilization following induction therapy with lenalidomide in myeloma. Leukemia. 2008;22: Popat U, Saliba R, Thandi R, et al. Impairment of filgrastim-induced stem cell mobilization after prior lenalidomide in patients with multiple myeloma. Biol Blood Marrow Transplant. 2009;15: Goterris R, et al. Bone Marrow Transplant. 2005;36(10): Micallef IN, et al. Hematol J. 2000;1: Stiff PJ. Bone Marrow Transplant. 1999;23(Suppl 2):S29-S33 . Wuchter P, et al. Biol Blood Marrow Transplant. 2010;16(4): Kumar S, et al. Leukemia. 2007;21: Mazumder A, et al. Leukemia. 2008;22(6); Paripati H, et al. Leukemia. 2008;22: Popat U, et al. Biol Blood Marrow Transplant. 2009;15: 108 108 108

Consequences of Suboptimal Mobilization
Failure to mobilize a sufficient number of CD34+ cells may result in: Ineligibility for transplantation Increased number of apheresis days Need for bone marrow harvest Repeated attempts at mobilization Increased resource utilization Use of suboptimal apheresis product yield may lead to: Delayed, partial, or failed stem cell engraftment Potential for increased risk of infections and/or bleeding Increased need for transfusions “Suboptimal stem cell mobilization and collection” is generally considered as collecting < 2.0 × 106 CD34+ cells/kg1 Failure to mobilize sufficient CD34+ cells may impede/prohibit a patient from proceeding to transplant2 There is a paucity of data demonstrating the exact number of patients who are unable to proceed to transplant due to insufficient stem cell collection. Literature review suggests that between 5% and 40% of patients fail to collect sufficient cells for autoHSCT1, 3 Conventional mobilization approaches often require several days of apheresis, which may limit both the number of patients who can be apheresed in a week and a center’s throughput4 Remobilization and bone marrow harvest in patients who have been unable to collect the optimal number of stem cells may increase resource utilization and decrease patient satisfaction4,5 A prospective multi-institutional study demonstrated that patients transfused with < 2 × 106 CD34+ cells/kg had longer time to platelet engraftment (median 21 vs 12 days) and significantly more red blood cell transfusion compared with those receiving > 2 × 106 cells, P = .0056 A retrospective analysis demonstrated that the use of a suboptimal apheresis product (defined as < 2.5 × 106 CD34+ cells/kg) resulted in delayed platelet engraftment, increased platelet transfusions, and increased use of antibiotics7 Retrospective series have demonstrated that when < 1 × 106 CD34+ cells/kg are transplanted, there is up to an 80% risk of delayed platelet engraftment, which may lead to increased risk of hemorrhage8 References: Bensinger W, DiPersio JF, McCarty JM. Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant. 2009;43: Pusic I, Jiang SY, Landua S, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14: Pavone V, Gaudio F, Console G, et al. Poor mobilization is an independent prognostic factor in patients with malignant lymphomas treated by peripheral blood stem cell transplantation. Bone Marrow Transplant. 2006;37:719–724. Glaspy JA. Economic considerations in the use of peripheral blood progenitor cells to support high-dose chemotherapy. Bone Marrow Transplant. 1999;23:S21-S27. Gertz MA, et al. Clinical impact and resource utilization after stem cell mobilization failure in patients with multiple myeloma and lymphoma. Bone Marrow Transplant Jan 11 [Epub ahead of print]. Schiller G, Vescio R, Freytes C, et al. Transplantation of CD34+ peripheral blood progenitor cells after high-dose chemotherapy for patients with advanced multiple myeloma. Blood. 1995;86: Haas R, Mohle R, Fruhauf S, et al. Patient characteristics associated with successful mobilizing and autografting of peripheral blood progenitor cells in malignant lymphoma. Blood. 1994;83: Stiff P. Management strategies for the hard-to-mobilize patient. Bone Marrow Transplant. 1999;23:S29-S33. Pusic I, et al. Biol Blood Marrow Transplant. 2008;14: Gertz MA, et al. Bone Marrow Transplant. 2010(45): Glaspy JA, et al. Bone Marrow Transplant. 1999;23: Suppl21-S27. Haas R, et al. Blood. 1994;83(12): Schiller G, et al. Blood. 1995;86(1): Stiff P, et al. Bone Marrow Transplant. 1999;23:S29-S33. 109 109 109 109

Conventional Mobilization Strategies
Growth Factor CT Advantages Predictable collection schedule Earlier engraftment Disadvantages Lower stem cells yields More apheresis days Advantages High stem cell yields Disadvantages Risk for infection Neutropenic fever and hospitalization Less predictable collection schedule Pusic I, et al. Curr Pharm Des. 2008;14(20): Gertz MA. Br J Haematol. 2010;150(6):

AUTOLOGOUS transplant When and How?

