Multiple Myeloma. Solving a growing puzzle

Multiple Myeloma Solving a growing puzzle

Disclosures Financial I wish. I eat too much. I did ask who the audience would be.

Nurses and Doctors

Goals 1. Understand the incidence, symptoms, and pathophysiology of myeloma. 2. Understand the past and current therapies of myeloma. 3. Have an understanding of the multiple treatment decisions in patients with myeloma. 4. Insight to developing therapies for myeloma.

Outline Introduction / Statistics Presentation / Diagnosis / Staging Treatments Past and Present Guidelines / Biomarkers Promising Future Treatments Conclusions

Trying to figure out Myeloma

Outline Introduction / Statistics Physiology / Presentation Diagnosis / Staging Treatments Past and Present Promising Future Treatments Conclusions

What is Myeloma Cancer of a type of lymphocyte called plasma cells Plasma cells make the antibodies for the immune system A typical antibody - 2 light chains (kappa or lambda) and 2 heavy chains (G,A,M,E,D). Myeloma will cause a monoclonal clone of a single antibody.

The Antibodies

Lets start with what we know 24,050 new cases in 2014. 11,090 estimated deaths from myeloma in 2014 (14 th ). 1.4% of all cancers. Incidence is estimated to increase 77% by 2030, due to aging population. Myeloma is not curable.

Lets start with what we know 5 year over all survival in 2009 was about 50%. Survival varies by age, race, patients comorbid conditions, and tumor biology (characteristics). But

The outlook is improving for patients with myeloma 2014 5 year OS = 66%. For the last 6 years, the 5 year survival rate as increased 2% each year. At the current rate the 5 year survival will = 100% by about 2030.

Who gets myeloma Elderly: median =70 y/o. Overall Woman > men But African American men have the highest risk %. (For both diagnosis and death) IgG = 52%, IgA = 21%, IgD = 2%, bi-clonal = 2% light chain only = 16%, From SEER data base.

Outline Introduction / Statistics Presentation / Diagnosis / Staging Treatments Past and Present Guidelines / Biomarkers Promising Future Treatments Conclusions

How they are found Abnormal Serum or urine protein electrophoresis. Tested because of: Total protein / albumin ratio >2 Renal disease. Unexplained anemia Other signs and symptoms worrisome for myeloma

What are the symptoms Hyper-calcemia Corrected calcium >10.5 mg/l or upper limit of normal Renal insufficiency Serum Creatinine > 2 mg/dl. Anemia Hemoglobin < 10 g/dl or 2 g < normal Lytic bone lesions / osteoporosis British Journal of Haematology (Kyle, et al. 2003).

Diagnostic work up History and physical Labs CBC, Calcium, Creatinine, SPEP, UPEP, Serum free light chains, B2 macroglobulin, Total protein, Albumin, LDH Bone marrow biopsy with Fluorescence in situ hybridization for chromosomal abnormalities and cytogenetic analysis Scans Bone survey (consider MRI or PET)

Staging International Staging System Stage I = B2-macroglobulin <3.5 and Albumin at least 3.5g/dL. Stage II = B2-macroglobulin <3.5 but Albumin < 3.5gm/dL. or B2-macroglobulin 3.5 to </=5.5 Stage III = B2-macroglobulin >5.5 Chromosomal abnormalities High risk = t(14;16) 17pt(14;16) Intermediate = t(4;14) Standard = trisomies t(11;14) t(6;14)

Outline Introduction / Statistics Presentation / Diagnosis / Staging Treatments Past and Present Guidelines / Biomarkers Promising Future Treatments Conclusions

Current Treatment Options Drugs Alkylating agents cyclophosphamide, Steroids prednisone Interferon Other chemotherapy melphalan, bendamustine. dexamethasone, doxorubicin, vincristine, etoposide cisplatin, liposomal Immune modulators lenalidomide, Proteasome inhibitors thalidomide, pomalidomide bortezomib, carfilzomib Stem cell transplant Histone deacetylase inhibitor vorinostat

Treatment Option Combinations basically any 1, 2, 3, or >3 drug combinations RVd Cybord DCEP DT-PACE VDT-PACE Rd, Thal/dex, Pom/dex Vd MP MPB, MPL, MPT VAD, DVD

The main question for induction therapy transplant or no?

Rules of thumb 1. Currently if patient is eligible for an auto-transplant they should have one (or at least the discussion). 2. Radiation is only used for palliation of symptomatic bone lesions. 3. Bisphosphonate agents should be used in patients with known lytic bone lesions and considered in all myeloma patients.

