By Jennifer Ahlstrom | Posted - Jan 4th, 2014

 

 

 

 

Myeloma Highlights from ASH 2013 in New Orleans - December 6-10, 2013

BY JACK AIELLO, MYELOMA SURVIVOR

PREFACE

This is my 8th year attending ASH (American Society of Hematology), where over 20,000 attendees from all over the world (hematologists/oncologists, lab researchers, scientists & 300 pharma companies) present latest research results via both oral presentations (1000) as well as posters (3000) on all blood cancers. This year there were 835 abstracts ( >100 clinical) on myeloma alone, many of which were selected for oral presentation. Rather than attending talks on Biology, I typically focus on the Clinical Trials, which I’m able to understand and are more relevant near-term to patients. Even at that, there are overlapping multiple myeloma oral sessions as well as 4’x6’ posters without reprints, so it’s always possible that I have not included something of interest to you or made a typo because I can’t read my own writing as detailed powerpoint slides are presented quickly. You might want to view the published abstracts at www.hematology.org and various press releases. [I’ve listed Day-Abstract#-Lead Investigator after the trial results, e.g. {Mon-405-M.Dimopoulos}.] There are other ways to learn more about results from this conference. The IMF and Patient Power were conducting video interviews of multiple myeloma experts for postings on their site. Some have also scheduled webinars (MMRF 12/18/13, IMF 1/16/14) which you can listen to live or by replay. You’ll also find some patient blogs (including mine) posted on the IMF website. And all of us in the SF bay area should attend the Emerging Therapies-LLS ASH Review Jan 25, 2013 in SF( call 866-450-0669 to register). Dr. Jeff Wolf of UCSF will do a great job presenting the latest information. Presentations and posters of clinical trial results follow the same format: Background, Goal, Treatment plan, Patient Characteristics & Cohorts, Responses (include high-risk cytogenetics), Toxicity (hematological and non-hematological), Conclusion, and Next Step. Remember, the goal of Phase I (typically handful of patients) is to determine “Maximum Tolerated Dose”; Phase I/II and II (typically 25-75 patients) continues to measure dosage escalation and safety while looking at responses; and finally Phase III (several hundred patients) compares response rates between new and current treatments. Treatment schedules are defined for stages of Induction, and optionally Transplant, Consolidation, and Maintenance with specified Randomization along the way; dosage amounts and scheduling are provided for each drug along with optimum number of treatment cycles (typically 28 days). Risk stratification correlates various techniques such cytogentics and FISH analysis (e.g. chromosome deletions and translocations) gene-expression profiling (GEP) and flow cytometry with patient responses.

OVERALL IMPRESSIONS

  • Monoclonal Antibodies This seems to be the next area beyond Proteasome Inhibitors (e.g. Velcade) and IMIDs (e.g. Revlimid) that will yield targeted drug therapies. Daratumumab, Elotuzumab, and SAR650984 are already in trials but I saw others which have showed success in the labs and mouse models that are heading to Phase 1 clinical trials. These monoclonal antibodies are designed to attack a specific antigen expressed by the Myeloma cell, thus causing cell death. Might we see a PI-IMID-mAb combination?
  • Fit/Unfit/Frail A way of using age, comorbidities (e.g. diabetis, cardio disease), and physical disabilities (e.g. arthritis) that will help determine a best treatment for older patients while focusing on quality of life.
  • Smoldering Multiple Myeloma (SMM) There's a belief that, like other cancers, earlier treatment means longer term success. While the standard treatment for SMM (M-spike >= 3g/dL and/or plasma% >= 10% but no CRAB damage) is watch-and-wait, there's a portion of SMM patients that are high-risk (defined as “and”, high free light ratio or flow cytometry that analyzes plasma cells and results in median time to progression to multiple myeloma < 2 years) and will likely progress to full-blown multiple myeloma within a couple of years. Perhaps treatment for high-risk SMM patients can significantly delay the on-set of myeloma, thus preventing earlier organ damage. Treatment regimens such as Rev-only, Rev-dex, and Cfz-Rev-dex are all being studied in high-risk SMM. Perhaps multiple myeloma will be redefined to include high-risk SMM and both will be treated the same.
  • Cytoxin instead of Melphalan Since Cytoxin is less likely to damage your bone marrow and blood counts, several presenters recommended using Cytoxin as the alkylating agent in treatment rather than Melphalan. For example, CyBorD (Cytoxin-Velcade-dex) would be a better choice than MVP (Melphalan-Velcade-Prednisone).
  • So many options In general better responses result in better survivals. The list of treatment options since last year's ASH continues to grow now that we have Carfilzomib and Pomalidomide, although I’ve listed new patient treatments involving these drugs under the “New drugs” category since they are only approved for relapsed/refractory patients. There are clinical trials for every diagnosis phase...smoldering through high-risk myeloma, newly diagnosed through relapsed/refractory. Trials are so important because that's how we move possible treatments and new drugs. Perhaps you want to ask your multiple myeloma doc if there's a trial that's beneficial for you.
  • Maintenance This is still a hot topic. Most agree that maintenance (a better name might be "continued treatment") improves progression-free survival. But does it extend overall survival? More maintenance studies are necessary before there's full agreement on the benefit.