High-dose Chemotherapy Prolongs Survival in MM
Author Study Treatment Patients (n) CR (%) EFS (months) OS P value Attal et al, 1996 IFM90 CT Auto Tx 100 5 22 18 27 44 57 .03 Fermand et al, 2005 MAG91 96 94 20 36 19 25a 48 Child et al, 2003 MRC7 200 201 9 32 42.3 54.1 Palumbo et al, 2004 IMMSG 98 97 6 25 16 28 43 58+ < .001 Blade et al, 2005 PETHEMA 83 81 11 30 33 42 66 61 Barlogie, et al, 2006 USIG 255 261 16% at 7 years 17% 38% Slide courtesy of Dr. Costa.

Melphalan Dose for Transplant
MEL 200 mg/m2 is standard MEL 200 – popularized by Royal Marsden , UK (Cunningham, et al) IFM 90 randomized trial (Attal, et al) established ASCT as standard of care Used MEL Gy TBI as conditioning Retrospective EBMT study (Bjorkstrand, et al) OS and PFS better for MEL over MEL TBI IFM Randomized study of MEL 200 vs MEL TBI ( total body irradiation)

Melphalan Challenges PK Variability Propylene Glycol Special Issues

A Phase 2a, Open-Label, Randomized, Pharmacokinetic Comparative, Cross-Over Study of Melphalan HCl for Injection and Standard Melphalan for Injection for Myeloablative Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation Screening Period Study Period Follow-up Period Day -3 CE-Mel 100mg/m2 IV Over 30 min Day -2 Standard Mel 100mg/m2 IV Over 30 min Day 0 ASCT ASCT Day +7 Daily CBC & weekly safety assessments until ANC engraftment Baseline tests for study and infectious disease testing Day 1 Rest Day ASCT Day +14 Daily CBC & weekly safety assessments until ANC engraftment Up to 7 days after Date of Engraftment End of Study Evaluations Randomization The other slides on this study are in the sample presentation. Day -3 Standard Mel 100mg/m2 IV Over 30 min Day -2 CE-Mel 100mg/m2 IV Over 30 min ASCT Day +21 Daily CBC & weekly safety assessments until ANC engraftment ASCT Day +30 Daily CBC & weekly safety assessments until ANC engraftment Date of Engraftment Enrollment (N=24) Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.

CE-Melphalan (Propylene Glycol-free): Efficacy Overview
All patients (100%) achieved myeloablation and engraftment Median time to myeloablation: 3 days Median time to neutrophil engraftment:11 days Time and Rate of Myeloablation Total (N=24) Experienced Myeloablation Yes 24 (100%) Time to Myeloablation (study days) Mean 2.9 SD 1.21 Median 3.0 Min Max 5 Time and Rate of Engraftment Total (N=24) Experienced Engraftment Yes 24 (100%) Time to Engraftment (study days) Mean 11.0 SD 1.08 Median Min 9 Max 13 The other slides on this study are in the sample presentation. Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.

CE-Melphalan (Propylene Glycol-free): Safety Overview
Adverse event safety profile appears consistent with what has been reported with high-dose standard Melphalan No patients discontinued prematurely Prolonged QRS in 2 pts receiving standard Melphalan first (1 required hospitalization for observation) Left bundle branch block pattern resolved within 2 days Pts subsequently received CE-Melphalan without further complications Treatment-emergent AEs ≥50% of Patients Nausea 100% Diarrhea 96% Vomiting 88% Hypokalemia Fatigue 83% Thrombocytopenia 75% Decreased appetite 63% Dizziness The other slides on this study are in the sample presentation. Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.

CE-Melphalan (Propylene Glycol-free): Results Overview
Results from the Phase 2a study (N=24): CE-Melphalan is propylene glycol-free More stable following reconstitution Longer infusion times / higher doses possible with CE-Melphalan (propylene glycol-free) could improve response to treatment CE-Melphalan (propylene glycol-free) is bioequivalent to standard Melphalan CE-Melphalan (propylene glycol-free) peak and systemic exposure were slightly greater than with standard Melphalan The efficacy and safety profile were consistent with that already established for high-dose Melphalan conditioning with ASCT for MM 100% of patients achieved myeloablation and engraftment Most frequent AEs included fatigue, nausea, and hypokalemia The other slides on this study are in the sample presentation. Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.