Older Regimens (historical) no transplant Melphalan / Prednisone (mp) (i.e. IFM-9906 mp vs. mtp vs. vad mel100) M= 0.25mg/kg D1-4 + P= 2mg/kg D1-4 (q6wk x 12) RR= 35%, >/=VGPR= 7% PFS= 17.8m, OS= 33m Note all arms lived about 12-14m after progression. T. Facon. Lancet, Oct.6,2007; vol.370; p.1209-1218.

Induction Older Regimens (historical) VAD (data from the HOVON-65 trial) 50mg/d vs. (P) 1.3mg/n2 q2wk x 2yrs. transplant eligible VAD vs. PAD then Auto-T, then Thalidomide Vincristine= 0.4mg/m2/d, A= 9mg/m2/d, D= 40mg/d (D1-4, 9-12, 17-20 q4wk) x 3 cycles was the VAD induction. 827 patients with follow up = 41m. RR= 54% with >/= ncr= 7% (induction part only included) PFS= 28m. (all), if cr.>2 PFS= 13m. P. Somneveld. JCO. 8/20/2012; v.30(24) p.2946-2955

Newer Single Agents Drugs (IMID s) Immune Modulator Rd vs. RD (E4A03) 445pts. Phase III, (median age = 65 y/o), Follow up = 17m. Dexamethasone 40mg. weekly vs. D1-4,9-12,17-20 q4wk. Both arms received Lenalidomide 25mg. D1-21 q4wk. RR= 68%(d) vs. 79%(D), >/=VGPR = 24%(d) vs. 42%(D). 1yr. OS = 96%(d) vs. 87%(D). 3yr. OS = 74%(d) vs. 75%(D) (all patients crossed over), 3yr. OS if Auto-T = 93%. Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37

Melphalan losing favor as first line therapy for the elderly First trial (Frontline investigation of Revlimid & dexamethasone vs. Thalidomide). 1623 patients (65+ y/o or no transplant candidate) 3 arms Len/dex to progression vs. Len/dex x 72 weeks vs. Melpalan/prednisone/Thalidomide x 72 weeks. PFS = 25.5m(L/d) vs. 20.7m(L/d72) vs. 21.2m(MPT). 4yr. OS = 59%(L/d) vs. 56%(L/d72) vs. 51%(MPT). RR = 75%(L/d) vs. 73%(L/d72) vs. 62%(MPT). Time to 2 nd therapy = 39m(L/d), 28.5m(L/d72), 26.7m(MPT). Grade III/IV neutropenia = 28%(L/d), 26%(L/d72), 80%(MPT). 1 Facon T, et al. Lancet 200L. Benboubker. NEJM. V.371(10). Sept.4,2014 906-916

FIRST Trial: Phase III Study Design Screening Active Treatment + PFS Follow-up Phase LT Follow-Up RANDOMIZATION 1:1:1 Arm A Continuous Rd Arm B Rd18 Arm C MPT LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 MEL + PRED + THAL 12 Cycles 1 (72 wks) MELPHALAN PREDNISONE THALIDOMIDE 0.25mg/kg D1-4/42 2mg/kg D1-4/42 200mg D1-42/42 PD or Unacceptable Toxicity PD, OS and Subsequent anti-mm Tx Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL 2 (100 mg D1-42/42); MEL 2 0.2 mg/kg D1 4 1 Facon T, et al. Lancet 2007;370:1209-18.

PFS and OS favored the RD Arm Overall survival Progression-free survival With permission from Facon T, et al. Proc ASH 2013;Abstract 2.

Newer Single Agents Proteasome Inhibitors VISTA (MP +/- Bortezomib(V)) no transplant M= 9mg/m2 D1-4 + P 60mg/m2 D1-4 q6wk x 9 q6wk. D1,4,8,11 (q3wk x 2) x 9 q6wk (total 1 yr.) 682 patients, PS= 0-2, F/U= 60m. RR= 35%(MP) vs. 71%(VMP); >/=VGPR= 8% vs. 41%(VMP). TTP= 20m(MP) vs. 30m(VMP). OS= 43m(MP) vs. 56m(VMP). OS after progression = 27m(MP) vs. 28m(VMP). J. Miguel. NEJM 8/28/2008. vol.359;9. p.906-917, J. Miguel. JCO, 2012.41.6180 +/- V= 1.3mg/m2 IV

