>> OKAY. LET'S GET STARTED. I'M DELIGHTED TO INTRODUCE TODAY'S SPEAKER DR. OLA LANDGREN. DR. LANDGREN WAS TRAINED IN SWEDEN IN LONDON UNIVERSITY AS AN UNDERGRADUATE AND AT CAROLYN SCA GOT HIS M.D., DID ADVANCED TRAINING IN FELLOWSHIP IN HEMATOLOGY AN INTERNAL MEDICINE THEN COMPLETED HIS Ph.D. WORKING ON LYMPHOPROLIFERATIVE DISORDERS SPECIFICALLY HODGKINS DISEASE. HIS RESEARCH CAREER IS UNDERSTANDING HEMATOPOIETIC MALIGNANCIES. LYMPHOPROLIFERATIVE MA MALIGNANCIESCH HE CAME IN THE CANCER OF EPIDEMIOLOGY AN GENETICS AND MOVED OVER TO BE A SENIOR INVESTIGATOR IN THE CENTER FOR CANCER RESEARCH AT NCI. FOR MANY YEARS NOW HE'S BEEN STUDYING MYELOMA WITH A PARTICULAR INTEREST IN WHAT ARE THE MOLECULAR PRECURSORS OF THE DISEASE HOW IT DEVELOPS AND HOW TO USE THE INFORMATION TO DEVELOP AND IMPROVETHER P PISCH HIS TALK IS ENTITLED MULTIPLE MYELOMA AND ITS PRECURSOR DISEASE, THE FUTURE IS ALREADY HERE. >> THANK YOU VERY MUCH FOR THOSE KIND WORDS. IT'S A HONOR TO PRESENT HERE TODAY. I'M GOING TO TALK ABOUT MYELOMA. AS YOU ALREADY HEARD. AND I'M GOING TO HAVE THREE AREAS I'M GOING TO HIGHLIGHT ON. GOING TO BE RATIONAL DRUG DESIGN, GOING TO BE EARLY DISEASE AND EARLY TREATMENT AND THEN FUNCTIONAL IMAGING. AS A BRIEF BACKGROUND FOR THOSE OF YOU NOT ENTIRELY FAMILIAR WITH MYELOMA, IT'S A MALIGNANCY DETECTABLE IN BLOOD AND AND OR URINE, THE SECOND MOST COMMON HEE POIETIC MALIGNANCY IN THE U.S. THERE'S 65,000 LIVING WITH THE DISEASE, AT THAT TIME THAT NUMBER WILL GO UP A LOT AND PEOPLE LIVE LONGER AND PATIENTS WITH MYELOMA LIVE LONG AS WELL. THE PRE-DISEASE STATE IS DEFINED BY LAB CRITERIA. FOR THOSE NOT FAMILIAR WITH CRITERIA WITH THE DISEASE ON THE RIGHT MYELOMA, LEFT YOU HAVE THE PRECURSOR STATE SO MYELOMA IS EVIDENCE OF MONOCLONAL PROTEIN IN BLOOD AND URINE AND PLASMA IN THE BONE MARROW AND PRESENCE OF SO CALLED END ORGAN DAMAGE. THIS IS AN ENTIRELY CLINICAL SYNDROME, THE DIAGNOSIS IS NOT PERFECT AND WE NEED TO DO A LOT MORE TO TRY TO IMPROVE ON WHAT MYELOMA REALLY IS AND HOW IT'S DIFFERENT FROM THESE PRECURSOR STATES. IT'S CURRENTLY DEFINED AS END ORGAN DAMAGE, HYPERANEMIA,LYTIC BONE LESIONS. ONE OR MORE OF THOSE WOULD QUALIFY FOR MYLOMA. YOU'RE NOT ALLOWED TO HAVE THAT IF YOU HAVE THE SIZE OF PROTEIN AND THE NUMBER OF PLASMAS IN THE BONE MARROW. IN ORDER YOU HAVE TO BE LESS THAN THREE GRAM, LESS THAN 10%. IF YOU HAVE ONE OF THOSE NOT FOLLOWING THAT RULE YOU WOULD BE SMALL BRAIN IN THE ABSENCE OF END ORGAN DAMAGE. SO THIS IS WHAT I'LL TALK ABOUT RATIONAL DRUG DEVELOPMENT EARLY MYELOMA POSSIBILITY FOR EARLY TREATMENT AND FUNCTIONAL IMAGINGCH THESE ARE THREE LEGS THAT OUR PROGRAM HERE AT THE NIH IS FOCUSING ON IF WE WERE TO SUMMARIZE WHAT WE'RE DOING IN THREE BULLETS. AS A LITTLE BIT BACKGROUND WHEN IT COMES TO THE RATIONAL STUDY RATIONAL DRUG DEVELOPMENT, A LOT OF DEVELOPMENT HAS BEEN DONE IN TERMS OF TREATMENT FOR MYELOMA, SIMILAR TO MOST OTHER CANCERS THAT DEVELOPMENT HAS BEEN PURELY EMPIRICAL. STARTED IN THE 60s WITH PREDNISONE AN ONLY THE PAST TEN YEARS NEW DRUGS HAVE BEEN INTRODUCED THALIDOMIDE, AN OLD DRUG REINTRODUCED TO MYELOMA AS WELL AS BOTISAMIB AND A SISTER DRUG TO THALIDOMIDE. HIGH DOSE AUTOLOGOUS SUPPORT WAS INTRODUCED IN THE MID 1990s. THIS HAS LED TO IMPROVED OVERALL SURVIVAL IN MYELOMA. IF YOU LOOK IN THE 1950s TO 60s PATIENTS USED TO LIVE AN AVERAGE ONE YEAR AND IT'S GONE UP TO FIVE OR MORE YEARS SO REALLY A LOT OF THINGS HAVE IMPROVED BUT IT'S INCURABLE FATAL DISEASE AND AROUND 6 TO 7 YEARS IN THE PRESENT TIME. BUT STILL AROUND ONE OUT OF FOUR PATIENTS ONLY SURVIVE ONE TO THREE YEARS AND NOT HAD ANY BENEFIT FROM THE DRUGS THAT I MENTIONED THAT HAVE BEEN INTRODUCED THE PAST TEN YEARS. SO THERE'S A LOT OF WORK TO BE DONE. EVERY PATIENT IS STILL BEING DIAGNOSED BY -- YOU FIND PLASMA CELLS, EVERY PATIENT TREATED SAME WAY WITH SAME DRUGS. ONE OF FOUR DON'T BENEFIT FROM THAT SO THAT NEEDS TO BE CHANGED THE FIRST GENOME SEQUENCING STUDY WAS PUBLISHED IN MULTIPLE MYELOMA, BASED ON 38 TUMOR GENOMES AND MASS NORMAL DNAS. IT'S DISAPPOINTING THAT THEY FOUND SO MANY ONCO GENIC LESIONS PRESENT IN THESE PATIENTS SO SHARP CONTRAST TO DISEASE SUCH AS HARRY CELL OR OTHER DISEASES LOOKED UPON THIS WAY, MYELOMA HAS THE TELEPHONE BOOK ON DIFFERENT TYPES OF MUTATIONS AND ABNORMALITIES. 