CE-Melphalan (Propylene Glycol-free)
FDA Approved March 2016 1st drug to gain FDA approval for the high-dose conditioning indication in MM Captisol-enabled melphalan (CE-melphalan) approved for two indications in MM High-dose conditioning treatment prior to HSCT for patients with MM Palliative treatment for MM patients who are not candidates for oral therapy Approval based on multicenter, open-label, phase 2b study of 61 patients (5 relapsed prior to HSCT; 56 with newly diagnosed disease)1 200 mg/m² CE-melphalan, administered in 100 mg/m² doses on day 3 and day 2 before transplantation ORR:95%; CR: 31% (16% stringent CRs) [as determined by investigator assessment] No treatment-related mortality; no new safety signals 1. Hari, et al. Biol Blood Marrow Transplant. 2015;21:

Autologous Transplantation. Transplant vs Conventional Therapy
Autologous Transplantation Transplant vs Conventional Therapy Initial Therapy Tandem Early vs Late

Transplant Outcomes Improving Over Time
Does anyone have a reference for this data? Probability, % Years % 47% %* 55%* %*# 57%* 1 2 5 100 20 40 60 80 90 10 30 50 70 (n=2,223) (n=686) (n=1,464) 3 4 NON STUDY PATIENTS – “STREET LEVEL VIEW” Significant portion of the benefit in post rel survival * vs , P< # vs , P<0.05

Expansion of ASCT Transplantation for MM in US
Does anyone have a reference for this data? <50 years 50-64 years ≥ 65 years

AHCT Has Changed Natural History of MM: Population-level Data
Changes in MM 5-year relative survival ratio in Sweden Figure from Kristinsson SY, et al. J Clin Oncol ;15:1993.

AHCT Has Changed Natural History of MM: Population-level Data
Changes in MM relative survival ratio in the Netherlands ≤ 65 years > 65 years Figure from Schaapveld M, et al. Eur J Cancer ;46:160.

AUTOLOGOUS TRANSPLANTATION Transplant vs Conventional Therapy

Conventional Chemotherapy
Conventional Chemotherapy vs ASCT: Historic Randomized Studies—Median OS Patients (n) Age Median Follow Up Conventional Chemotherapy ASCT IFM90[1] 200 <65 7 years 44 months 57 months MAG91[2] 190 55-65 56 months 50 months 55 months MRC7[3] 403 42 months PETHEMA[4]* 164 64 months 72 months S9321[5] 516 ≤70 76 months 38% at 7 years Median Survival *in patients responding to conventional chemotherapy [1] Attal M et al. N Engl J Med. 1996;335:91. [2] Fermand JP et al. J Clin Oncol. 2005;23:9227. [3] Child A et al. N Engl J Med. 2003;348:1875. [4] Blade J et al. Blood. 2005;106:3755. [5]Barlogie B, et al. JCO. 2006;24:

Mel200-ASCT vs Chemotherapy + Lenalidomide: PFS
Median Follow-up from Randomization: 4 Years 1.00 0.75 0.50 0.25 PFS (% of patients) Mel200-ASCT: PFS 41 months Gay F, Cerrato C, Hajek R, et al (2014). Impact of Autologous Transplantation Vs. Chemotherapy Plus Lenalidomide in Newly Diagnosed Myeloma According to Patient Prognosis: Results of a Pooled Analysis of 2 Phase III Trials. Blood, Dec 2014,124(21). Abstract 198. CC + R: PFS 26 months HR, .55; 95% CI, ; P < .0001 Months Gay, et al. Blood. 2014;124:Abstract 198. 127

Mel200-ASCT vs Chemotherapy + Lenalidomide: OS
Median Follow-up from Randomization: 4 Years 1.00 0.75 0.50 0.25 Mel200-ASCT: OS 84% OS (% of patients) CC + R: OS 71% HR, .59; 95% CI, ; P = .008 Months Gay, et al. Blood. 2014;124:Abstract 198. 128

Mel200-ASCT vs Chemotherapy + Lenalidomide
Age <60 Age ?60 KPS 60 - 70% KPS 80 100% ISS I/II ISS III No del17, t(4;14), t(14;16) Del17, t(4;14), t(14,16) LDH < ULN LDH ? ULN HR (95% CI) P value 0.67 (0.41 1.11) 0.44 (0.23 0.86) 0.76 (0.33 1.72) 0.54 (0.34 0.85) 0.55 (0.34 0.89) 0.75 (0.38 1.45) 0.57 (0.34 0.94) 0.60 (0.31 1.14) 0.62 (0.41 0.95) 0.23 (0.03 1.92) Favors Chemotherapy + Lenalidomide Mel200 ASCT Gay, et al. Blood. 2014;124:Abstract 198.