RVD Most commonly used regimen and has no phase III data. R= 25mg/d D1-14, V= 1.3mg/m2 IV D1,4,8,11, D= 20mg D1,2,4,5,8,9,11,12 q3wk (>/=4 if Auto-T and x8 if no Auto-T) 66pts. Follow up 21m. PS= 0-2 RR= 100% with >/=VGPR= 67% 18m PFS= 75% and 18m OS=97% All received ASA(81mg), Acyclovir prophylaxis, and Zoladronic acid. Allowed to continue RVD in a maintenance phase. P. Richardson. Blood 8/05/2010. vol.116(5); p.679-686

Evolution trials Also large phase II study. 4 arms RVD, R-CyborD, CyborD, (mod)cybord. D= 40mg/wk., C= 500mg/m2 D1,8 or D1.8,15(mod) q3wk. R and V same dosing as RVD. 145pts. Follow up= 20m. RR= 85-100% with >/= VGPR= 51-58% 1yr. PFS= 83-100% 1yr. OS= 93%(4 drug) & 100%(all other regimens) S. Kumar; Blood. vol.119(19); p.4375-94

Structure of newer IMIDs and proteasome inhibitor.

How long do we go? Maintenance or Consolidation

Maintenance Lenalidomide (no transplant) MM-015 MPR-R vs. MPR vs. MP R= 10mg/d D1-21 q4wk. (until progression) 300pts with Follow up 30m. RR= 77%(R) vs, 50% with >/= VGPR= 33%(R) vs. 12%. PFS= 31m(R) vs. 13m (65-75 y/o greatest benefit) 3yr. OS= 70% vs. 66% 2 nd malignancies 7% vs. 3% A. Palumbo. NEJM. Vol.366(19). P1759-68.

Maintenance Lenalidomide transplant) (with CALGB100104 460pts. Median age=59, PS=0-1, Follow up= 34m. Any induction with at least stable disease after Auto-T Lenalidomide (5-15mg/d) TTP= 46m(L) vs. 27m. (HR=0.48) 3yr. OS = 88%(L) vs. 80% (HR=0.62) 2 nd malignancies 8%(L) vs. 3% K. Anderson. NEJM (5/10/2012); VOL.366(19) P.1770-80

Maintenance Lenalidomide transplant) (with IFM 614pts. Median age= 55y/o. Follow up= 30m VAD or Bort./Dex Auto-T Consolidation (Lenalidomide 25mg D1-21 q4wk) x 2 +/- Lenalidomide 10-15mg/d. Consolidation improved >/=VGPR from 58% 69% PFS= 41m(L) vs. 23m. 4yr. OS= 73%(L) vs. 75% 2 nd malignancies= 3.1/100pt.-yrs. Vs. 1.2/100pt-yrs. M. Attal. NEJM(5/10/2012) vol.366(19). P1782-92

Hovon-65 trial 827pts. VAD vs PAD (11% with del17p) Dox=9mg/m2/d D1-4, Dex 40mg D1-4,9-12,17-20 + V=0.4mg/m2/d vs. P=1.3mg/m2 IV D1,4,8,11 q3wk. Induction was 3 cycles Followed by Auto-T, then Thal. 50mg/d vs. (P (bortezomib)) q2wk. X 2 years. RR= 90%(P) vs. 83%(V) with >/= VGPR= 76%(P) vs. 56%(V). PFS= 35m(P) vs. 28m(V). PFS after HDM= 31m(P) vs. 26m(V). 5yr OS= 61%(P) vs. 55%(V). the negative impact of del17p on PFS & OS is less with Bortezomib based treatment. PFS= 22m(P) vs. 12m(V). And OS >%54m(P) vs. 24m(V). P. Somneveld. JCO. 8/20/2012; v.30(24) p.2946-2955 & K. Neben. Blood;(1/26/12); vol.119(4); p.940-948

Outline Introduction / Statistics Presentation / Diagnosis / Staging Treatments Past and Present Guidelines / Biomarkers Promising Future Treatments Conclusions

Rules to remember IMID s 1. Need thrombi prophylaxis. 2. Watch blood counts. 3. IMID + Melphalan increase risk of second malignancies. (First trial) 4. Lenalidomide is excreted mainly via urine dose adjustment in renal disease. Proteasome inhibitors 1. Shingle prophylaxis. 2. Monitor platelet counts. 3. Monitor peripheral neuropathy 4. Standard of care in high risk myeloma initial therapy.