Of course, there are still so many unanswered questions such as:

  • Best treatment for me as a newly diagnosed or relapsed/refractory patient? What if I’m standard or high-risk [del 17, t(4;14), t(14;16) about 20% of patients]?For transplant-eligible,do it now, later or never?
  • Length and type of maintenance? Yet, I’m very encouraged by the continued progress to understand everything about multiple myeloma, determine new MM cell targets, and learn what treatments work best.

COMMENTS I FOUND PROVOCATIVE

  • “Maintenance is really Continued Treatment.” A. Palumbo, Italy. Or stated another way “Maintenance after a stem cell transplant removes the allure of a treatment-free benefit.” S. V. Rajkumar
  • Discussing whether or not to do a transplant, S. Kumar (Mayo) said “While a stem cell transplant can clearly help some patients, we don’t know who they are.”
  • O. Landren suggested that one might think of Myeloma as a metastatic disease that evolves from a Solitary Plasmacytoma (passing through the MGUS and SMM phases).
  • “While all treatments are available to Fit patients, dose reduction should be considered for Unfit patients while those who are Frail prefer oral meds and should avoid melphalan.” M-V. Mateos (Spain) A. Palumbo (Italy) categorized older patients via a geriatric assessment and suggested that Fit patients use 3-drug combinations, Unfit use 2-drug, and Frail use dose-reduced 2-drug regimens.
  • More on Maintenance: “The benefit of Revlimid maintenance is an early benefit so one can stop after 2 years.” M.Attal. While P.Singh said “We don’t know the subset of patients who will benefit most be Revlimid maintenance.” To summarize, “We still need more study on maintenance.” P. Richardson

TREATMENTS FOR NEWLY DIAGNOSED PATIENTS

  • This plenary session (a required session) attended by 10, 000 examined a Phase 3 trial results for 1623 (!) patients at least 65 years old randomized into 3 study arms: (A) Rev-dex until disease progression; (B) Rev-dex for a fixed 18 cycles (72 weeks); and (C) Mephalanl-Prednisone-Thalidomide for a fixed 12 cycles (72 weeks). The overall response rate (ORR) % was (75-73-62) respectively, progression free survival in months (26-21-21) and Median 4-yr overall survival % (59-56-51) appear close. However, there were differences. For example, progression free survival curves for (A) and (B) were very close through 18 months but then the curve separation became apparent and expanded. And while Arms (A) and (B) both had about 28% grade 3-4 neutropenia (low white count), Arm (C) had 45%. {Sun-2-T.Facon}
  • Outcomes for Velcade-Cytoxin-Dex (CyBorD) versus Velcade-Revlimid-Dex (VRD) were examined. Besides comparable progression free survival (PFS) (70% vs 68% at 2 yrs) and overall survival (OS) (92% vs 85% at 2yrs), cost was also analyzed. The cost for 4 cycles of  CyBorD versus VRD was $37K vs $67K. {Sun-3178-S.Kumar}
  • Another poster for CyBorD induction determined that 81% of standard risk patients are alive at 5 years. {Sun-3192-C.Reeder}
  • This poster examined patient (n=283) responses to Revlimid in newly diagnosed patients with and without continuous therapy. It demonstrated that patients stopping Revlimid after 1 year and achieving a VGPR or better can result in long-term (4 yrs) disease control and can be considered a treatment strategy.{Sun-3209-T.Kourelis}
  • A Phase 2 study compared sequential (9 + 9 cycles) versus alternating (18 cycles) treatments of VMP and Revlimid. After 18 cycles, 60 vs. 69% objective response rate (ORR) but after 20 months overall survival and progression free survival were similar. Adverse events were also similar. High risk patients responded similarly to standard risk patients. {Mon-403-M-V.Mateos}