High-dose Melphalan + ASCT vs Chemotherapy + Lenalidomide Followed by Lenalidomide + Prednisone vs Lenalidomide Maintenance in MM Induction Four 28-day cycles of lenalidomide (25 mg on days 1–21) and dexamethasone (40 mg on days 1, 8, 15, and 22) Induction CY (3g/m2) MOBILIZATION CY (3g/m2) MOBILIZATION Collection Cyclophosphamide, Lenalidomide, Dexamethasone High-dose Melphalan + ASCT Consolidation Lenalidomide Lenalidomide + Prednisone Lenalidomide Lenalidomide+ Prednisone Maintenance Gay, et al. Lancet Oncol. 2015;16: 130

Longer PFS with High-dose Melphalan + ASCT vs Chemotherapy + Lenalidomide
Median follow-up was 52.0 months Median PFS with consolidation therapy High-dose melphalan + ASCT: 43.3 months Chemotherapy + lenalidomide: 28.6 months (HR for the first 24 months = 2.51, P < .0001) Median PFS with maintenance therapy Lenalidomide + prednisone: 37.5 months Lenalidomide: 28.5 months (HR = 0.84, P = .34) 4-year OS High-dose melphalan + ASCT: 86% Chemotherapy + lenalidomide: 73% (HR = 2.40, P = .004) Gay, et al. Lancet Oncol. 2015;16:

High-dose Melphalan + ASCT vs Chemotherapy + Lenalidomide: PFS
Total Population Patients Eligible for Consolidation Patients Eligible for Maintenance A) Progression-free survival from diagnosis in the total study population. (B) Progression-free survival in patients eligible for consolidation. (C) Progression-free survival in patients eligible for maintenance. Figures from: Gay, et al. Lancet Oncol. 2015;16:

High-dose Melphalan + ASCT vs Chemotherapy + Lenalidomide: OS
Total Population Patients Eligible for Consolidation Patients Eligible for Maintenance Overall survival from diagnosis in the total study population. (E) Overall survival in patients eligible for consolidation. (F) Overall survival in patients eligible for maintenance Figures from: Gay, et al. Lancet Oncol. 2015;16:

High-dose Melphalan + ASCT vs Chemotherapy + Lenalidomide: Safety
Patients in the chemotherapy + lenalidomide group had a lower frequency of grade 3/4 AEs than melphalan + ASCT group Hematologic events: 26% vs 84% Gastrointestinal events: 5% vs 20% Infection: 5% vs 19% There was no marked difference between the maintenance lenalidomide and lenalidomide + prednisone groups Gay, et al. Lancet Oncol. 2015;16:

AUTOLOGOUS TRANSPLANTATION Initial Treatment

Phase III Trials: Induction Regimens for Transplant-Eligible Patients
100 80 60 40 20 Cavo PETHEMA/ GEM IFM HOVON-65 GMMG-HD4 E4A03 62 60 50 Pts Achieving ≥ VGPR (%) 42 40 38 28 29 HOVON, Dutch-Belgian Cooperative Trial Group for Hematology-Oncology; IFM, Intergroupe Francophone du Myelome; IFN, interferon; nCR, near-complete response; PAD, bortezomib, doxorubicin , and dexamethasone; TD, thalidomide and dexamethasone; VAD, vincristine, doxorubicin , and dexamethasone; VD, bortezomib, dexamethasone; VMBCP/VBAD/B, vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib; VTD, TD plus bortezomib. 15 14 VD[1] VTD[1] TD[2] VAD[3] VD[3] Rd[5] RD[5] VTD[2] VAD[4] PAD[4] [1] Cavo M, et al. Lancet. 2010;376: [2] Rosiñol L, et al. Blood. 2012;120: [3] Harousseau JL, et al. J Clin Oncol. 2010;28: [4] Sonneveld P, et al. J Clin Oncol. 2012;30: [5] Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

A Meta-Analysis of Phase III Randomized, Controlled Trials Overall survival 3-year OS rates Non-bortezomib—based: 75% Bortezomib-based: 80% There was a significant improvement in OS in the bortezomib-based induction group (HR, 0.81; 95% CI, 0.66 to 0.99; P ); 3-year OS rates were 79.7% and 74.7%, respectively. HRs for OS were consistent across studies (Appendix Figure A3). Sonneveld. J Clin Oncol. 2013;31(26):