NEJM 364;11. 3/17/2011 p.1046-1060

Any guides to treatment Cereblon levels Cereblon is the primary target of teratogenicity with IMID s. Resistance to IMID s often had a 20-90% decrease in cereblon levels from baseline (but not all patients)

Any guides to treatment NRAS mutation RAS family (KRAS, HRAS, NRAS). Mutations are mutually exclusive. In most tumors one subtype is predominately mutated In solid cancers usually KRAS, in Hem cancers usually NRAS Myeloma has about 20% KRAS and 20% NRAS mutations Tissue from 133pts in Bortezomib trials (APEX & 2 phase II) 71/133 had mutations (20% had NRAS mutation) RR to Bortezomib 7%(NRAS) vs. 53% and shorter TTP No OS difference and NRAS mutation did not effect steroid activity. G. Mulligan Blood (1/30/14). Vol.123(5); p632-638.

Is there a subtype where standard treatment is not good enough? Patients with the combination of: 1. Stage III 2. t(4;14) or 17p- 3. High LDH Accounts for 5-8% of myeloma patients. 50% 2yr. failure rate of standard induction and auto-t. P. Moreau. JCO. V.32(20); 7/10/14. p.2173-2180

Outline Introduction / Statistics Presentation / Diagnosis / Staging Treatments Past and Present Guidelines / Biomarkers Promising Future Treatments Conclusions

Antibodies Anti-CS1(Elotuzumab) + Lenalidomide / Dexamethasone E= 20mg/kg IV Elotuzumab weekly + D= 40mg/wk. + L= 25mg/d D1-21 q4wk. Single agent Elotuzumab has no activity. Phase I; 29pts. Age= 60. Follow up= 16.4m. Median 3 prior regimens and >5yrs.from diagnosis. Combination RR=82% and TTP= not reached. S. Lonial JCO. Vol.30(16); 6/1/2012.

Antibodies Anti-CD38 Daratumumab. Novel, high-affinity, human mab against a unique CD38 epitope induced potent Ab-dependent cellular cytotoxicity. A response was seen 67% patients receiving more than 4 mg/kg. (42%= PR and 25%= minimal) Approximately 80% of patients were double-refractory. 1 st monoclonal antibody to receive breakthrough therapy designation by the FDA. 18th Congress of the European Hematology Association (EHA): Abstract S576. Presented June 15, 2013

Histone deacetylase inhibitors Panorama-1: Bortezomib 1.3mg./m2 IV D1,4,8,11 Dexamethasone 20mg. PO D1,2,4,5,8,9,11,12 +/- Panobinostat 20mg. PO 3x/week. Q3 week x 8 Relapsed or refractory disease (>1/2 had >2 prior regimens). 768 patients PFS = 12m (pan) vs. 8m DOR = 13.1m (pan) vs. 10.9m. RR = 61% (pan) vs. 55% ncr/cr = 28% (pan) vs. 16% Toxicity = thrombocytopenia, neutropenia, diarrhea

Rationale for BTK inhibitors B cell-activating factor (BAFF) of the TNF family (BAFF-R) is coupled to the NFκB pathway by Bruton s tyrosine kinase (BTK). BAFF-induced signaling to NF-κB via BTK serves to promote B-cell survival. Proteasome inhibitors block NF-kB activity via blocking destruction of the inhibitor protein of NF-kB (IK-B(alpha)). S. Rushworth. Abstr.181P Queen Elizabeth II Conference Centre London BPS Meeting 2012.

Activation of Bruton s Tyrosine Kinase (BTK) pathway

Ibutinib Bruton s tyrosine kinase inhibitor. Potently enhances Bortezomib and Lenalidomide activities through NF-kB. Approved in CLL and Mantle cell. Likely approval in Waldenstrom s. Ibutinib blocks phosphorylation of serine-536 resulting in down regulation of BCLxL, FLIP, Survivin, and increases caspace-mediated apoptosis. S. Rushworth. Cellular Signaling. Vol.25(1); 1/2013. p.106-112.

Outline Introduction / Statistics Presentation / Diagnosis / Staging Treatments Past and Present Guidelines / Biomarkers Promising Future Treatments Conclusions

Conclusion Myeloma is still a disease with no cure in 2014. New medications and how to use those medications most effectively is still a work in progress. We are making strides in the management of myeloma. Soon we may turn myeloma into a chronic disease and away from being a terminal disease. Thank You.