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February 10, 2014

MMRF Scientific Steering Committee Roundtable

Aiming even higher, with a little help from our friends…

Despite heavy snow and freezing rain, some of the most esteemed scientists and researchers in academic institutions and the pharma/biotech industry in North America convened this week in Boston for the MMRF Scientific Steering Committee roundtable to help identify and prioritize the most promising science and new therapy areas as part of the Research Agenda for our next three-year Strategic Plan.

It was a rare opportunity to exchange ideas and learn from an impressive array of preeminent experts, many specialists outside the myeloma field (from CML to melanoma to lung cancer), who dedicated their time to enthusiastically address our most critical challenges:

  • How can we enable all myeloma patients to understand and obtain the most effective treatments for their specific subtype or version of multiple myeloma?
  • How can we harness the power of the immune system to rapidly advance immunotherapy in myeloma, particularly for patients at greatest risk of disease progression?

Participants outside of the myeloma field also took note of lessons learned by the MMRF. Like other cancers such as leukemias or melanoma, a proportion of myeloma patients who may respond well to initial therapies are confronted with more aggressive forms of disease later on. Even worse is the case where patients have little to no response from the outset. It was clearly recognized that many of the techniques and initiatives the MMRF developed over the past five years are the benchmarks that other types of cancers are working to achieve as well.

In many respects we’re ahead of the curve in helping to inform scientists and research partners on how to proceed; the disadvantage is that there does not appear to be a ‘smoking gun’ that we can target in myeloma to help a large proportion of patients. With at least four and up to 10 different subtypes or versions of myeloma in patients – even when they are newly diagnosed, a truly comprehensive approach is needed to reach a cure.

The main takeaways, in this regard, fall into three main categories as we map our MMRF research plan over the next three years:

  1. Pursue a ‘three-pillar’ approach to get new treatments to patients: immunotherapies, targeted/precision therapies, and therapies from new classes/novel mechanisms
  2. Standardize access to and the tools used in identifying subtypes or versions of myeloma in patients during the course of their disease to provide the best treatments and speed new approaches, even in those with smoldering or the earliest forms of myeloma
  3. Develop and standardize the tools used to reveal how immune and targeted therapies work in myeloma, and in understanding how patients respond to therapy

A great deal of progress has been made in our understanding of myeloma and new ways to overcome this disease. With two new drugs approved in the last year, and the potential for double that number over the next three years, the horizon for patients is improving. However, the new research programs outlined above and the support to put them into action offer the most promise for long-term remission – and possibly a cure – over the next five years.

For all of the support that has led to our results thus far, and that which will enable the next breakthroughs, we are eternally grateful to our donors, patients, patients' families and all of our partners who make what we do possible.

Walter M. Capone
Multiple Myeloma Research Foundation

December 11, 2013

MMRF Newsflash from ASH 2013 - Volume 5

Welcome to the final day of MMRF onsite coverage from the 2013 American Society of Hematology (ASH) Annual meeting.

The abstracts focused on first-line therapy and relapsed/refractory treatment, including some featuring compounds in very early development for multiple myeloma. Additionally, an initial interim analysis of the MMRF CoMMpassSM Study was presented. To hear perspectives from myeloma experts on the data from ASH, please watch the MMRF webcast with Drs. Ola Landgren and Maria-Victoria Mateos. Watch now! Learn more about the latest advances in myeloma research and treatments by participating in the MMRF Highlights From the 2013 ASH Annual Meeting Webcast/Teleconference scheduled for December 18th at 1:00PM ET. Register now!

Upfront Therapy

Dr. Shaji Kumar from the Mayo Clinic presented data from a Phase I/II trial on ixazomib (aka MLN9708), a new oral proteasome inhibitor, combined with Revlimid and dexamethasone in previously untreated myeloma patients. The overall response rate in this trial was 100%, with 23% complete responses (CR). Based on the positive results, a Phase III trial is underway and enrolling. Call the MMRF Patient Support Center at 1-866-603-6628 to find out more.