IFM / n=482 PETHEMA n=390 GIEMEMA n=480 HOVON-65 n=827 Bortezomib induction VD±DCEP VTD PAD Control induction VAD ±DCEP VMBCP or TD TD ASCT 1 or 2 (or RIC) 1 2 1 or 2 Consolidation Len x 2 -- Maintenance Random: Len vs Obs Random: IFN, Thal or VT All: Dex Assigned: Bort Thal HOVON is largest trial so impact of assigned bortezomib to maintenance also impacts. All European trials, so limited availability to all drugs at relapse Control arms are obsolete: TD and VAD since both are very toxic In all but the Giemema trial there is randomization to maintenance that confounds interpretation Sonneveld. J Clin Oncol. 2013;31(26):

Effect of Pre-transplant Salvage Therapy Prior to ASCT in Patients Not Responding to Initial Induction for MM Salvage Cohort Salvage Chemotherapy Autologous Transplant Diagnosis and Initial Induction < PR to induction No Salvage Cohort Autologous Transplant 12 months from diagnosis to ASCT Diagnosis ASCT Vij, et al. Blood ;120(21):abstract 597. MM _6.ppt

Lenalidomide/Dexamethasone Induction Followed by AHCT: OS
E4A03 trial RD vs. Rd - Landmark analysis at 4 mos Early SCT after 4 cycles vs. continued lenalidomide 94% 78% Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 48 12 24 36 Mo Early SCT: no 141 Early SCT: yes 68 132 68 122 64 53 34 0 0 Log-rank test: (P = .008) Early SCT: no (n = 141) Early SCT: yes (n = 68) 3 yrs 3 yrs Non randomized, retrospective, unplanned post hoc analysis Selection Bias OS, overall survival; Rd, lenalidomide, low-dose dexamethasone; RD, lenalidomide, standard-dose dexamethasone; SCT, stem cell transplant. Similar nonrandomized retrospective data in BIRD regimen follow up --- Post hoc analysis by transplant status showed no effect on PFS or OS, indicating the benefit of lenalidomide maintenance exists even in the absence of transplantation, however formal conclusions regarding ASCT should be addressed by prospective randomized studies. Patients who underwent ASCT (33) received a median of 10 cycles [range 2-36] of BiRd, compared to 26 cycles [range 3-93] for those on continuous therapy. HOWEVER note numbers in this study were 72 pts Siegel D, et al. ASH Abstract 38.Rajkumar, et al. Lancet Oncol. 2010;11:29-37.

Autologous transplantation Tandem

Single vs Tandem ASCT Trial N ASCT CR+VGPR (%) Median PFS (months)
Median OS (months) Attal et al, 2003 IFM94 399 Single 42 25 48 Tandem 50 30* 58* Fermand et al, 2003 MAG95 227 39 31 49 37 33 73† Cavo et al, 2007 BOLOGNA 96 321 23 65 47* 35* 71 Goldschmidt et al, 2005 GMMG-HD2 268 NR NYR 29* Sonneveld et al, 2007 HOVON 24 303 13 (CR only) 27* 32* (CR only) 24 55 *P < .05. †OS significant for non-CD34 selected tandem transplants in subset analysis. NR = not reported. Attal M, et al. N Engl J Med. 2003;349: Fermand JP, et al. Hematol J. 2003;4(Suppl 1):S59. Lazarus, Harry M. and Laughlin, Mary J. Allogeneic Stem Cell Transplantation. Second Edition. Cleveland, OH; Humana Press, Cavo M, et al. J Clin Oncol. 2007;25: myeloma.org/pdfs/Sydney2005_Goldschmidt_P8.pdf. Accessed July 18, Sonneveld P, et al. Haematologica. 2007;92(7):

Tandem Transplantation in MM
Study ASCT Age (years) Patients (n) CR (%) EFS (months) OS Attal et al, 2003 IFM94 Single Tandem < 61 199 200 42 50 7-year 25 30 48 58 Cavo et al, 2007 Bologna96 163 158 33 47 23 35 65 71 Sonneveld et al, 2007 HOVON24 < 66 148 155 13 32 21 22 55

Autologous transplantation Early vs Late HCT

Early vs. Late SCT Early HDT Late HDT P (survival) Months Early HDT
.9 .8 .7 .6 .5 .4 .3 .2 .1 .0 Early HDT Late HDT P (survival) Months 100 90 80 70 60 50 40 30 20 10 Late HDT Median OS 64 months I early and late HDT groups. Average time without symptoms and toxicity (TWISTT) was longer in HDT group Partitioned Kaplan-Meier survival curves according to treatment group, ie, early HDT group (top plot) and late HDT group (bottom plot). Each plot displays the Kaplan-Meier estimations of time to OS, EFS, and time to end-of-treatment, either conventional chemotherapy (CCT) or transplantation (HDT), since randomization. Note that two EFS were considered in the late HDT group (after conventional chemotherapy, “post-CCT” and after transplantation, “post-HDT”). The areas between these curves and the vertical line at 58 months, which corresponds to the median follow-up of the whole cohort, represent estimates of the mean durations between these events, namely treatment duration (either CCT [▧] or HDT [⊞]), time without symptoms and treatment toxicity (TWISTT [▧]), and time between relapse and death (▨). All patients were included in the analysis on an intent-to-treat basis. IFN was not taken into account because it was usually maintained only when well tolerated. Figures from Fermand J , et al. Blood. 1998;92:3131. 145