50% OF THE PATIENTS HAD RAS MUTATIONS, NRAS IN NINE AND KRAS IN 10 MIEW TRAITIONS. HAVING RAS MUTATIONS LEADS TO ACTIVATION OF MAP KINASE PATHWAY AND WE HAVE AN INTEREST IN THAT. HERE IS A CARTOON OF THE MAP KINASE PATHWAY, AS YOU CAN SEE IN THE MIDDLE IF YOU HAVE RAS MUTATIONS YOU HAVE ACTIVATION OF MEK, ERK STEP HERE LEADING TO HYPOPHOSPHORYLATION OF ERK TO THE NUCLEUS AND ACTIVATES TRANSCRIPTION FACTORS THAT ARE REPORTED ON CELL PROLIFERATION, MOTILITY AND STRESS RESPONSE. WE HAVE BEEN LOOKING AT PRE-CLINICALLY FOR OTHER TYPE OF ACTIVATING TRANSLOCATION, MUTATIONS THAT COULD PLAY A ROLE IN ACTIVATE THE SAME PATHWAY. THAT'S IMPORTANT PART OF OUR CURRENT CUSS PRE-CLINICALLY AND DR. KEEL WHO IS HERE IN THE AUDIENCE HAS WORKED MANYp%) YEARS $i–-WITH LEASE BURGLARY TO DEFINE A MOLECULAR CHARACTERIZATION OF MYLOTHAT WHICH ALLOWS US TO GO OUT OF THE JUST LOOKING FOR THE PLASMA CELL PERSPECTIVE. THIS IS THEIR MODEL WITH SEVEN MOLECULAR CELL TYPES. TWO SUBTYPES ON THE LEFT IS MASS AND MMS SUB TIME TYPES THERE'S 414 AND 416 TRANSLOCATIONS. PATIENTS WITH THESE TRANSLOCATIONS ALSO HAVE ACTIVATION OF THE MACK ERK PATHWAY. WE HAVE DONE WORK ON THAT, PRE-CLINICALLY, THIS WAS PUBLISHED LAST YEAR IN THE BLOOD JOURNAL WITH LEAD AUTHOR INITIATED BY LOU STAT AND OTHERS. THE MASS AND 3 MYELOMA HAVE INCREASED TRANSCRIPTION OF MAS AND ALSO THE SIGNATURE GENES, THREE GENES INTE GRAIN BETA 7 AND CHEMOKINE RECEPTOR ONE BEING UP REGULATE IN THESE TWO PATIENT GROUPS. FURTHERMORE THE WORK THAT TINA PUBLISHED IN THE BLOOD JOURNAL LAST YEAR SHOWED IF YOU INHIBIT THE M EK ERK PATHWAY BY A MEK INHIBITOR YOU CAN INDUCE APOPTOSIS IN THOSE CELL LINES THAT DO HAVE MAP EXPRESSING. THAT ARE MAP EXPRESSING AND YOU CAN SEE ON THESE SLIDES, IN BLUE, THE MASS AND IN RED CELL LINE. THE OTHERS ARE NOT IMPACTED. SO WHAT I SHOWED YOU NOW IS THAT HAVING RAS MUTATIONS ACTIVATED THE MAP KINASE PATH WHICH BUT HAVING MAS AND MM 7 TRANSLOCATIONS COULD ACTIVATE THE SAME PATHWAY. SO WE HAVE DEVELOPED A CLINICAL TRIAL IN COLLABORATION WITH THE UNIVERSITY OF COMMONWEALTH IN VIRGINIA WITH STEVEN GRANT AND CANCER CENTER IN FLORIDA AND OTHER CENTERS ON EAST COAST AND WE JUST COMPLETED THIS STUDY A FEW WEEKS AGO THE LAST PATIENT WHO WAS IN THE STUDY FINISHED THERAPY SO THIS IS AN EXAMPLE HOW WE TAKE WORK FROM PRE-CLINICAL BENCH IN BUILDING TEN INTO CLINICAL STUDY IN COLLABORATION WITH OTHER CENTERS IN THE COUNTRY. SO IT' AN ORAL MEK INHIBITOR, GIVEN EVERY DAY ON A FOUR WEEK SCHEDULE, PATIENTS WENT ON REFRACTORY SO THEY RECEIVE SINGLE DRUG THERAPY, THERE WERE 37 PATIENTS ON THE ENTIRE TRIAL WE TREATED 8 PATIENTS IN BUILDING 10 AND THERE WERE A TOTAL OF 12 CORRELATIVE SAMPLING SO FOUR ADDITIONAL PATIENTS WITH SAMPLESCH THIS IS WHAT WE EXPERIENCED WORKING WITH OUTSIDE CENTERS THAT THERE COULD BE TECHNAL AND OTHER PROBLEMS SENDING SAMPLES BUT OTHER PATIENTS WE HAVE THE SAMPLES CHECKED. FOR THESE PATIENTS IN THE LAB, -- COLLECTED. FOR THESE PATIENTS IN THE LAB, (INDISCERNIBLE) IN OUR LAB DID FABULOUS WORK, QPCR FOR MASS 8 EXPRESSION AS WELL AS RT PCR FOR MM SETH AND (INDISCERNIBLE) GROUP IN THE MOLECULAR PATHOLOGY HAS DONE PIE ROW SEQUENCING FOR RAF AND IN BUILDING 37 NANOIMMUNE ASSAY FOR PHOSPHORYLATED ERK AND 1 AND 2. SO I'LL SHOW SOME RESULTS AND TRY TO PUT IT TOGETHER IN CLINICAL CONTEXT AND SHOW HOW THESE MOLECULAR PROVILES ARE VERY HIGHLY ASSOCIATED WITH WHAT WE SEE IN THE CLINIC. THESE ARE 12 PATIENTS WHERE WE HAD ACCESS TO SAMPLING. AS YOU CAN SEE IN YELLOW, IN ORANGE AND RED WE SEE UP REGULATION OF CMAS, MASS B AND MASS A AND CMAS IS PRESENT IN 3 OUT OF 12 AND MASS A IS ONE OUT 12 SO 8% OF THE PATIENTS. THE PATIENTS HAVE OVERLAP BETWEEN THESE. AT THE PRESENCE OF MM TRANSLOCATION IN ONLY ONE OF THESE PATIENTS. WHB WE LOOK FOR RAS MIEW TAILINGSES IN MORE -- BLACH WHEN WE LOOK FOR RAS MUTATIONS, WE FOUND FIVE OF 11, ONE PATIENT DIDN'T HAVE SAMPLES SO WE COULD LOOK FOR RAS. SO FIVE OUT OF 11 HAD RAS MUTATIONS, ONE HAD A B RFA WHICH IS HIGHER UPSTREAM. IF WE PUT IT TOGETHER IN CLAM