Relapsed/Refractory Disease

Dr. Antonio Palumbo from the University of Torino in Italy presented results on a trial evaluating, cyclophosphamide, and prednisone in relapsed/refractory patients followed by Pomalyst and dexamethasone maintenance therapy. This trial is ongoing. At the time of this presentation, 55 patients had received at least 1 treatment cycle. Patients with relapsed/refractory disease who had received at least 1 to 3 prior therapies were eligible to participate. The overall response rate was 51%, with 6% achieving a CR and 24% a VGPR.

Dr. Noopur Raje from Mass General Hospital presented data for a Phase I trial of the new anti-BAFF antibody tabalumab, combined with Velcade and dexamethasone. 48 patients were enrolled, who had a median of 3 prior treatments. Adverse events observed were similar to those seen with Velcade. 2 patients had a CR, 20 had a PR or VGPR and 21 had stable disease. The Phase II trial is ongoing.

Dr. Jatin Shah from MD Anderson in Texas presented the results of a Phase II trial assessing ARRY-520, with or without dexamethasone. Patients enrolled had relapsed/refractory disease and had received a median of 6 previous therapies in the ARRY-520 alone arm, and 10 previous therapies in the ARRY-520 plus dexamethasone arm. Most patients had undergone previous stem cell transplantation. Grade 3 and 4 toxicities were low, there was no cumulative toxicity, and the treatment was well tolerated. Responses ranged from PR to SD, with no CR in these heavily treated patients, and 34% had progressive disease. Interestingly, responses to this agent corresponded to serum levels of alpha-1-acid glycoprotein, which can act as a marker for patients who may respond to this agent. Predose levels of alpha-1-acid glycoprotein indicated the response to ARRY-520. This was also found in the Emory study presented earlier in the day.

Dr. Sundar Jagannath from The Mount Sinai Hospital presented results of an age analysis from a Phase II trial of Pomalyst with low-dose dexamethasone in patients with relapsed/refractory multiple myeloma who have received prior therapy with Revlimid and Velcade. The results showed that patients aged 65 years or older did about as well as patients aged less than 65 years, confirming Pomalyst as an important option for elderly relapsed patients.

MMRF CoMMpassSM Study

Perhaps the pinnacle for the MMRF at this meeting was the first presentation of data from the MMRF CoMMpass study. An interim analysis of 178 patients (today we are now up to 400!), which included sequencing data on more than 30, was presented. Already, even with this preliminary data set, we are seeing brand new genomic alterations, as well as confirming others seen in our earlier Genomics Initiative and separate research initiatives. Attendees were highly engaged and were very much looking forward to the data maturing, as longitudinal data sets that integrate clinical and comprehensive (DNA and RNA sequencing) genomic data on 1,000 patients are not currently publicly available for myeloma or any cancer.

MMRF ASH Coverage

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

The MMRF Highlights From the 2013 ASH Annual Meeting Webcast/Teleconference will be held on Wednesday, December 18, at 1:00 PM ET! Hear our experts' perspectives on key myeloma clinical updates from ASH and learn about the latest advances in myeloma research and treatments. Register now by completing this form or calling 1-877-264-4949.

December 11, 2013

MMRF Newsflash from ASH 2013 - Volume 6: Highlights

MMRF Highlights from ASH 2013

Below are four key takeaways from the meeting.

Improvements and refinements to proteasome inhibitors and/or IMiDs abound

Data showing the utility and safe use of next-generation proteasome inhibitors, including Kyprolis (carfilzomib), as well as the oral agents, ixazomib (MLN9708 from Millennium) and oprozomib (from Onyx), were shown in 100+ presentations and posters. Kyprolis is increasingly being tested in newly diagnosed patients and in combination with both standard and investigational agents. Furthermore, it is highly effective (100% response rate with Revlimid-dex upfront to 60+% in the relapsed population with a variety of agents from Pomalyst to ARRY-520). Even ixazomib, which is in Phase III clinical, is being investigated – with promising results – in a variety of settings – from first-line to maintenance to salvage.

In terms of the IMiDs, Pomalyst remains one of the most active compounds available when used in combination with steroids and/or proteasome inhibitors. The Phase III trial comparing it to high-dose dex now shows a clear survival benefit. And, a sub-analysis of the data from that trial found that the drug appears to work well in patients with a chromosome 17p deletion – which is typically called “high-risk”.