Early vs Late SCT: Ongoing Phase-3 Study in Newly Diagnosed MM SCT Candidates (IFM/DFCI 2009)
Randomize RVDx3 Induction RVDx3 CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg Collection VGPR pre Maintenance translates into PFS? Powered to detect ≥ 9 months improved PFS Melphalan 200 AHCT + RVD x 2 Consolidation RVD x 5 Lenalidomide Maintenance Lenalidomide RVD: lenalidomide, bortezomib and dexamethasone AHCT at relapse ClinicalTrials.gov Identifier: NCT 146

Allogeneic transplantation

Survival after Transplant for MM 1998-2008
Does anyone have a reference for this data? Years 2 6 1 3 4 5 Probability of Survival (%) HLA-matched sibling, Allo (N=878) ASCT (N=22,254) Unrelated, Allo (N=143) 20 40 60 80 100 10 30 50 70 90 P < .0001 Multiple myeloma (MM) is the most common indication for an autologous transplant. Among 22,254 patients who received a single autologous transplant for MM between 1998 and 2008, the 3-year probability of survival was 68% ± 1%. Allogeneic transplantation for MM is reserved for patients with high risk disease, and the majority are performed after an autologous transplant with reduced-intensity or nonmyeloablative conditioning regimens. Among the 1,021 patients who received an allogeneic transplant for MM from 1998 to 2008, the 3-year probabilities of survival were 47% ± 2% for the 878 recipients of HLA-matched sibling donor transplants and 28% ± 4% for the 143 recipients of unrelated donor transplants. HLA= human leukocyte antigen.

Barriers to HCT in MM

Barriers to Autologous Transplant Access
HEALTH CARE SYSTEM Limited number of HCT centers Workforce shortage Capacity limitations Infrastructure issues ACCESS TO TRANSPLANT SOCIAL Age Ethnicity and race Language Culture Health literacy Patient/family attitudes Caregiver availability ECONOMIC Socioeconomic status Education Number of wage earners Employment status Insurance coverage Place of residence Transportation PROVIDER Physician referral Provider attitudes/biases Provider expertise Provider diversity Majhail NS, et al. Biol Blood Marrow Transplant. 2010;16(8): Disparity in cancer care, including HCT, has been identified for certain high-risk populations, including elderly patients, patients of black or Hispanic race/ethnicity, and women. Barriers to receiving optimal health care may include demographics, cultural differences, lack of culturally sensitive resources, cost concerns, logistical problems, and insurance coverage. Some of these factors may overlap; for example, white patients are more likely than racial minorities to have insurance coverage. With respect to HCT for hematologic malignancy specifically, additional barriers may exist, given the expense of the procedure and the high level of interaction that typically occurs between patients and HCPs before, during, and after the procedure. Reference Majhail NS, Omondi NA, Denzen E, et al. Access to hematopoietic cell transplantation in the United States. Biol Blood Marrow Transplant. 2010;16(8): Adapted from: Majhail NS, et al. Biol Blood Marrow Transplant. 2010;16(8):

Elderly Patients and Black Patients Are Less Likely to Obtain HCT Referral
Survey of hematologists/oncologists in the United States about HCT referral practices The odds of not receiving HCT are listed in the table Characteristic OR (95% CI) P Age, 60 years vs 30 years 8.29 (5.89, 11.69) <.001 Race, black vs white patients 2.35 (1.93, 2.87) Pidala et al. surveyed hematologists/oncologists in the United States about their HCT referral practices. The investigators found that clinicians were less likely to refer elderly patients and black patients for HCT evaluation than younger patients and white patients. Reference Pidala J, Craig B, Lee SJ, et al. Practice variation in physician referral for allogeneic hematopoietic cell transplantation [published online ahead of print June 18, 2012]. Bone Marrow Transplant doi: /bmt CI, confidence interval; OR, odds ratio. Pidala J, et al. Bone Marrow Transplant. 2013;48:63–67.