CONTEXT WITH THE -- CLINICAL CONTEXT, WE ACTUALLY SEE FOUR OUT 8 PATIENTS WE TREATED IN BUILDING 10 HAS BENEFIT FROM THIS DRUG. THEY'RE HIGHLIGHTED IN GREEN, NUMBER 1, 2, 3, 4 ON TOP AND FOUR HAD PROGRESSIVE DISEASE. ALL THE PATIENTS THAT HAD SOME TYPE OF ACTIVATING MUTATIONS IN THE MIDDLE, THE DIFFERENCE BETWEEN PATIENTS WHO DIDN'T RESPOND VERSUS THOSE WHO DID RESPOND ON A CLINICAL NOTE WAS THE NON-RESPONDERS HAD A LOT OF TOXICITIES AN HAD TO DO DOSE REDUCTIONS AN I WOULD THINK THAT THEY PROBABLY DIDN'T HAVE AS GOOD AN EFFECT. WE HAVE SOME DATA, I DON'T HAVE TIME TO SHOW YOU THAT BUT MOLECULARLY THEY SEEM TO RESPOND BUT DOSES WERE REDUCED SO CLINICALLY DIDN'T WORK. IT WAS A STABLE DISEASE THAT LASTED 13 MONTHS AND ONE PATIENT WHO WAS HEAVILY PRE-TREATED BEFORE AND CAME HERE RELAPSE DISEASE WENT ON THE STUDY AND HE HAD WHAT WE CALL: A VERY GOOD PARTIAL REMISSION, VERY CLOSE TO COMPLETE REMISSION BUT WE COULD PICK UP A LITTLE PROTEIN WITH THE FIXATION ASSAY IN THE BLOOD. SO HIS DISEASE ALMOST JUST MELTED AWAY, WHICH IS WHAT'S AMAZING ON THE SINGLE DRUG. HE'S LISTED ON TOP. I'M GOING TO SHOW YOU A FEW D STAINS ABOUT THIS PATIENT. 52-YEAR-OLD GENTLEMAN, AFRICAN AMERICAN DESCENT, DIAGNOSED IN 2005 WITH IDG LAMB DA, HE HAD NINE GRAMS PER DECALITER, HE WAS ANEMIC WITH KIDNEY FAILURE ANALYTIC BONE LESION. HE WAS TREATED WITH COMBINATION THERAPY FOLLOWED BY HIGH DOSE (INDISCERNIBLE) WITH SUPPORT AND HE HAD A RESPONSE WHICH WAS VERY GOOD PARTIAL REMISSION, SAME MAGNITUDE WE SHOWED WITH OUR THERAPY. THREE YEARS LATER THE GENTLEMAN RELAPSED. HE'S END SPIKE WENT UP. HE UNDERWENT IMAGING WORK UP SHOWING MULTIPLE NEW LESIONS AND THERE WAS OUTGROWTH OF EXTRA MEDULLARY DISEASE IN RIGHT GROIN. HE WAS RETREATED AFTER THE PLASMA CYTOMA WAS REMOVED, THEN PUT ON (INDISCERNIBLE), WITH A COMPLETE REMISSION AND THEN STAYED FOR A LONG TIME. TWO YEARS LATER HE RELAPSED, HIS END SPIKE WENT UP AN NEW YOUTH GROWTH OF EXTRA MEDULLARY DISEASE. I'M TALKING ABOUT TODAY IN JULY HE WENT ON STUDY IN JULY OF 2010. SO SINGLE DRUG AFTER EPISODES I LIST ON THIS SLIDE. WE DID BONE MARROW 24 HOURS LATER. AS WE CAN SEE ON THIS SLIDE, THE MEK DRUG, THIS ORAL DRUG GIVEN ONCE IN THE MORNING, ONCE IN THE EVENING WHEN WE DID THE BONE MARROW THE NEXT DAY THE MEX INHIBITION DOWN REGULATED EXPRESSION BOTH OF MAF AS WELL AS ITS TARGETS GENES. YOU CAN SEE HOW CMAP GOES DOWN, INTEGRIN BETA 7 AND CHEMOKINE RECEPTOR 1. WHEN WE LOOKED AT INTRACELLULAR LEVELS OF HYPERPHOSPHORYLATED ERK ON BASE LINE WITH DAY 2 ON THESE SPEAKS HERE, WE SAW ALSO SIGNIFICANT DROPS IN THESE PATIENTS. THIS WAS DONE BY THE IMMUNOASSAY IN BUILDING 37. CLINICALLY WHEN WE MONITOR HIS M SPIKE WHICH WAS THE BIOMARKER FOR MYELOMA FOR THOSE NOT FAMILIAR WITH THAT YOU CAN SEE HOW THE ENSPIKE WENT DOWN TO 0-GRAMS PER DECALITER AFTER THE END CYCLES. WE HAD UNIT FBI FIXATION SO THAT'S WHY WE CAN'T CALL IT FORMALLY COMPLETE REMISSION AND WE USE VDPR, THERE WAS NO QUANTIFIABLE PROTEIN. AFTER THREE CYCLES, THIS GOLF BALL SIZE LARGE PLASMA CYTOMA IN RIGHT GROIN WAS GONE. HE WAS FEELING GREAT AND NORMAL BLOOD COUNT, HIS OTHER BLOOD COUNT NORMALIZED. HIS CBC NORMALIZED. AFTER 8 CYCLES ENSPIKE CAME BACK AN PLASMA CYTOMA STARTED TO COME OUT AGAIN IN GROIN AND STARTED TO FEEL A LITTLE FATIGUED SO THEN HE HAD TO GO OFF STUDY. WE TOOK OUT THE PLASMA CYTOMA AN TREATED IN LABORATORY. ON TOP IT STILL HAD THE OVEREXPRESSION OF PHOSPHORYLATED ERK AND AFTER SIX, 24 AND 48 HOURS THE LEVELS WERE DROPPED TO ZERO AFTER EXPOSURE TO THE DRUG. SO WE CAN TREAT THE PLASMA CYTOMA IN LAB BUT NOT ON THE PATIENT OBVIOUSLY. WE THEN CONDUCT AD MAP KINASE GENE EXPRESSION ARRAY INCLUDING MAP KINASE CAS CAITDS NOT INCLUDING THE MAP ERK PATHWAY BUT ERK 5 P-38 AND THE JUNK CASCADE. AS YOU CAN SEE ON THIS SLIDE I HAVE OVEREXPRESSION OF ADDITIONAL GENES THIS THIS PATHWAY. WE'RE LOOKING INTO THIS AS WE SPEAK SO I DON'T HAVE A LOT MORE INFORMATION BUT I THINK WHAT'S STRIKING HERE IS THAT MEK ERK PATHWAY IS STILL ACTIVE, IT'S STILL POSSIBLE TO DISRUPT IT AND WE SEE THERE IS GOOD RESPONSE BUT THERE'S OTHER THINGS BEING ACTIVATED, TUMOR IS BYPASSING ONCE WE'RE TRYING TO INTERRUPT HERE. WE