TREATMENTS FOR RELAPSED/REFRACTORY (R/R) PATIENTS

  • Bendamustine-Vel-Dex (BVD) in 73 elderly patients in first relapse provided a high overall response rate (ORR) 70% and complete response (CR) 14%. {Sat-1971-P.Rodon} In another Phase 2 study of 70 relapse/refractory myeloma patients, BVD showed 77% overall response rate (20% complete response, 20% very good partial response, and 37% partial response) {Sat-1974-M.Offidani}
  • Bendamustine-dex-Rev (BdL) in a Phase 1/2 for 37 patients showed a 45% overall response rate (including an 11% complete response), 74% 1-yr overall survival, and 45% 1-year progression free survival. {Sun-3212-S.Pozzi}
  • Phase 1/2 trial (n=21) of Rev+Cytoxin (Endoxan)+Pred (REP) in 100% Revlimid-refractory patients (76% also refractory to Velcade) showed 67% overall survival, 6 month progression free survival and 16 month overall survival.
  • Pom-Dex-Doxil in a Phase 1/2 trial demonstrated early overall response rate (ORR) of 22% for Rev-refractory patients. {Sun-3218-J.Berenson}
  • Pom-dex for high-risk patients with 17del [a] and/or t(4;14) [b] produced: 1) 22% overall response rate (32% [a]; 16% [b]); 2) duration of response 6 months (8 [a]; 2 [b]); and 3) median overall survival of 12 mos (12 mos [a]; 9 mos [b]), so Pom-dex is more beneficial for 17del than t(4;14). {Mon-689-X.Leleu}
  • Good results from two early trials Pom-Vel-Dex (PVD) for patients resistant or refractory to Revlimid and Velcade-exposed (Richardson) have been incorporated in a Phase 3 trial comparing PVD with Velcade-Dex. {Sat-1969-P.Richardson, Sat-1940-J.Mikhael}
  • This Phase 1/2 trial analyzed Carfilzomib-Pom-dex for relapsed/refractory and prior Velcade patients (n=67), which resulted in a 70% overall response rate (ORR) (28% >= very good partial response rate) and median progression free survival and overall survival of 12 and 16 mos. Responses were similar for high-risk 17p deletion patients. {Mon-690-J.Shah}

TRANSPLANTS

  • This study examined stem cell transplants (SCT) in age groups (A) > 70, (B) 60-69, and (C) 18-59 yrs of age for more than 1200 patients. Three-year overall survival (OS) and progression free survival (PFS) were 72/33%, 75/38% and 78/42% respectively. In summary, survival differences are driven partly by higher co-morbidities and lower post relapse survival. {Mon-416-M.Sharma}
  • This interim randomized study (n=47) compared Rex-dex (8 cycles) versus Rex-dex (4 cycles) + stem cell transplant (SCT), both followed by 2 years of Revlimid maintenance. After 3 years of analysis, while the stem cell transplant had a better overall response rate (ORR) (77 vs 96%), this didn’t translate into significant differences in median progression free survival (25 vs 17 months) or overall survival (not yet reached vs 58 months). {Sun-3180-S.Lentzsch}

MAINTENANCE (including CONSOLIDATION)

  • In this long-term study, PFS2 (progression free survival plus next line therapy) was examined for regimens MPR-R (40 mos), MPR (28 mos), and MP (29 mos) but the overall survival was similar. {Mon-405-M.Dimopoulos}. In another study after stem cell transplant, patients were entered into arms (A) Rev vs (B) no maintenance. While progress free survival (46 vs 24 months) was better for (A), overall survival was the same (81 vs 82 mos). It was shown that the 2nd progression free survival was shorter for (A) suggesting that it’s more difficult to treat patients who have progressed while on maintenance, thus introducing quite a maintenance controversy that needs more study. {Mon-406-M.Attal}.
  • Phase 3 study (n=425) of newly diagnosed elderly patients who were randomize to VD, VTD, or VMP (8 cycles) all followed by 5 cycles of Velcade maintenance. Overall response rates were 70-80% (CR/nCR 30-40%). Median progression free survival was 15-17 months and overall survival was 50-53 months. VD was just as effective with less toxicity. {Sat-1966-R.Niesvizky}
  • This is a Phase 3 (n=413) study of PAD (Vel-dox-dex) followed by a stem cell transplant followed by 2 years maintenance of either daily Thalidomide (50mg) or two Velcade infusions per month. Overall response rate was 91% (complete response 49%, very good partial response 226%). Median overall survival after 7+ years was not yet reached. {Mon-404-P.Sonneveld}
  • This Phase 3 (n=243) stem cell transplant patients looked at maintenance with (A) indefinite prednisone (50 mg every other day) or (B) in combination with 12 months of Thalidomide consolidation (100-200mg). Five year progression free survival rates were 15/27% and 5 year overall survival was 47/66% respectively. However, if >=very good partial response was obtained by stem cell transplant (SCT), the Thalidomide arm did not show progression free survival/overall survival benefit. {Mon-537-A.Kalff}
  • Good Phase 2 trial results from the maintenance of an all oral regimen MLN9708 + Rev after a stem cell transplant (SCT) is leading to a Phase 3 trial comparing it to Rev-only. {Sat-1983-J.Shah}

