Myeloma Support Group: Now and the Horizon Brian McClune, DO
Disclosures Consultant to Celgene
Objectives Transplant for myeloma- is there any thing new? High risk disease University protocols New therapies? What did we learn at ASH 2016/ASCO 2017
How do we prognosticate, i.e. risk stratification Stage International Staging System (ISS): uses albumin, beta-2 microglobulin (B2M) and Revised International Staging System (R-ISS)
International Staging System Philip R. Greipp et al. JCO 2005;23:3412-3420. Criteria Median Survival (mo.) Stage I Albumin 3.5 g/dl B2M < 3.5 mg/l 62 Stage II Not I or III 44 Stage III B2M 5.5 mg/dl 29
Palumbo et al. Journal of Clinical Oncology 33, no. 26 (September 2015) 2863-2869.
How do we prognosticate, i.e. risk stratification Stage International Staging System (ISS): uses albumin, beta-2 microglobulin (B2M) Genetics Standard Risk vs. High Risk
Risk stratification based on cytogenetics Standard Risk High Risk Hyperdiploidy Non-hyperdiploidy t(11;14) Del 17p t(6;14) t(14;16) Del 13/13q by FISH 1p deletions/1q amplifications t(4;14) Del 13 by conventional karyotyping GEP Fonseca et al. Semin Oncol. 2013;40:554-566. Bergsagel et al. Blood. 2013;121:6. Zhan et al. Blood. 2006;108:2020-2028.
msmart Three risk categories Standard risk: Trisomies, t(11;14), t(6:14) Intermediate risk: t(4;14), 1q gain High risk: Del 17p, t(14;16), t(14;20), GEP high risk panel
BMT-CTN: Multicenter Ph II, double-blinded placebo controlled trial of maintenance Ixazomib after allogeneic transplant for high risk myeloma Eligibility: 18-65 years, matched donor and good organs Plasma cell leukemia Relapse from therapy (including auto transplant) within 18 months with either standard risk or high risk myeloma >18 years to <65 years High Risk Multiple Myeloma OR Standard Risk Progression <18months from prior autohct OR Plasma Cell Leukemia Related or Unrelated PBSC Donor Fludarabine/Melphalan/Bortezomib Conditioning Regimen (Day -5 to + 7) + PBSC Infusion (Day 0) del 13 by karyotyping, hypodiploidy, 1q amplification or 1p deletions, t(4;14), t(14;16), t(14;20), deletion 17p, high-risk GEP Randomization (Day +60 to +120) Ixazomib Maintenance Therapy x12 cycles Placebo Maintenance Therapy x12 cycles
When/why do you transplant?
Mateos et al. Blood Reviews. 2015;29:387-403
Why transplant at all? Sometimes a bigger, harder hit is what you need
Koreth et al. BBMT. 2007;13:183-196.
Study Overview In this trial, 700 patients with myeloma were randomly assigned to receive RVD therapy (lenalidomide, bortezomib, and dexamethasone) with or without autologous stem-cell transplantation. Patients who underwent transplantation had significantly longer progression-free survival.
Kaplan Meier Curves for Progression-free Survival and Overall Survival. Attal M et al. N Engl J Med 2017;376:1311-1320
Subgroup Analyses of Progression-free Survival. Attal M et al. N Engl J Med 2017;376:1311-1320
Baseline Characteristics of the Patients Who Underwent Randomization. Attal M et al. N Engl J Med 2017;376:1311-1320
Response to Treatment. Attal M et al. N Engl J Med 2017;376:1311-1320
Grade 3 and 4 Adverse Events That Occurred in At Least 2% of Patients. Attal M et al. N Engl J Med 2017;376:1311-1320
Conclusions Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches.
Anything else to do to get to MRD? Maintenance therapy! Revlimid (lenalidomide) Phase III data that suggests: 1) prolongs PFS; 2) in the US study prolongs OS; 3) associated with inc d secondary malignancies
McCarthy et al. Journal of Clinical Oncology - published online before print July 25, 2017
What about Velcade maintenance?