HAVE FOUND IN THIS PATIENT ALLELIC DELETION OF RB-1 AND ALSO WE HAVE FOUND A 10% OF THESE CELLS, THEY HAVE ONLY ONE COPY OF P-53. SO THERE IS P-53 DELETION. REACHING OVER FROM THE TYPE OF EXAMPLE WE ARE WORKING ON WHEN IT COMES TO RATIONAL DRUG DEVELOPMENT, WE'RE LOOKING INTO MANY OTHER MOLECULES AND WE ARE TRYING TO DO THING BUS I'M JUST GIVING YOU A LITTLE APPETIZER HERE FROM EACH OF THESE THREE. SO EARLY MYELOMA, EARLY TREATMENT THAT'S ANOTHER WAY ONE COULD LOOK AT THE DISEASE LIKE MYELOMA. IF YOU DON'T THINK RATIONAL THERAPY WILL BE THE WAY ONLY, MAYBE TREATING LITTLE BIT EARLIER MAYBE TRYING TO GET AT THE DISEASE BEFORE WE HAVE FULL CLONAL EXPANSION COULD BE ANOTHER WAY OF DOING IT. MYELOMA IS REALLY FANTASTIC DISEASE IF ONE BELIEVES IN THAT CONCEPT BECAUSE WE HAVE THESE DEFINED PRECURSOR STATES. DR. KYLE AT THE MAYO CLINIC COIN IN 1978 MONOCLONAL UNDETERMINED SIGNIFICANCE AND IN 1980, SMALL MYELOMA. HE HAS SHOWN IN HIS SERIES OF PAIRNS WITH SMALL RING MYELOMA AVERAGE HAVE 10% ANNUAL RISK OF DEVELOPING MYELOMA. THE ANNUAL RISK FOR THOSE PATIENTS IS 1%. THESE ARE EPIDEMIOLOGICAL DATA IN THAT EACH PATIENT PROBABLY HAS DIFFERENT RISK THAN THIS AVERAGE 10% RISK. IN FACT THE MAYO CLINIC LOOKED INTO THAT AND HAVE USED BASIC CLINICAL THINGS, LOOKED AT THE NUMBER OF PLASMA CELLS, THE SIZE OF M SPIKE AN ADDITIONAL PROTEINS IN THE BLOOD, THE FREE LIGHT CHAINS AND THEY HAVE SHOWN IF YOU HAVE MORE THAN 10% OF PLASMA CELLS IN THE MARROW, GREATER THAN 3-GRAMS PER DECALITER AN ASKEWED LIGHT CHAIN RATIO THESE ARE RISK FACTORS AS HIGH AS 76% AT FIVE YEARS IN YOUR EPIDEMIOLOGICAL STUDIES. FOR THOSE PATIENTS WHO DON'T HAVE THREE, THEY HAVE ONLY ONE OF THEM YOU NEED TO HAVE 10% PLASMA MORE THAN 3-GRAMS TO HAVE SMALL RING, THAT'S PART OF THE DIAGNOSTIC CRITERIA, THEN THE RISK IS ONLY 25%. THE SPANISH STUDY GROUP HAVE USED OTHER MARKERS AND LOOKED FOR NUMBER OF CELLS IN THE MARROW ABNORMAL AS THE RATIO TO THOSE ABOVE NORMAL AND IF YOU HAVE MORE THAN 95% ABNORMAL PLASMA CELLS THAT ADVERSE IF YOU HAVE IMMUNEPHORESES SUPPRESSION OF NORMAL IMMUNE GLOBULINS, IF YOU HAVE AN IGG M SPIKE, IF IGA OR IGM OR BOTH ARE SUPPRESSED, THAT WOULD BE CONSIDERED TO BE IMMUNOPHORESES. THEN YOUR RISK COULD GO FROM 4% TO 72% AT FIVE YEARS FOLLOW-UP IF YOU HAVE 0, 12 OR HIGH RISK FACTORS. SO MYELOMA LESS THAN TWO YEARS, SO THESE ARE FACTS WE CAN DO THIS IN THE THE CLINIC. DWOA THIS A LOT WHICH I THINK WE CURRENTLY HAVE AROUND 100 SMALL RING PATIENTS FOLLOWENING BUILDING 10 AND WE HAVE PROBABLY BETWEEN 2 AND 5 PATIENTS CONTACTING US EVERY MONTH COMING AND GOING ON STUDIES. WE HAVE GOOD INFLUX OF PATIENTS. I WOULD LIKE TO HIGHLIGHT A FEW THINGS HERE, THE STUDIES ARE SMALL, 273 PATIENTS MAYO STUDY AND 89 PATIENTS IN THE STUDY FROM SPAIN, ALSO I WOULD LIKE TO HIGHLIGHT AROUND A THIRD OF PATIENTS FALL INTO EACH OF THESE THREE GROUPS. SO SMALL RING MYELOMA PER SE DOESN'T MEAN THAT ONE SIZE FITS ALL IN TERMS OF RISK. THE RISK IS DIFFERENT BECAUSE THEY FALL INTO THESE DIFFERENT GROUPSCH ONE THIR OF THE PATIENTS FALL INTO THESE GROUPS. I ALREADY MENTIONED HOW THE RISK RANGES FROM 25 TO 76% MAYO AND 4 TO 72% FOR SPANISH GROUP. HUGE DIFFERENCE. THE CURRENT CLINICAL GUIDELINES BY THE INTERNATIONAL MYELOMA WORKING GROUP UNDERGO BIOPSY, SHOULD BE IMAGED AND BLOOD WORK AND FOLLOWED 2 TO 3 MONTHS OVER TIME AND IF STABLE DONE A LITTLE LESS OFTEN WITH BLOOD WORK BUT MORE IMPORTANTLY, TREATMENT IS NOT INDICATED AS PART OF A CLINICAL TRIAL FOR CURRENT GUIDELINES THE ANSWER TO WHY THAT IS STILL THE CASE IS BECAUSE DRUGS HAVE BEEN VERY TOXIC AND ONCE WE USE THE DRUGS NO PATIENT WITH MYELOMA HAS BEEN ABLE TO BE CURED VIRTUALLY, MAYBE THERE ARE A FEW BUT VAST MAJORITY NOT. SO FOR THAT REASON THE GUIDELINES SAY WE SHOULDN'T DO IT BUT THE GAME IS CHANGING RAPIDLY, WE HAVE VERY, VERY EFFECTIVE DRUGS, WITH MINIMAL TOXICITIES. BASICALLY SEIBERT CLINICAL EFFECT THAN IF WE HAVE -- SO I THINK THE QUESTION HAS TO BE REVISITED. THE MOST RECENT VERSION OF THE GUIDELINES SAY THAT CLINICIANS SHOULD CONSIDER CLINICAL TRIALS TO SELECT PATIENTS WITH THE AIM TO DELAY AND PREVENT PROGRESSION INTO SIMILAR P TOMATIC MYLOMA. THIS