More data continues to emerge on optimizing use of the first novel agent approved more than 10 years ago for multiple myeloma – Velcade. A presentation from Dr. Maria-Victoria Mateos from Spain showed that the more Velcade a patient receives, the better the outcome. With weekly dosing and sub-cut administration, patients are less likely to discontinue due to side effects. Further, a subanalysis of large trials involving Velcade showed no further increase in risk of cardiotoxcity.

Exciting new classes – particularly antibodies – are emerging

Data on SAR650984, the second anti-CD38 antibody after daratumumab, were presented publicly for the first time and did not disappoint. Though based on a very small sample, at therapeutic doses, as a single agent, response rates were similar to daratumumab in patients who had failed nearly every available option. Preliminary data on the combination of daratumumab and Rev-dex were also shown in another small population with impressive response rate (8/11 patients who had received a median of 3-4 prior treatments). Trials with these agents (including ones with SAR650984) are enrolling quickly so call our Patient Support Center (1-866-603-6628) if you might be a candidate.

Novel agents in emerging classes all of which are either in Phase I or just moving into Phase II but have produced responses in patients even at low doses included:

  • ARRY-520, a KSP inhibitor, which has been studied in an MMRC trial
  • Akt inhibitors like afuresertib, which was conducted in part through the MMRC
  • Kinase inhibitors like ibrutinib and LGH447

Finally, just prior to the start of the meeting, Novartis announced that the Phase III trial of the HDAC inhibitor panobinostat + Vel-dex vs Vel-dex in patients who had received 1-3 prior treatments, found a survival benefit for patients treated in the panobinostat combination. No further details were given but positive data bodes well for a potential 2015 FDA approval. An abstract looking at the combination in Velcade-refractory patients demonstrated that the addition of panobinostat can overcome resistance to Velcade, which is encouraging for patients who thought Velcade was out as an option and consistent with lab data.

Long-term maintenance or continuous therapy continues to be a hotly discussed topic

Prior to ASH, three studies had established improvement in progression-free survival with use of maintenance Revlimid, and two had shown survival benefits. A plenary presentation at this year’s meeting found a clear survival benefit when comparing continuous Revlimid+low-dose dexamethasone vs melphalan-prednisone-thalidomide in patients who are not candidates for high-dose chemotherapy and stem cell transplant with no increased risk of second cancers. The presenter, Dr. Thierry Facon, proclaimed that this combination represents a new standard of care for elderly patients. It is important to note that less than half of the patients randomized to continuous Rev-low dose dex were on therapy for more than two years.

Other data presented at the meeting revealed somewhat of a mixed picture. A meta-analysis from the Mayo Clinic confirmed the PFS benefits of Revlimid post-transplant, as well as longer-term use leading to deepened responses. However, the analysis also showed that benefits for those who had a very good partial response (VGPR) or better may not reap any added benefit of continuing past two years. And the French IFM group found that there was no survival advantage given an overall shorter PFS following the next line of therapy for those who had received Revlimid maintenance. However, the difference was primarily in those who went to another IMiD and at the time the trial was conducted neither Kyprolis nor Pomalyst was available, which may have made a significant difference.

Data from large groups of patients followed longitudinally are needed to address important questions and drive precision medicine

For the first time publicly, data from the landmark MMRF CoMMpassâ„  Study was presented. Already we are seeing repetition in genomic alterations – some that have been previously identified through the MMRF Genomic Initiative and other research efforts and some that are brand new. Those who attended the session were highly engaged offering unsolicited public comments about how critical it is to collect and integrate uniform longitudinal clinical and genomic data in a large sample of patients to characterize the diversity of the disease and begin to match patients with treatments that are right for them.

MMRF ASH Coverage

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

The MMRF Highlights From the 2013 ASH Annual Meeting Webcast/Teleconference will be held on Wednesday, December 18, at 1:00 PM ET! Hear our experts' perspectives on key myeloma clinical updates from ASH and learn about the latest advances in myeloma research and treatments. Register now by completing this form or calling 1-877-264-4949.