Del 17p13: Better PFS with Velcade (PFS: VAD P<0.001 and PAD P=0.48; ) Better OS (VAD P<0.001 and PAD P=0.54) The OS rates after 96 months in PAD treated patients were similar with or without deletion 17p13 (52% versus 54%). t(4;14): was not overcome by VAD nor PAD OS at 96 months was inferior in both VAD and PAD treated patients harboring a translocation t(4;14) (VAD: 23 versus 48%; PAD: 33 versus 57%). Gain 1q21: similar results on PFS and OS In most recent update, neither VAD and PAD did not overcome the negative prognostic effect Goldschmidtt advance online publication 1 August 2017; doi: et OSal.atLeukemia 96 months was significantly shorter in patients with10.1038/leu.2017.211 gain 1q21
Other potential strategies
Natural killer (NK) cells: important roles in immune surveillance Myeloma cells interfere with NK cell activity with NK cell number/activity negatively correlating with disease burden Postulated that escape of MM cells from immune surveillance is associated with the impairment of NK cell function. https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=44062 NK cells often display reduced
New project- Cellular therapeutics PNK-007 cells are expanded from CD34+ cord blood hematopoietic stem/progenitor cells Composed of highly enriched CD56+CD3- NK cells The cells, in in flow cytometry studies, showed in vitro activity against Myeloid tumor cell lines, specifically HL-60 and K562 MM cell lines, such as RPMI-8226, IM-9, NCI-H929 and OPM-2; and Against primary AML and MM samples Adoptive transfer of haploidentical NK cells Cytokine-dependent expansion phase after infusion Interleukin-2 (IL-2) is generally used to stimulate NK cells
CAR- T cells
CAR T Cells/ ASC0 2017 Chinese CAR-T cell protocol BCMA construct N= 35 patients with rel/ref MM Treated with T-cells at 3 dosings over 1 week Response rate: 100% with 33/35 patients getting VGPR or CR within 2 months Cytokine release syndrome (CRS): 85% BCMA target is also being used at Mayo and NIH
Vaccine therapy
Thank you!
Criteria for Diagnosis of Myeloma MGUS Smoldering Myeloma (SMM) Active Myeloma (MM) <3 g/dl M spike <10% plasma cells* 3 g/dl M spike OR 10% plasma cells* M spike and 10% plasma cells* NO anemia, hypercalcemia, bony lesions, or renal dysfunction * in marrow Kyle RA et al. NEJM 2002;346(8): 564-569. C: high calcium levels (>10.5 mg/dl) R: renal dysfunction (Cr >2 mg/dl) A: anemia (Hgb< 10 g/dl) B: bone destruction (usually lytic bone lesions)
CRAB Plus Biomarkers Rajkumar et al. at Mayo SMM (n= 655 patients) over 14 yrs 3.2% at diagnosis had marrow plasmacytosis >60% Median time to progression (TTP) 7 months High marrow plasmacytosis identifies high risk population -> myeloma Rajkumar et al. NEJM 2011;365:474-5. P<0.001
CRAB Plus Biomarkers (2) Dispenzieri et al. at Mayo If involved/uninvolved FLC ratio 8, 40% risk of progression within 2 years in SMM Larsen et al. SMM; n= 586 patients Examined FLC ratio correlating with 80% risk of progression to MM within 2 years Dispenzieri et al. Blood 2008;111:785-89. Larsen et al. Leukemia 2013;27:941-46. TTP 15 months P<0.0001 TTP 55 months
CRAB Plus Biomarkers (3) Hillengrass et al. n=149 patients with SMM and whole-body MRI at diagnosis Focal lesion 42(48%); 23(15%) had more than one lesion >1 focal lesion was associated with increased TTP 13 months with 70% progressing by 2 years Hillengrass et al. JCO 2010; 28:1606-10.
2014 Criteria for Diagnosis of Myeloma MGUS Smoldering Myeloma Active Myeloma <3 g/dl M spike <10% plasma cells* 3 g/dl M spike OR 10% plasma cells* M spike and 10% plasma cells* NO anemia, hypercalcemia, bony lesions, or renal dysfunction * in marrow Rajkumar et al. 2014;346(8): 564-569. C: high calcium levels (>10.5 mg/dl) R: renal dysfunction (Cr >2 mg/dl) A: anemia (Hgb< 10 g/dl) B: bone destruction (usually lytic bone lesions) M: MRI with > 1 focal lesion (at least 5 mm) E: elevated FLC ratio >100 with involved light chain also 100mg/L P: marrow plasmacytosis 60% in aspirate or trephine biopsy