IS A VERY INTERESTING OPPORTUNITY. SO WHAT'S THE CURRENT FOCUS ALONG THESE LINES? JUST AS A BASELINE HERE, I WOULD LIKE TO SAY THAT WE WANT TO ASK A FUNDAMENTAL QUESTION WHETHER THE MYELOMAS THAT WE SEE IN THE CLINIC ARE ALWAYS FROM THE POOL OF PATIENTS THAT HAD SMALL RING. WE WANTED TO KNOW THAT BECAUSE IF THAT'S THE CASE WE COULD START DEVELOPING STUDIES PROSPECTIVE NATURAL HISTORY DESIGN AND FOLLOW PATIENTS OVER TIME TO TRY TO UNDERSTAND HOW PATIENTS MAYBE ACQUIRE ADDITIONAL LESIONS OR IS THERE A DRIVER ABNORMALITIES FROM THE BEGINNING. SO IN ORDER TO ANSWER THE QUESTION IF MYELOMAS ARE PRECEDE BADE PRECURSOR STATE WE USE THE NIH BIOBANK FROM THE (INAUDIBLE) STUDY. THIS IS A VERY COOL RESOURCE, THIS IS FANTASTIC. 77,000 PEOPLE ARE ENROLLED, HEALTHY MEN AND WOMEN, BLOOD EVERY YEAR UP TO SIX YEARS AND DID MASSIVE SCREENINGS WITH IMAGING AND BLOOD TESTS AND BEYOND. THIS RESOURCE IS STILL AVAILABLE THE BIOBANKS ARE HERE, THIS IS A COOL THING FOR THOSE WHO ARE INTERESTED IN BIOMARKERS PROCEEDING CANCER DEVELOPMENT AND OTHER DISEASES. 71 PEOPLE DEVELOPED MYELOMA AND WE ASSAYED ALL INDIVIDUALS PRECEDING SAMPLES DRAWN UP TO SIX YEARS BEFORE. AS WE SEE ON THE LEFT NUMBER OF YEARS BEFORE MYELOMA, AND ON THE RIGHT PREVALENCE OF PATIENTS WHO DID HAVE EVIDENCE OF PRECURSOR DISEASE BEFORE. YOU CAN I THINK YOU CAN SEE HERE YOURSELF MYELOMA SEEMS TO BE CONSISTENTLY PRECEDED BY THESE PRECURSOR STATES SO ALMOST ALWAYS THERE. THAT COULD BE PATIENTS THAT DON'T HAVE THIS AND THERE COULD BE PATIENT WHOSE HAVE IT FOR A SHORT PERIOD OF TIME, THIS DATA IS STRIKING. WE ALSO LOOK FOR SOMETHING CALLED THE FREE LIGHT CHAINS AND WE SEE PATIENTS WITH BLOOD 8 YEARS BEFORE VERSUS TWO YEARS BEFORE AND I PICKED THESE ARBITRARILY SO I DIDN'T HAVE TO BOG YOU WITH DETAIL BUS MESSAGE IS EIGHT YEARS BEFORE, 35% OF THE PATIENTS HAD SKEWED LIGHT CHAINS AND TWO YEARS BEFORE, 85% HAVE SKEWED LIGHT CHAINS. SO USING A BLOOD BASED MARKER SUCH AS HIEG CHAINS ALLOWS US TO SEE THAT THERE IS CLEARLY SOMETHING GOING ON BEFORE MYELOMA IS GOING TO HAPPEN. ALONG THE SAME LINES WE LOOK AT THE CON TRAITION OF THE SPIKES AND -- CONCENTRATION OF THE SPIKES. MEDIAN CONCENTRATION WAS 0.9-GRAMS PER DECALITER AN AS BLOOD DRAWS WERE DONE SUBSEQUENT TO MYELOMA DIAGNOSIS YOU CAN SEE THE IMMEDIATE YAP CONCENTRATIONS GO UP. THAT'S SIGNIFICANT. THE P VALUE IS 0.025. I GUESS THAT LOOKS CONVINCING. HOWEVER, IF YOU LOOK AT INDIVIDUAL PATIENTS YOU NOW SEE THAT THERE ARE PATIENTS MUCH MORE HAVE HIGHER INCREASE IN SLOPE AND - PATIENTS THAT ARE FLAT. AROUND 50% OF THE PATIENTS HAVE SPIKES GOING UP DRASTICALLY EVOLVING RIGHT INTO MYELOMA. SO EVERY YEAR THE N SPIKE INCREASED. BUT 50% PATIENTS COULD HAVE LIKE 1.2, 1.2, 1.2, 1.2 AND THEN HAVE MYELOMA SO THEY HAVE NON-EVOLVING M SPIKES. SO 50% OF THE PATIENTS END UP IN EACH OF THESE CATEGORIES. WHY IS THIS, IS THERE A SWITCH IN GENETIC SWITCH IN THE TUMOR? CHANGING THE HOST -- CHANGES IN CONTROL AND MICROENVIRONMENT OR IS THERE A COMBINATION OF THESE? DO THESE PATIENTS RESPOND DIFFERENTLY TO THERAPY, ARE THEY ENTIRELY DIFFERENT, SHOULD THEY BE PREET TREETED IN A DIFFERENT FASHION, ET CETERA? ALL THESE QUESTIONS WE DONE KNOW THE ANSWER TO. BUT WE'RE LOOKING INTO THIS AS WE SPEAK. WE HAVE LAUNCHED THE PERSPECTIVES STUDY IN MAY 2010 AND ENROLLED 160 PATIENTS AT THIS TIME. IN BUILDING 10. WE SEE PATIENTS BASELINE 6, 12 MONTHS, WHEN THEY COME WE DO BONE MARROW, IMAGING, BLOOD WORK, WE DO FLOW, WE DID WORK UP OF THESE PATIENTS AND PROVIDE WITH ALL THE BEST CLINICAL WORK UP THAT'S POSSIBLE TO DO INCLUDING EVERYTHING SHOWN SO FAR WITH THE SPANISH AND MAYO CRITERIA, ET CETERA. AS PART OF THE O SECONDARY OBJECTIVE STORE BLOOD BONE MARROW AN URINE. WE HAVE SET UP PROCEDURES SO WE SORT ALL THE BONE MARROW, WE HAVE 138 POSITIVE NEGATIVE CELLS, WE HAVE THE SUPERNATANTS AND WE ALSO PROCESS THE BLOOD. USING THIS FOR THE RESOURCES WE'RE DOING. SO WE ARE RIGHT NOW IN THE PROCESS WORKING WITH LOU STAWT USING GENOME SEQUENCING RNA SEEK TO DEFINE MECHANISTIC PROGRESSION, WE HAVE 50 PATIENTS WITH SMALL RING MYELOMA WHO WENT ON THE STUDY AND 5 OR 6 PATIENTS AT THIS TIME HAVE ALREADY PROGRESSED SO