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December 8, 2013

MMRF Newsflash from ASH 2013 - Volume 2

Breaking News from the Plenary Session!

The penultimate honor at a meeting like ASH is to present at a plenary session. Multiple myeloma does not have a slot every year, so it was a rare honor for the FIRST study to be presented to be presented by Dr. Thierry Facon in front of thousands of attendees. The study consisted of 1,623 patients from 246 centers from 18 countries on four continents, and compared continuous Revlimid-dex (until disease progression) vs 18 cycles of Revlimid-dex vs melphalan-prednisone-thalidomide (a regimen not used in the US but still occasionally in some countries worldwide) in patients ineligible for high-dose chemotherapy and stem cell transplant.

The primary endpoint was measuring progression free survival (the amount of time patients were alive with their disease worsening). The group who received continuous Rev-dex had a PFS of 25.5 months vs. 20.7 and 21.2 for the other groups. There are 121 patients still receiving Revlimid-dex today. PFS was superior in this group regardless of factors like age, sex, and stage of disease. The toxicity profile for the Rev-dex arms was superior with fewer Grade 3-4 (serious) toxicities, with infection being most commonly reported. Importantly, there was no increased risk of second cancers, which has been seen in other Revlimid maintenance studies; it seems that this slightly elevated risk may be due to the combination of Revlimid with an alkylating agent like melphalan.

Both Dr. Facon and Dr. San Miguel who had introduced the abstract stated that continuous Revlimid-dex represents a new standard of care in this population. It is important to note that the study did not include comparisons with other regimens commonly used today in the US (Velcade-dex and Revlimid-Velcade-dex) or outside the US (Velcade-melphalan-prednisone and Velcade-thalidomide-dex), but nonetheless, the results are certainly encouraging, particularly when considering other trials showing a PFS benefit for prolonged or continuous Revlimid early in the disease course.

To see the full MMRF coverage from ASH with ongoing updates, please visit: www.themmrf.org/ash2013.

December 7, 2013

MMRF Newsflash from ASH 2013 - Volume 1

Welcome to our first report on the 2013 American Society of Hematology (ASH) Annual meeting, featuring many posters on multiple myeloma.

Tonight, the poster session focused on new agents being tested in patients with relapsed and refractory disease. These included new doses/schedules and combinations of the most recently FDA approved agents, ie, Kyprolis (carfilzomib) and Pomalyst (pomalidomide) as well as novel agents in early phase clinical trials.

Highlights included:

  • Results from a Phase I/II study of the combination of Kyprolis plus panobinostat (an HDAC inhibitor with recently announced positive Phase III data) presented by Dr. Berdeja from Sarah Cannon Research Institute and a member of the Multiple Myeloma Research Consortium (MMRC). Overall, 66 patients were treated, many of whom were refractory to IMiDs, proteasome inhibitors or both. The overall response rate was 64% when all patients were considered, and 67% in PI refractory patients. The median time to progression in the overall and PI refractory populations was 7.56 and 4.83 months, respectively. Thrombocytopenia (low platelets) was the only serious (Grade 3 or 4) side effect seen with any frequency.
  • Very preliminary results (on a total of 11 patients) looking at the combination of the antiCD38 antibody daratumumab in combination with Revlimid and dexamethasone (Rev-dex) were presented. To date, 8/11 in this dose-finding study had a partial responses (PR) or better, 10/11 were receiving clinical benefit (minor responses and better), and the side effects seen were predominantly consistent with those seen with Rev-dex. Though very early, the early signal is very promising.
  • Dr. Jim Berenson of the Institute for Myeloma & Bone Cancer Research presented the results of a Phase I study (CHAMPION-1) investigating once weekly Kyprolis combined with dexamethasone. Kyprolis was given as a 30-minute infusion at three different doses. Results were available for 27 patients. Eight patients (30%) achieved a complete response (CR) and the overall response rate was 63%. Side effects were predominantly myelosuppression (low blood counts) and gastrointestinal (GI) related.
  • Dr. Chari from Mount Sinai in New York presented the results of a Phase I study of a new KSP inhibitor – ARRY-520 combined with Velcade and dexamethasone. All patients in the trial had previously received a proteasome inhibitor. The ORR was 42%, and it was 30% in the PI refractory patients. Toxicities were generally mild and largely GI-related or low blood counts. Another poster examined the compound with Kyprolis with similarly promising results in a refractory population.
  • Dr. Mikhael of the Mayo Clinic Arizona in Scottsdale presented the results of a Phase I/II trial of Pomalyst, Velcade, and dexamethasone in 16 patients in the phase II part of the trial. All patients had been treated previously with Revlimid. Though only a few patients were treated, the ORR was an impressive 94%. The most common drug-related toxicities were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2.

Other novel compounds presented included quisinostat, a novel HDAC inhibitor and veliparib, a PARP inhibitor, both of which show some promise in very early trials.