NEW DRUGS FOR NEWLY DIAGNOSED PATIENTS

  • Carfilzomib plus Melphalan and Prednisone for elderly patients is a promising therapy. In a Phase I/II trial, it showed an overall response rate (ORR) of 91%, including 10% complete response and 45% very good partial response. {Sat-1933-P.Moreau}
  • Phase 2 (n=45, ages 40-88, median 60 yrs old) Cfz-Rev-Dex followed by Rev 2-year maintenance (CRD-R) resulted in 67% complete response and 98% overall response rate with progression free survival at 18 months of 91%. Using flow cytometry, all 27 complete response/near complete response patients were MRD-negative. {Mon-538-N.Korde}
  • This Phase 1/2 trial examined the all-oral regimen of MLN9708 (Ixazomib)-Rev-dex. A 21-day cycle Phase 2 dosage is MLN9708 3mg (d 1,4,8,11), Rev 25mg (d 1-14), and dex 20/10mg (cycles 1-8/9-16; d 1,2,4,5,8,9,11,12). For Phase 2 (n=57) overall response rate was 95% (complete response 27%, very good partial response 48%). The worst Grade 3/4 adverse effect was rash (11%) and there were no Grade 4 adverse effects. {Mon-535-P.Richardson}
  • CYCLONE [Cytoxin-Cfz-Thal-Dex] (don’t ask me where the Thal-Dex fits in) in a Phase 1/2 after 4 cycles showed 96% overall response rate (76% >= VGPR) and 2-year progression free survival and overall survival of 77% and 98% respectively. (Only grade 1 neuropathy even though daily Thalidomide of 100mg.) {Sun-3179-J.Mikhael} In a similar trial after 4 cycles of Cytoxin-Cfz-Dex (but no Thalidomide), CCd showed 92% overall response rate (67% >= very good partial response) and 2-year progression free and overall survival of 76% and 87% respectively. {Mon-685-S.Bringhen} And a third trial Cfz-Thal-dex (no cytoxin) showed 93% overall response rate (60% >= very good partial response). {Mon-688-P.Sonneveld}.

NEW DRUGS FOR RELAPSED/REFRACTORY (R/R) PATIENTS

  • MLN9708 (Ixazomib) as a single agent in a Phase 2 trial (n=32) not refractory to Velcade showed 16% >= partial response (PR) after 4 cycles and is expected to improve. {Sat-1944-S.Kumar}
  •  ARRY-520 (KSP Inhibitor) plus Velcade in a Phase I suggested >= 1.25 mg/m2 dosage is quite effective, resulting in 30% overall response rate for Velcade-refractory and 63% overall response rate for Velcade-sensitive, or 42% overall response rate. {Sat-1938-A.Chari} Another presentation showed an inverse correlation between ARRY-520 and Acid Glycoprotein (AAG) levels suggesting that single agent ARRY-520 is more effective with low AAG (e.g. OS 23 vs 4.5 mos). {Mon-285-J.Kaufman (S.Lonial not available)}
  • A phase III poster showed that Perifosine with Velcade plus Dex in patients previously treated with Velcade showed no benefit in progression free survival or overall response rate {Sun-3189-P.Richardson}
  • An oral AKT inhibitor Afuresertib (GSK2110183) has previously shown single agent activity. Given together with Vel-dex (n=37) showed 65% overall response rate (ORR), although these were Velcade-naive/relapsed but not refractory. However, Velcade-refractory patients in a Part 1 study also showed a response. Grade 3/4 >10% adverse effects were thrombocytopenia (27%), diarrhea (14%), skin rash (13%) and anemia (10%). {Mon- 283-P.Voorhees}
  • Panobinostat, an HDAC inhibitor, is combined with Vel-Dex (PANORAMA) in a Phase 2 trial of Vel-refractory patients and showed a progression free survival and overall survival of 5.4 months and 17.5 months respectively. {Sat-1970-P.Richardson}
  • SAR650984 is a CD38 monoclonal antibody (mAb) in a Phase 1 trial (n=24) showed no hematological Grade 3/4 adverse effects, while providing a single agent overall response rate of 31% with dosage >= 10mg/kg. These patients averaged 5 lines prior therapies, all Velcade and Revlimid, some Carfilzomib and Pomalidomide. {Mon-284-J.Mikhael (T. Martin not available)}