Factors to be Considered in the Treatment of Elderly Patients
Lower functional capacity (performance status, activities of daily living [ADL score], cognitive function) Comorbidities (renal, pulmonary, hepatic, cardiac, bone marrow) Disability Frailty (weakness, poor endurance, weight loss, low physical activity, slow gait speed) A higher prevalence of unfavorable prognostic factors (β2-microglobulin ≥3.5 μg/mL, albumin <3.5 g/dL, hemoblobin <10 g/dL, International Staging System [ISS] stage III) Polypharmacy Lower capacity to tolerate toxicity Therapy should be adjusted according to risk groups defined by age, comorbidity, organ function, disability, and frailty Ludwig, et al. Oncologist. 2012;17: 592–606

High-Risk Myeloma and Transplant PFS in TT4 for GEP70 Low-risk Myeloma by Arm and Metaphase Cytogenetics PFS in TT4 for GEP70 low-risk myeloma by arm and metaphase cytogenetics. (A) Comparison of no CA vs hypodiploidy or del.13. (B) Comparison of no CA vs other CA. CA, metaphase cytogenetic abnormalities are present; No CA, metaphase cytogenetic abnormalities absent; Other CA, CA present, but not hypodiploidy or del.13; TT4-L, TT4 light arm; TT4-S, TT4 standard arm. Patients with abnormal metaphase cytogenetics have significantly better PFS with melphalan 50 m/m2 for 4 days with VTD (light arm of TT4) vs single dose of melphalan 200 mg/m2 (standard arm of TT4) The reverse applied for patient normal metaphase cytogenetics Figures from: Frits van Rhee, et al. Blood. 2014;124:

NewER agents/Regimens

EMN 02: Phase 3 Study of VMP with High-dose Melphalan Followed by VRD Consolidation and Lenalidomide Maintenance 1570 patients (younger than 65 years) randomized from 12 countries Newly diagnosed MM: Symptomatic disease, organ damage, measurable disease VMP Four 42-day courses V: 1.3g/m2, d 1,4,8,11 M: 9 mg/m2, d 1-4 P: 90 mg/m2, d 1-4 MEL 200 Two courses M: 200 mg/m2 day -2 Stem cell support day 0 1° R A N D O M I Z T 2° CONSOLIDATION two 28-day course V: 1.3 mg/m2 d 1,4,8,11 R: 25 mg/day, d 1-21 D: 40 mg, d 1,4,8,11 MAINTENANCE day course until relapse R: 10 mg/day, days 1-21 MAINTENANCE 28-day courses until relapse One course VCD Three 21-day courses C: 500 mg/m2, d 1,8 A Randomized Phase III Study to Compare Bortezomib, Melphalan, Prednisone (VMP) With High Dose Melphalan Followed by Bortezomib, Lenalidomide, Dexamethasone (VRD) Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Multiple Myeloma Slide courtesy A Palumbo V, bortezomib; C, cyclophosphamide; D, dexamethasone; R, lenalidomide; M, melphalan; P, prednisone

High dose Melphalan + ASCT Lenalidomide versus Placebo
Myeloma XI: Thalidomide and Lenalidomide Combinations in Myeloma Patients of All Ages Intensive CTD CRD Randomize Assess response PD + NC CR + VGPR PR + MR CVD Nothing High dose Melphalan + ASCT Lenalidomide versus Placebo Slide courtesy F Davies Abbreviations: CTD Cyclophosphamide (500mg p.o. D 1,8,15) Thalidomide ( mg p.o. daily) Dexamethasone (40mg p.o. D1-4, 12-15) , CTDa Cyclophosphamide (500mg p.o. D 1,8,15, 22) Thalidomide (50-200mg p.o. daily) Dexamethasone (20mg p.o. D1-4, 15-18), CRD Cyclophosphamide (500mg p.o. D 1,8) Lenalidomide (25mg p.o. daily) Dexamethasone (40mg p.o. D1-4, 12-15) , CRDa Cyclophosphamide (500mg p.o. D 1,8) Lenalidomide (25mg p.o. daily) Dexamethasone (20mg p.o. D1-4, 15-18), CVD Cyclophosphamide (500mg p.o. D 1,8,15) Bortezomib (1.3mg/m2 i.v. D 1,4,8,11) Dexamethasone (20mg p.o. D1-2, 4-5, 8-9, 11-12) Melphalan (200mg/m2) ASCT Autologous stem cell transplant.