Finally, in addition to the clinical posters, several others looked at evaluating minimal residual disease through more sensitive DNA sequencing techniques, as well as markers to determine how well patients will do with treatment. These studies included a study done in collaboration with the MMRC reporting on the use of SKY92, a genetic marker of high risk multiple myeloma. These studies will help with diagnosis and treatment decisions, and help evaluate the responses to treatment for myeloma patients.

To see the full MMRF coverage from ASH with ongoing updates, please visit: www.themmrf.org/ash2013.

June 4, 2013

MMRF Newsflash from ASCO 2013 - Volume 3

Welcome to our third and final report on the 2013 American Society of Clinical Oncology Annual meeting featuring the Multiple Myeloma poster session.

Key takeaways from posters reporting studies in newly diagnosed patients were:

  • The question of early versus delayed autologous stem cell transplant for patients receiving upfront therapy RVD - Revlimid (lenalidomide) in combination with Velcade (bortezomib) and dexamethasone (dex) - was addressed. Findings suggest that delayed transplant is feasible with similar rates of disease progression and survival.
  • Updated results of a phase I/II trial with the combination of Kyprolis (carfilzomib), Revlimid (lenalidomide)-dex demonstrated high response rates, including a high rate of minimal residual disease negative status among the patients achieving stringent CR (92%). Two year survival was 98%. This regimen was well tolerated and the most common side effects were low platelet counts and infection. A Phase III study assessing this combination in newly diagnosed patients is planned.

Updates on previously reported trials, new combinations and new agents for relapsed refractory patients were highlighted.

  • Analyses of the phase III trial with relapsed/refractory patients treated with Pomalyst (pomalidomide) and low-dose dex showed that patients with moderate kidney problems (renal impairment) and those with high-risk features achieved similar benefit to other patients in the study. Benefits were also similar regardless of age.
  • A phase I/II MMRC study of the combination of Kyprolis, Revlimid and dex in 84 patients showed high overall response rates (69-77%) including 36% very good partial responses (VGPR). Most impressive was the rapid time to response (1 month) and 22 month duration of response. Results of the Phase III study looking at this combination versus Revlimid-dex in relapsed/refractory myeloma are eagerly awaited.
  • An analysis of the PANOROMA-2 study which evaluated the HDAC inhibitor, panobinostat, in combination with Velcade and dexamethasone in Velcade-refractory patients was reported. The overall response rate was 34.5% and the time without disease progression (progression-free survival) was 5.4 months. The analysis looked at outcomes based on patients’ prior therapies. Progression-free survival was shorter in those who had previously progressed while still taking Velcade (4.2 months) compared with those who progressed after stopping Velcade (7.6 months). Additionally, patients whose last prior therapy included dex had worse outcomes.
  • Updated results for the phase I/II study with elotuzumab in combination with Revlimid-dex showed that this combination resulted in an overall response rate of 84% with 12% of patients achieving CR. The most common severe side effects were low white blood cell counts and low platelet counts. Phase III trials in both relapsed/refractory patients and new diagnosed patients are underway.

June 3, 2013

MMRF Newsflash from ASCO 2013 - Volume 2

Welcome to our second day of on-site coverage of the 2013 American Society of Clinical Oncology (ASCO) Annual meeting.

Today’s oral presentations featured results from studies in both patients with newly diagnosed and relapsed refractory disease.

Dr. Palumbo from Università di Torino presented final results from a study of 402 patients

1) How does the combination of Revlimid (lenalidomide) and melphalan-prednisone (MPR) compare to autologous stem cell transplantation?
2) What is the role of maintenance therapy with Revlimid following either MPR or stem cell transplantation?

  • Results of this study showed that time without disease progression (progression-free survival) was extended in patients undergoing transplantation as compared with MPR.
  • Maintenance therapy with Revlimid significantly reduced the risk of disease progression and extended survival time.
  • Patients who had the best outcomes were those who received a stem cell transplant followed by maintenance therapy with Revlimid.

Dr. Palumbo also addressed the risk of developing a second cancer in patients treated with Revlimid in an analysis of 7 clinical studies with 6383 patients.

  • The results of the study confirmed earlier findings and indicated that there is a small increased risk of a second cancer that is primarily associated with the combination of oral melphalan and Revlimid. These cancers included only hematologic cancers (those related to the blood) such as acute leukemia and myelodysplastic syndrome (MDS) and not any solid tumors.
  • Despite this risk, the overall survival benefits far outweighed the small risk of a second cancer.

Dr. Martinez-Lopez from the Hospital Universitario 12 de Octubre presented data illustrating the value of achieving minimal residual disease in newly diagnosed patients versus those with relapsed/refractory disease.

  • He concluded that the depth of response (i.e. CR) and achievement of minimal residual disease predicts for longer time without disease progression and increased survival in newly diagnosed patients.
  • In contrast, any response to treatment in relapsed/refractory disease can lead to improved survival—even minor responses or stable disease.

Data from SWOG, a major cancer study group, looking at risk factors for progression from MGUS and asymptomatic myeloma to active myeloma, was presented by Dr. Dhodapkar from Yale University.