OTHER RESULTS

  • If a solitary plasmacytoma has abnormal PET-CT scans and serum Free-Light-Chain values, perhaps multiple myeloma treatment should start after appropriate surgery/radiation. {Sat-1888-G.Fouquet}
  • This poster looked at 1018 myeloma patients during the 2002-2009 timeframe from the VA Registry who took either Zometa or Aredia but not both. Zometa improved overall survival by showing a reduced risk of death by 16%. {Sun-3182-K.Sanfilippo}
  • Several trials integrated Minimum Residual Disease (MRD) testing, which is important as part of the IMF’s Black Swan Research Initiative. There still needs to be a consistent definition of MRD but this is the first year I remember seeing it at all. Abstracts included 535, 538, 762, 2077, 3126, 3152, 3220, 3223, and 4647.

SUMMARY

For someone diagnosed with stage III MM 19 years ago with only 2 treatment options (Melphalan-Prednisone or VAD-SCT) and given 2-3 years expected survival, I’ve seen incredible progress since 2000. While there are many unanswered questions, we now have many more effective treatments for multiple myeloma, providing patients with better opportunities to manage their disease.

GLOSSARY (according to Jack)

Drug Class/Category

IMID – Immunomodulary Drug PI – Proteasome Inhibitor mAb – Monocloncal Antibody Drugs B - Bendamustine C - Cytoxin Cfz - Carfilzomib Dox - Doxil E - Elotuzumab M – Melphalan P – Prednisone Pom - Pomalidomide R – Revlimid T – Thalidomide V- Velcade Vor-Vorinostat (Zolinza®) Treatment Success Measurements EFS – Event-free Survival ORR – Overall response (>=PR) OS – Overall Survival PD – Progressive Disease PFS – Progression-free Survival PFS2 – PFS + next-line treatment PFS TTP - Time to Progression TTR - Time to Respond Treatment Response CR – Complete Response: No sign of MM (0 M-spike) nCR – Near CR (positive M-spike, may be same as VGPR) MR – Marginal Response: 0-50% reduction in MM PR- Partial Response: 50% reduction in MM SD – Stable Disease i.e. no response but also not worse sCR-Stringent CR: CR+ normal FLC & no clonal cells VGPR – 90% reduction in MM MRD – Minimum Residual Disease (further defn needed); Immunophenotypic CR uses Flow Cytometry and is an example of a possible MRD defn. Side Effects AE – Adverse Event (aka Side Effects) DVT - Deep Vein Thrombosis (blood clots) MTD – Maximum Tolerated Dose ONJ – Osteonecrosis of the Jaw PE – Pulmunary Embolism PN – Peripheral Neuropathy QOL – Quality Of Life VTE - Venous Thromboembolism (PE + DVT) Tests/When to treat? CRAB – High Calcium, Renal, Anemia, and Bone… CRABi – CRAB + “i” increased infections FLC – Free Light Chain SCT – Auto stem cell transplant. “d” and “D” – Typically both mean Low-dose Dex (40 mg/week) these days MGUS – Monoclonal Gammopathy of Undetermined Significance R/R- Relapsed/Refractory Ref defined progressing while on Tx or within 60 days. SMM – Smoldering MM

 
Jennifer Ahlstrom
About the Author

Jennifer Ahlstrom - Jenny A - Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical trials. Founder of Myeloma Crowd, Myeloma Crowd Radio, HealthTree and the CrowdCare Foundation.

ADVERTISEMENT
ADVERTISEMENT
ADVERTISEMENT
 

Add a Comment

 

MORE MYELOMA CROWD NEWS

Thanks to our site sponsors:

.