WE HAVE THE PAIRED SAMPLES. WE HAVE EXTRACKED RNA INFORMATION BACK FROM FREDERICK THIS WEEK THEY HAVE NOT SET UP THE LIBRARY FOR THESE PATIENTS SO WE HOPE TO HAVE THE RNA SEEK RESULTS HOPEFULLY IN A FEW WEEKS SO WE CAN ANALYZE IT. WE SEE THESE AS A PLATFORM TO DISCOVER SOMATIC MUTATIONS, CHROMOSOMAL TRANSLOCATIONS WITH THE AIM TO DEFINE TREATMENT TARGETS. THAT'S WHY WE DO IT SO WE STUDY BIOLOGY BUT LOOKING FOR TREATMENT TARGETS. I MENTIONED THIS BEFORE, ULTIMATELY OUR GOAL WOULD BE TO I WOULD THINK PROBABLY PREVENT BUT DELAY MYLOTHAT,iiy THAT WOULD ALSO BE PRETTY GOOD. SO WE'RE VERY EXCITED ABOUT THIS. OF COURSE A LOT OF OTHER O THINGS THAT WE ARE PLANNING ON DOING GENOME SEQUENCING, WE ARE DOING DISCOVERY WORK WITH MICRORNA CYTOKINES AND ALL THE PROTEOMICS ET CETERA. BUT WE DECIDED THE TO FOCUS ON RNA SEEK AS THE FIRST STEP AND WE'RE ENROLLING A LOT OF PATIENTS SO A NUMBER OF PATIENTS WILL INCREASE AND ALSO UNFORTUNATELY IF YOU FOLLOW MANY PATIENTS THERE WILL BE MORE PATIENTS THAT DEVELOP MYELOMA AN PARTICIPATE IN THE STUDY WITH PAIR SAMPLES AS WELL. WE'RE NOT JUST WATCHING ALL THEE THINGS AN WAITING FOR THE RESULT TO COME BACK WITH TARGETS, WE STARTED TO THINK HOW WE COULD TREAT THESE PATIENTS WITHOUT KNOWING MOLECULAR TARGETS WE'RE LOOKING FOR STRATEGIES WITH EXPERTISE FROM OTHER AVENUES IN MULTIPLE MYELOMA. WE HAVE HIGH RIS SMAM RING THAT HAVE TWO YEARS AVERAGE TIME TO DEVELOPMENT, AND JUST THINKING AB THEE THINGS ONE COULD COME UP WITH THESE THREE MAJOR APPROACHES. SO IF YOU DONE DO ANYTHING WE HAVE FUM BLOWN MYELOMA, WE ALREADY KNOW ABOUT ON THE LEFT. IF WE CAN DELIVER A DRUG TO CONTROL THE DISEASE, HIGH BLOOD PRESSURE, THINGS LIKE THAT, WE COULD HAVE SOME TYPE OF LONG TERM DISEASE CONTROL, CONVERT MYELOMA INTO CHRONIC DISEASE STATE. THAT'S RESIDUAL DISEASE BUT FUNCTIONALLY THE PATIENT IS CURED. THE DISEASE IS THERE BUT WE COULD CONTROL IT. THE OTHER APPROACH IS TO GO FOR THE ELIMINATION, REMISSION, ERADICATING THE DISEASE. NOT SURE WE WOULD EVER GET THERE BUT THAT WOULD I GUESS BE ONE EXTREME TO GOAL TO TRY TO REACH. SO WHAT ARE WE DOING RIGHT NOW AS WE SPEAK IN BUILDING 10? ONE THING WE'RE DOING IS WORKING WITH RICH CHILES AT THE NHLBI AND HIS GROUP WITH GREAT INTEREST IN NK CELLS USING STRATEGY WE'RE HOPING NK CELLS GO AFTER THE MYELOMA CELLS. WE ALREADY KNOW THAT HAPPENS. BECAUSE THEY CAN RECOGNIZE TUMOR ANTIGENS ON THE SURFACE OF MYELOMA CELLS BUT WE ALSO UNFORMATLY KNOW THESE TUMOR CELLS EXPRESS ONE LIGAND, THERE ARE KEY LIGANDS TO TRIGGER INHIBITORY RECEPTORS. THE IMMUNOGLOBULIN LIKE RECEPTORS WHICH DEACTIVATE THE MYELOMA KILLING. WE KNOW THIS. BEFORE WE KNOW THE SETTING OF ALLOGENEIC TRANSPLANT THAT IF THERE IS A SLIGHT MHC MISMATCH BETWEEN DONOR AND RECIPIENT, THE KEY CELLS THEY CANNOT RECOGNIZE THE CURE ANTIGEN THE TUMOR CELLS EXPRESS BECAUSE OF THIS GENETIC DIFFERENCE. SO IN THIS SETTING THE NK CELLS MAINTAIN THEIR ANTITUMOR EFFECT AND THIS HAD BEEN PROPOSED TO BE ONE OF THE LEADING CAUSES WHY ALLOGENEIC TRANSPLANT HAS ACTIVITY IN MYELOMA AND OTHER DISEASES AS WELL. SO USING THIS AS A RATIONAL APPROACH, WE HAVE BEEN WORKING IN LABORATORY TO BLOCK THESE KEY RECEPTORS AND WE HAVE SEEN WE CAN KILL OFF MYELOMA CELL LINES USING NK CELLS, BASICALLY TRYING TO MIMIC THE MISMATCH SITUATION BY BLOCKING THESE RECEPTORS WE HAVE TRANSLATED THIS INTO A CLINICAL STUDY AND WE HAVE LAUNCH AD STUDY OF PHASE 2 STUDY DEVELOPED ENTIRELY BIOCELLS. WE HAVE TREATED SO FAR NINE PATIENTS. THESE ARE PATIENTS THAT HAD THE BEST RESPONSE SO FAR. ON TOP YOU SEE FROM LEFT H AND E, CD 138 AND KAPPA AND DA, KAPPA MEANS YOU HAVE KAPPA POSITIVITY AND LAMB DA MEANS IN THIS CASE NEGATIVITY SO WE SEE 30, 40% CD 138 POSITIVE PLAZ MANY CELLS. HERE ARE SMALL RING MYELOMA CELLS, 30, 40% BASELINE. AFTER SIX SAKE CYCLES OF THE DRUG, THESE PATIENTS ON THE BOTTOM YOU CAN SEE HOW THE CD 138 AND KAPPA STAININGS ARE MUCH LESS PRONOUNCED THERE. IS A DROP MAYBE TO NOT SURE MAYBE 20 OR SO PERCENT. N SPIKE FROM ONE TO 8-GRAMS PER DECALITER AT STARTING POINT AND AFTER SIX CYCLES THE N SPIKE GOES TO 1.2-GRAMS PER DECALITER. THIS IS THE BEST RESPONSE WE HAVE SEEN SO FAR. OTHER PATIENT