GEM14 MAIN: Maintenance R MRD ASCT Mel-200 Bu-Mel MRD Consolidation
Induction VRDx6 R MRD ASCT Mel-200 Bu-Mel MRD Consolidation VRDcon x 2 This new trial consists in: 6 cycles of VRD as induction treatment followed by ASCT with either mel200 or busulfan-melphalan, consolidation with 2 cycles of VRD and then maintenance R MRD Maintenance LEN/DEX x 2 yrs* LEN/DEX + MLN9708 x 2 yrs* * Patients with positive MRD will continue with LEN/DEX for 3 more years V, bortezomib; D, dexamethasone; R, lenalidomide; MRD, minimal residual disease; LEN/DEX, lenalidomide/dexamethasone 157

Hovon/IFM: Daratumumab Trial in Transplant-eligible NDMM
VTD + Dara Observation Induction 4 cycles MaintenanceUntil progression VTD R HDM ASCT Stratify by: dara treatment, response, MRD status Consolidation 2 cycles Endpoints: sCR PFS, OS Slide Courtesy of P Sonneveld R, randomize; V, bortezomib; T, thalidomide; D, dexamethasone; Dara, daratumumab; ASCT, autologous stem-cell transplant; sCR, stringent complete response; PFS, progression-free survival; OS, overall survival

Recently Approved Agents for Treatment of MM
FDA Approval Type Mechanism Clinical Status Daratumumab 11/2015: MM pts who received ≥3 prior treatments Human IgG1ĸ mAb that binds to a unique epitope on CD38 Induces lysis of CD38-expressing tumor cells At least 5 clinical trials underway in both untreated and R/R MM patients Elotuzumab 11/2015: For use in combination with lenalidomide/dexamethasone to treat MM pts who have received 1 to 3 prior medications Humanized IgG1 mAb targeted against SLAMF7 Selectively targets and kills SLAM F7-expressing myeloma cells Phase 2 trials are evaluating adding elotuzumab to lenalidomide/low-dose dex (ELOQUENT-2, ELOQUENT-1), and bortezomib-dex Phase 1/2 study of lenalidomide-dex-bortezomib ± elotuzumab in patients with newly diagnosed, high-risk myeloma Ixazomib (MLN9708) 11/2015: For use in combination with lenalidomide/dexamethasone to treat MM pts who have received ≥ 1 prior medications Oral 2nd-generation proteasome inhibitor Potently, reversibly, and selectively inhibits the proteasome. Phase 3 study in R/R MM (TOURMALINE-MM1) or newly diagnosed myeloma (TOURMALINE-MM2) Additional clinical trials in relapsed and/or refractory myeloma, in newly diagnosed disease, as maintenance therapy, and in asymptomatic (smoldering) myeloma

Newer Agents in Development for Treatment of MM
Type Mechanism Clinical Status Ibrutinib (PCI–32765) First-in-class selective, irreversible small molecular inhibitor of Bruton’s tyrosine kinase (BTK) Inhibitory effects upon OC function, micro-environmental interactions important for MM cell adherence and growth, MM repopulating cell growth Ongoing Phase 2 trial in R/R MM Phase 1/2 study for use in combination with carfilzomib ± dex in R/R MM Indatuximab Ravtansine (BT062) Immunoconjugate consisting of anti-CD138 chimerized mAb and the cytotoxic agent maytansinoid Tumor Activated Prodrug (TAP) Binds to CD138-positive MM cells Once the immunoconjugate is internalized into the target cell, cytoxic DM4 is released Studies underway for use in combination with Len/Low-dex in R/R MM Oprozomib Orally-administered epoxyketone proteasome inhibitor Primarily targets the chymotrypsin-like activity of the 20S proteasome Orphan drug designation for the treatment of MM Phase 1b/2 studies with dex for R/R MM Phase 1b/2 studies with dex + lenalidomide or cyclophosphamide in newly diagnosed MM Phase Ib/2 study with melphalan and prednisone in transplant-ineligible patients with newly diagnosed MM

Newer Agents in Development for Treatment of MM
Type Mechanism Clinical Status Pembrolizumab (MK-3475) Highly selective humanized IgG1ĸ mAb mAb Blocks the interaction between PD-1 and its ligands without ADCC or CDC activity Ongoing Phase 1 study, both as a single agent and in combination with lenalidomide and dexamethasone SAR650984 Humanized version of a murine anti-CD38 Ab Selectively binds to CD38-expressing cells and disrupts intracelllular signaling Ongoing Phase 1b study in combination with lenalidomide and dex in R/R MM Ongoing Phase 1 study as monotherapy in selected CD38+ hematological malignancies Selinexor (KCP-330) Orally bioavailable, selective inhibitor of nuclear export (SINE) compound First in class, slowly reversible, potent SINE compound that specifically blocks XPO1 Selectively cytotoxic for cells with genomic damage Demonstrated anti-MM activity in preclinical studies and in an ongoing Phase 1 clinical study, both as a single agent and in combination with dexamethasone

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Considerations for Optimizing Transplant in Multiple Myeloma Patient Management The first 68 slides of this library should be considered a sample presentation.

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