December 10, 2013

MMRF Newsflash from ASH 2013 - Volume 4

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

Highlights from yesterday morning’s early presentations included:

Relapsed refractory disease

  • Dr. Voorhees from the University of North Carolina, Chapel Hill, presented the results of a Phase I/II trial of the AKT inhibitor, afuresertib, combined with Velcade and dexamethasone. Phase II is ongoing, with 37 patients enrolled in part 2. Patients had a median of 3 prior lines of therapy (82% had prior proteasome inhibitors and 96% had prior IMiDs). The most common adverse events were fatigue, diarrhea, nausea, and constipation. The overall response rate was 65%, including many responses in Velcade refractory patients. Eight Multiple Myeloma Research Consortium (MMRC) sites participated in this trial.
  • Dr. Martin of the University of California, San Francisco presented the preliminary results of a Phase I study of the SAR 650984, a new anti-CD38 monoclonal antibody, in CD38-positive hematologic malignancies including multiple myeloma patients. SAR650984 is also being evaluated in an MMRC trial in combination with Revlimid-dex, and is in the same class as daratumumab. So far, 39 patients previously treated with a median of 6 prior therapies have been treated at various doses. The results are early, but patients have experienced very low rates of toxicities, the most common of which were fatigue, nausea, fever, cough and anemia, and were mostly mild. There have been no Grade 3-4 hematologic toxicities, which is promising given the side effects often seen with proteasome inhibitors and IMiDs. 31% of patients have responded so far to clinically meaningful doses, and there have been two complete responses.
  • Preliminary results of a Phase II trial of the KSP kinase inhibitor, ARRY-520 (filanesib) were also reported. Filanesib was given as a single agent or in combination with low-dose dexamethasone. Patients enrolled in the 2 treatment groups had a median of 6 or 8 previous therapies, and were refractory to their last line of therapy. Hematologic toxicities included neutropenia, thrombocytopenia, and anemia. The primary reason for discontinuation was progressive disease, with few patients discontinuing due to toxicity. The overall response rate was 16% for filanesib alone and 15% for filanesib plus dexamethasone. Interestingly, patients who did not respond to filanesib therapy expressed high levels of a protein called alpha-1 acid glycoprotein (AAG), suggesting that AAG is a marker for those who will not respond to this agent. Filanesib is also being studied with Velcade-dex and Kyprolis-dex (both posters were presented on Saturday); the MMRC is part of the Velcade-dex study.
  • Dr. Schey of King's College London, London, presented a trial evaluating the dose of bendamustine combined with thalidomide and dexamethasone in relapsed/refractory patients. This regimen showed a 55.6% response rate in the primary population of patients, with the most common toxicities being neutropenia, thrombocytopenia, and anemia. This is further evidence that bendamustine may be an option for some individuals, particularly as, in the US, it is approved for a different blood cancer and may be used off-label.
  • Dr. Dimopoulos of Greece presented a final analysis of the Phase III, MM-003 trial comparing low-dose dexamethasone with Pomalyst to high-dose dexamethasone in relapsed refractory disease. The analysis showed that high-risk cytogenetics, including t(4;14) and del17p-, did not impact median progression-free survival for patients receiving Pomalyst with low-dose dexamethasone.

Newly diagnosed disease

  • Dr. Sonneveld of the Netherlands presented an extended follow up of the HOVON-56/GMMG-HD4 trial of Velcade Induction and maintenance treatment in newly diagnosed patients. The follow up after 74 months was reported. Velcade treatment during induction and maintenance improved complete responses and as well as progression-free and overall survival, and rates of second primary malignancies were low.
  • Dr. Attal of France presented a follow up study of the IFM 2005-02 trial of Revlimid maintenance after stem cell transplantation. The new analysis found that Revlimid effectively prolonged progression-free survival after transplantation, but this has not yet translated into improved overall survival as patients in the Revlimid arm of the trial who then went on subsequent therapy experienced a shorter progression free survival and overall survival on their next line of therapy as opposed to those on the placebo arm.
  • Dr. Singh from the Mayo Clinic, Rochester, MN, presented a meta-analysis of randomized trials of lenalidomide maintenance therapy after induction therapy alone or post-autologous stem cell transplant. This analysis indicated significant improvement in progression free and modest improvement in overall survival with lenalidomide maintenance. An increased risk of grade 3-4 toxicities, including second primary malignancies was also indicated.