VERSUS STABLE DISEASE EXCEPT ONE THAT HAS A PROGRESSION TO MYLOMA. THESE ARE INTRIGUING RESULTS AND WE'RE WORKING TO FOLLOW-UP ON THIS. WE HAVE ALSO DONE EXVIVO EMPERIMENTS FROM THESE PATIENTS BY DOING BLOOD DRAW. WE HAVE TAKEN OUTPATIENTS NK CELLS, WE HAVE MYELOMA CELL LINES MATCHED TO THE PATIENTS HLA TYPE AND WE HAVE EXPOSED MYELOMA CELL LINES TO PATIENTS NK CELLS DRAWN OVER TIME AND IN RELATION TO EXPOSURE TO THE*: DRUG. WE SHOW NK CELLS HAVE INCREASE ANTI-MYELOMA ACTIVITY AS WE KEEP ONGOING. I DON'T HAVE THOSE SLIDES HERE BUT WE HAVE DATA SHOWING THAT 70 TO 80% CIRCULATED NK CELLS IN THE PERIPHERAL BLOOD THEY HAVE ANTIBODY BOUND TO ITS TARGETS SO WE KNOW THE DRUG BINDS TO THE TARGETS, I SHOW M SPIKES GOING OWN, I KNOW IS PLASMA CELL PERCENT IS GOING DOWN AND EXVIVO RESULTS. ONLY ONE OF NINE PATIENTS RESPONDED SO ONE SIZE DOESN'T FIT ALL. THESE ARE INTRIGUING RESULTS AND WE'RE WORKING TO MOVE THE PROJECT FURTHER. ANOTHER PROJECT WE'RE WORKING ON IS ON A PROTOSOME INHIBITOR. WE KNOW FROM THESE EMPIRICAL STUDIES THAT PROTOSOME INHIBITION IS EFFECTIVE IN MYELOMA. IT WAS APPROVED BY THE FDA IN 2003. UNFORTUNATELY IT HAS A LOT OF SIDE EFFECTS IN TERMS OF NEUROPATHY. 50% OF PATIENTS HAVE APRIL RFA NEUROPATHY AND 15% HAVE GRADE 3 NEUROPATHY AS INTRAVENOUS INJECTION PER THE INITIAL FDA SUBMISSION. THIS IS THE SECOND GENERATION PROTOSOME INHIBITOR, NOT YET APPROVED BY THE FDA. IT'S A TETRA PEPTIDE HYPOXIDE BASED INHIBITOR. IT'S DIFFERENT IN THAT IT IS AN IRREVERSIBLE INHIBITOR, HIGHER DEGREE OF INHIBITION. DECREASED NON-SPECIFICKEST RACE BEHINDING AND SIGNIFICANTLY LESS NEUROPATHY. THERE HAVE BEEN MORE THAN 1,000 PATIENTS EXPOSED TO THE DRUG AT THIS TIME AND MOST HAD PRELAPSED PATIENTS. LESS THAN 1% DEVELOPED NEUROPATHY. THAT SEEMS TO BE A MAJOR DIFFERENCE. THE RESPONSES ARE VERY GOOD. THIS IS THE ONLY ONGOING STUDY IN U.S. AND WORLDWIDE AT THIS TIME USING THESE DRUGS FOR NEWLY DIAGNOSED MYELOMA PATIENTS LED BY DR. CORDER AND OUR TEAM. THESE ARE FROM THE THREE FIRST PATIENTS THAT HAVE ACHIEVED COMPLETE REMISSION. WE HAVE 8 PATIENTS ENROLLED. WE ENROLLED PATIENT NUMBER NINE YESTERDAY AND NEXT WEEK WE'LL ENROLL 10 AND 11. SO THIS STUDY LOOKS VERY GOOD AND I'M SHOWING YOU THIS DATA BECAUSE I WANT TO SHOW YOU HOW SUPEREFFECTIVE THESE DRUGS ARE. ON TOP YOU SEE PATIENTS 1, 2, 3 AT BASE LIE THE WHOLE MARROW ON THE LEFT IS FILLED WITH TUMOR, PROBABLY 80 OR MORE PERCENT BONE MARROW HAD TUMOR. IN THE MIDDLE MAYBE 50% AND ON THE RIGHT 20 OR 30%. PAICIALT HAD NORMALIZED BONE MARROWS. WHEN WE RAN FLOW LED BY (INDISCERNIBLE) AND GROUP ALL THESE PATIENTS WERE COMPLETELY NEGATIVE SO MINIMAL RESIDUAL DISEASE NEGATIVE. MRD NEGATIVE. EAR USING THESE NEWLY DIAGNOSED MYELOMA PATIENTS IN BUILDING 10 WITH REALLY GOOD RESULTS. SO WE'RE THINKING CAN WE USE THIS APPROACH AND CAPITALIZE ON THIS WHOLE THINKING OF TREATING EARLIER. SO WE HAVE SET UP A STUDY THAT WILL OPEN PROBABLY THE FIRST WEEK OF MAY. IT WILL BE THE FIRST MULTI-DRUG STUDY FOR SMALL RING MYELOMAjT> QUESTIONS. MAYBE I SHOULD START. SO YOU ALLUDED BRIEFLY TO THE HETEROGENEITY OF THE GEOGRAPHIC HETEROGENEITY OF THE DISEASE AND IMPLIED THERE MIGHT BE MOLECULAR HETEROGENEITY AS WELL. THERE'S OBVIOUSLY A FLURRY OF PUBLICATIONS ABOUT HETEROGENEITY IN SOLID TUMORS DOING SEQUENCING AND SO ON. DO YOU THINK DATA TO SUGGEST THAT WITHIN ONE PATIENT THERE MIGHT BE EVIDENCE OF SMOLDERING DISEASE AND MORE ADVANCED DISEASE AND MOLECULAR MARKERS THAT WOULD DRAMATICALLY CHANGE THE WAY YOU TREAT THOSE PATIENTS? >> >> ARE YOU ASKING IF THERE'S EVIDENCE OF HETEROGENEITY IN SINGLE PATIENTS. WE DO NOT YET HAVE TREATMENT TRIALS, WE'RE COLLECTING FROM THE STUDY WE'RE (INDISCERNIBLE) WE ARE DOING SEQUENCING BASELINE AND IF THERE ARE PATIENTS THAT RELAPSE LATER WE WILL LOOK FOR THAT. SO WE HAVE SET OUT TO DO IT. WE ARE DOING IT AS WE SPEAK IN THE SMOLDERING SETTING TO SEE IF THERE ARE ACQUIRED CHANGES OVER TIME SO THAT WE'RE DOING. THERE'S DATA FROM THE MAYO CLINIC IN ARIZONA BY DR. STEWART AND OTHERS. HAS BEEN PRESENTED AT ASH AND OTHER MEETINGS RECENTLY SHOWING THAT IN SINGLE PATIENTS I THINK THEY HAVE DONE ONE PATIENT VERY CAREFULLY, DIFFERENT