  • Factors associated with progression to active myeloma included an increased genetic expression profile risk score, the degree of M protein spike, and the level of monoclonal free light chains. The greater the number of risk factors present, the more likely the progression to myeloma.
  • Dr. Kaufman from Emory University, in a discussion of these data, noted that even among patients with these risk factors 25% do not progress. Thus, we still do not have sufficient information to determine which patients with asymptomatic disease need to be treated.

Dr. Weisel, presenting on behalf of Dr. San Miguel from Hospital Universitario de Salamanca, provided an update on the results of the phase III trial which compared the combination of Pomalyst (pomalidomide) and low-dose dexamethasone to high dose dexamethasone in 455 patients with relapsed and refractory myeloma. These patients were “double refractory”, ie, they had failed both Velcade (bortezomib) and Revlimid.

  • Results confirmed earlier reported findings and showed significantly increased response rates, a significant improvement in time without disease progression (4 months with Pomalyst-low dose dexamethasone versus 1.9 months with high-dose dexamethasone) as well as increased survival time (12.7 months with Pomalyst-low dose dexamethasone versus 8.1 months with high-dose dexamethasone).
  • Side effects were manageable with the most common serious side effects being low white cell blood counts.

There were also presentations on two new agents, daratumumab and ixazomib, as well as a new combination of myeloma drugs for patients with relapsed/refractory myeloma.

  • Dr. Lokhorst from University Medical Center presented results from a Phase I/II trial with a monoclonal antibody, daratumumab, in relapsed/refractory myeloma. In this early study 75% of patients were refractory to both Velcade and Revlimid. 31% of patients responded, which is similar to what has been reported with recently approved agents, Pomalyst and Kyprolis, in this patient population which is promising as side effects were minimal and dexamethasone was not part of the treatment regimen.
  • Dr. Kumar from the Mayo Clinic presented data from a Phase I study with weekly ixazomib, an oral proteasome inhibitor in the same class as Velcade and Kyprolis (carfilzomib) in relapsed/refractory myeloma patients who progressed after an average of 4 therapies. 26% of patients responded at the dose level that was established. Serious side effects included diarrhea, pneumonia, vomiting, increased creatinine levels (a measure of kidney function), hypercalcemia (increased calcium levels), nausea and fever. Phase III trials evaluating this ixazomib and Revlimid (lenalidomide)-dexamethasone are underway in both relapsed/refractory patients and newly diagnosed patients.

Look for our next posting on the multiple myeloma poster session!

June 2, 2013

MMRF Newsflash from ASCO 2013 - Volume 1

Multiple Myeloma Education Session


Welcome to our first day of on-site coverage of the 2013 American Society of Clinical Oncology (ASCO) Annual meeting.

Today, a Multiple Myeloma Education session focused on advances in diagnostics and management. The session featured Drs. Donna Reece from the Princess Margaret Hospital in Toronto, Robert Orlowski from MD Anderson Cancer Center in Houston, and Jesus San-Miguel from the Hospital Universitario de Salamanca in Spain.

Dr. Reece focused on initial therapy, highlighting advances with the integration of newer therapies, for both patients eligible for transplant and those ineligible for transplantation. The integration of newer agents, ie, Velcade and Revlimid, before and after autologous stem cell transplantation has extended time without disease progression (progression-free survival) from 2 years to approximately 3 years.

  • Newer regimens being explored for patients eligible for stem cell transplantation include Kyprolis (carfilzomib), Pomalyst (pomalidomide), and ixazomib, an oral proteasome inhibitor (in the same class of drugs as Velcade and Kyprolis) that is being evaluated in Phase III clinical trials
  • Progress in treatment of elderly, non-transplant patients, has been made with the addition of newer agents (i.e. Revlimid, Velcade, Thalomid) to melphalanprednisone (MP), but these regimens come with significant side effects. Revlimd-dex is a commonly used regimen which is better tolerated

Dr. Orlowski focused on new approaches to treatment of patients who are refractory to both Velcade and Revlimid (aka “double-refractory patients”).

  • The introduction of both Kyprolis and Pomalyst has improved outcomes in these patients, but further advances are still needed given that typically 20-30% of patients respond to either of these treatments and for a duration of approximately 9-12 months. To this end, new combinations including these drugs are being studied
  • New novel drugs in development for double-refractory patients appear promising and include ARRY-520 and daratumumab

Dr. San-Miguel reviewed current and emerging techniques for diagnosis and monitoring.

  • Emerging tests, specifically the Hevylite assay and flow cytometry immunophenotyping, may be able to help predict the risk of progression from MGUS and smoldering myeloma to symptomatic disease
  • Measuring minimal residual disease (MRD) is a growing area of interest as the presence (or absence) of MRD appears to be a strong indicator, even independent of response, of a patient’s prognosis. Many countries in Europe are collaborating to develop standards for evaluating MRD, and those discussions are extending to the US as well
  • Additionally, flow cytometry immunophenotyping may have a role in monitoring, particularly during maintenance therapy

Following the Education Session, the MMRF recorded a webcast with these doctors to discuss these topics in more detail as well as review data being presented at the meeting. The webcast will be available beginning Tuesday. In the meantime, check back here for ongoing updates.

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