MMRF ASH Coverage

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

The MMRF Highlights From the 2013 ASH Annual Meeting Webcast/Teleconference will be held on Wednesday, December 18, at 1:00 PM ET! Hear our experts' perspectives on key myeloma clinical updates from ASH and learn about the latest advances in myeloma research and treatments. Register now by completing this form or calling 1-877-264-4949.

December 9, 2013

MMRF Newsflash from ASH 2013 - Volume 3

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

Highlights from Sunday’s session included:

Newly diagnosed patients

Dr. Kourelis of the Mayo Clinic reported on an analysis of continuous therapy in newly diagnosed multiple myeloma patients who remained on Revlimid (lenalidomide) for more than three years and compared them with patients who discontinuing Revlimid and were able to maintain disease control on observation. This study found that patients with standard risk cytogenetics and a very good partial response or better were more likely to be long-term responders, and that long-term responders were more likely to be slow responders. Though the absolute number of patients analyzed was small, the results further suggest that patients with a very good partial response or better may be able to stop Revlimid therapy after one year without any greater risk of progression.

In elderly newly diagnosed patients, Dr. Baz of the Moffitt Cancer Center showed that “response adapted” therapy, that is Revlimid alone followed by dexamethasone rather than Revlimid and dexamethasone together, was effective in elderly transplant ineligible patients. The outcomes were similar to those in younger patients treated with the doublet therapy.

Dr. Kumar from the Mayo Clinic presented an analysis comparing newly-diagnosed patients who had been treated with Velcade, cyclophosphamide, and dexamethasone (VCD aka CyBorD) versus Velcade, Revlimid, and dexamethasone (RVD) as upfront treatments. The analysis showed that the overall response rates, progression-free survival, and overall survival of patients treated with these regimens were similar, and that the toxicities of the treatments were also similar.

Dr. Mark from Weill Cornell presented preliminary results from Car-Bird (Kyprolis-Biaxin-Revlimd-dex), which had previously been studied in relapsed and refractory patients. The overall response rate was 87% with is consistent with other upfront studies using a prosteasome inhibitor and IMiD and with longer follow-up, the rate could increase. There were a number of Grade 3-4 toxicities including two cases of renal failure and one of congestive heart failure so it will be important to closely monitor patients on this regimen.

A number of abstracts were presented looking at the addition of bendamustine, an older chemotherapy drug, to Velcade and /or Revlimid. In the elderly, non-transplant population, overall response rates were close to 90%. Grade 3-4 hematologic adverse events were approximately 40%, so particularly in light of other studies presented at the meeting, it will remain to be seen whether this is an optimal regimen for this population.

Relapsed/refractory patients

Dr. Usmani of the University of Arkansas for Medical Sciences in Little Rock presented the final results of a Phase II trial of Pomalyst in heavily pretreated, GEP-defined high risk relapsed/refractory patients. The results show that Pomalyst alone or combined with dexamethasone is active in this subgroup of patients.

Dr. Baz of the Moffitt Cancer Center presented results of Pomalyst and dexamethasone with or without cyclophosphamide in Revlimid-refractory patients. Results by arm were not reported, but the regimens are active with an overall response rate of 48.5% so far in this ongoing study which is encouraging in this population.

Dr. Weisel performed a subset analysis of elderly patients from the Phase III study of Pomalyst+Low-dose dex vs. High-dose dex and found that those patients responded as well and experienced similar toxicities as compared to their younger counterparts in the study, suggesting that this combination is feasible and effective in this population.

Early results were reported for several new agents, including the anti-KIR antibody, IPH2101 with lenalidomide, the Pan-Pim Kinase inhibitor, LGH447, and the selective histone deacetylase 6 inhibitor, ACY-1215, in very small patient populations. In each, there were patients who had a partial response or a very good partial response, which is encouraging; however, more patients need to be enrolled and followed to ensure each drug is safe enough to move forward and determine the right dose.

MMRF ASH Coverage

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

The MMRF Highlights From the 2013 ASH Annual Meeting Webcast/Teleconference will be held on Wednesday, December 18, at 1:00 PM ET! Hear our experts' perspectives on key myeloma clinical updates from ASH and learn about the latest advances in myeloma research and treatments. Register now by completing this form or calling 1-877-264-4949.

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