SIZES OF SUB CLONES IN THE SAME PATIENTS. THEY HAVE TREATED AND WHEN THE PATIENT SUBSEQUENTLY RELAPSED THEY REDID ALL THESE ANALYSIS. THEY SHOWED UP TO SEVEN LINES OF THERAPY THAT USE PIE CHARTS TO ILLUSTRATE THE SIZE OF DIFFERENT CLONES AND THE SHORT VERSION IS THAT THE CLONE THAT WAS VERY SMALL IN THE BEGINNING, THAT WAS THE ONE, THAT WAS 100% IN THE VERY END, WHEN THE PATIENT ALSO DEVELOPED PLASMA CELL LEUKEMIA. THAT'S NOT YET PUBLISHED BUT THEY HAVE PRESENTED THAT AT MEETINGS. SO THERE IS HUGE DIVERSITY TO BEGIN WITH. I GUESS WHAT I'M PROPOSING AND TRYING TO BE SELF-CRITICAL HERE ALSO, WHEN WE ARE TREATING VERY EARLY ON, COULD THAT BE DANGEROUS? MAYBE. COULD IT BE BENEFICIAL? COULD IT BE BEFORE THE DISEASE HAS BECOME SO SUPER HETEROGENEOUS, MAYBE BUT IF YOU DON'T DO EXPERIMENT WE WILL NEVER KNOW THE ANSWER. DOING IN A CONTROL FASHION WITH MOLECULAR MARKERS AND IMAGING, THAT'S THE ONLY WAY TO DO IT. THAT'S WHY WE HAVE SET UP OUR STUDY TO DO WHAT I TRY TO EXPLAIN HERE. >> COULD YOU GO TO THE MICROPHONES BECAUSE PEOPLE ARE LISTENING AT A DISTANCE. >> I'M CONDONING THE FIRST AND SECOND PARTS OF YOUR TALK. DO YOU HAVE ANY DATA ON SENSITIVITY OF PRE-CURSOR CELLS FROM THE SMOLDERING STATE OR THE TO SOME OF THESE TARGETED AGENTS COMPARED TO THE SENSITIVITY OF FULL BLOWN MULTIPLE MYELOMA CELLS TO THE SAME AGENT? >> WE HAVE NOT DONE ANY -- >> IN IN VITRO. >> WE HAVE NOT DONE IN VITRO EXPERIMENTS. ON A CLINICAL NOTE THE ANSWER TO THAT SNOW. ON A CLINICAL NOTE IN MY EXPERIENCE AND ALSO BASED ON DATA FROM SPAIN THAT THERE ARE CURRENTLY THAT'S AN ONGOING STUDY WITH IMAGE RANLAMID. PATIENT WHOSE HAVE MORE EARLIER STAGES OF DISEASE SUCH AS SMALL RING IS IT TAKES LONGER TO HAVE A RESPONSE TO RANLAMID COMPARED TO MORE AGGRESSIVE DISEASE. ONE MORE -- OR MORE ESTABLISHED DISEASE. ALSO I THINK PATIENTS WHO HAVE VERY AGGRESSIVE NEWLY DIAGNOSED MYELOMA VERSUS INDOLENT MYELOMA SEEM TO HAVE DIFFERENT RESPONSES TO DRUGS. AT THE SAME TIME THEY HAVE SHORTER TIME TO RELAPSE SO IF YOU HAVE HIGH PROLIFERATIVE DISEASE MORE LIKELY TO RESPOND TO THERAPY AND MORE LIKELY TO RELAPSE. SO JUST ON A CLINICAL GUT FEELING NOTE, THAT'S FOLLOWS THE SAME TRAJECTORY BUT WE HAVE NOT DONE SENSITIVITY ANALYSIS IN THE LAB. >> DO YOU THINK THAT SUCH IN VITRO COMPARISONS COULD BE USEFUL IN SELECTING APPROPRIATE THERAPIES FOR THESE PRECURSOR LESION? >> ABSOLUTELY A VERY INTERESTING AVENUE TO PURSUE.H >> SO I WANT TO GO BACK TO THE CLINICAL TRIAL WITH THE AZZD INHIBITOR. SOME PATIENTS THAT HAVE RAS MUTATIONS EITHER HAVE RESPONSE AND SOME DON'T. SO IS THERE A CORRELATION BETWEEN RESPONSE TO THE EXTENT OF ERK INHIBITION AS YOU SEE FROM THE NANOPHOSPHOPROTEIN ANALYSIS? THE QUESTION IS LIKE ARE THE PATIENTS RESPONDING TO AZD 6244 THE ONES THAT ARE STILL REMAINING ADDICTED TO THE MAP KINASE PATHWAY? >> SO THE PATIENTS THAT HAD A RESPONSE, THEY HAD HIGH LEVELS OF PHOSPHOERK 1 AND 2 BASELINE AND THEY ALL DROP DOWN AT 24 HOURS WHEN WE DID THE BONE MARROW BIOPSY BUT THE SAME ASSAY I JUST SHOWED YOU. THERE WERE OCCASIONS IN THE NON-RESPONDING GROUP CLINICALLY NON-RESPONDING GROUP THAT HAD SIMILAR PATTERNS BUT AS I MENTIONED THOSE PATIENTS THERE WERE SOME PATIENT THERE IS WHO HAD SIDE EFFECTS SO WE HAD TO DO DOSE REDUCTION. SO I DON'T KNOW THIS BUT I WOULD THINK THAT MOLECULARLY SUSCEPTIBLE TO IT BUT THEY COULDN'T TOLERATE THE DRUG. ALSO THERE WERE PATIENT WHOSE HAD THE ACTIVATING MUTATIONS TRANSLOCATIONS. THAT DIDN'T HAVE HIGH LEVELS OF PHOSPHOPHOSPHOERK 1 OR 2 SO MULTIPLE PATTERNS. I WAS HOPEFUL WHEN WE DID THE STUDY THAT WE SHOULD HAVE 37 PATIENTS VALUABLE TO THESE ASSAYS BUT AS I SHOWED YOU WE HAD ONLY 12 AND 8 WERE IN BUILDING 10. SO WE'RE WRITING UP THE MANUSCRIPT AS WE SPEAK ON THE 12 PATIENTS. BUT WE ARE NOW TRYING TO DEVELOP A NEW STUDY ON NIH BUILDING 10 STUDY ONLY, WE'RE HOPING TO GENERATE MORE SOLID DATA. I THINK THE ANSWER IS WE NEED LARGER SAMPLE SIZE TO LOOK FURTHER INTO THAT. THAT'S WHAT WE'RE HOPING TO DO. >> LET'S THANK DR. LANDGREN FOR A VERY STIMULATING LECTURE. [APPLAUSE] >> I'M SURE THAT HE'S WILLING TO STAY A LITTLE BIT IF YOU HAVE QUESTIONS THAT YOU WOULD LIKE TO ASK HIM ONE ON ONE.