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November 2013 Archives : Myeloma Voices

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Last week, in Part I of my overview of abstracts released by the American Society of Hematology (ASH) in advance of the group's annual meeting in New Orleans, I focused on combinations using the approved novel agents. Hearing more details and follow-up about these novel combinations at the ASH meeting, Dec. 7-10, will be very important.

In this segment, I start by summarizing where we are with new agents in earlier trials at the Phase I-II or preclinical stages. There are eight agents which are of interest. 

  • anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284) 
  • MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983)
  • ARRY 520 (abstracts #285 and #1982) 
  • ACY-1215 (abstracts #759 and #3190)
  • selinexor (also known as KPT-330, abstract #279)
  • anti-CD 138 monoclonal antibody (BT062, abstract #758) 
  • panobinostat (abstract #1970)
  • bendamustine (abstract #1971)

As was the case last year at ASH, the most promising single-agent activity against a new target is with anti-CD 38 monoclonal antibodies. The single-agent activity of the Sanofi compound (SAR 650984; abstract #284) is illustrated in a dose escalation study involving 32 patients which produced several greater than or equal partial responses. With daratumumab in combination with Revlimid/dexamethasone (anti-CD 38 MAb; abstract #1986) all 6 patients had greater than or equal partial responses with 3 having greater than or equal VGPR. Laboratory studies using a human-mouse hybrid model  (abstract #277) have shown strong synergy with lenalidomide (Revlimid). 

With ARRY 520 (a kinesin spindle protein [KSP] inhibitor), a 16% partial response rate was noted in a study of 32 patients incorporating weekly dexamethasone (#285). Combined with carfilzomib, a small study showed a 58% response rate (#1982). There were again several reports about MLN 9708, the new oral proteasome inhibitor. Results in the newly diagnosed (#535), relapse (#1944), and maintenance settings (#1983) all showed promise and good tolerability. 

Results with ACY- 1215 and selinexor are still early. ACY-1215 (selective HDAC 6 inhibitor) is an oral agent being evaluated in combination with Velcade (#759) and Revlimid/dexamethasone (#3190). Although the combinations are well tolerated, only a few higher-level responses have been seen thus far.

The preclinical results with the XPO 1/CRM 1-dependent inhibitor (selinexor) are reported and show good synergy with carfilzomib (abstract #279). Results with panobinostat (abstract #1970) again show some promise in combinations with Velcade and dexamethasone. Rather surprisingly, the combination of bendamustine with Velcade plus dexamethasone shows really excellent results in the relapsed/refractory setting, with PFS median results of 10.8 months and overall survival median of 23 months (abstract #1971).

And there you have it!  Not a lot dramatically new to add, but it is quite encouraging that several agents are continuing to move strongly forward in clinical trials.

As we move towards 2014, the ASH abstracts that will have the biggest impact are those which provide a better understanding of underlying biology and how to test for minimal residual disease (MRD) and risk factors, and those which provide insight into trigger factors and disease subtypes such as extramedullary disease and plasma cell leukemia.

Testing for Minimal Residual Disease (MRD) and MRD-Zero

Over 25 abstracts deal with minimal residual disease testing, monitoring, and risk assessment. Abstract #402 from the Salamanca/Pamplona team with Bruno Paiva as the lead author characterizes minimal residual disease at the immune and molecular level. In abstract #531, Paiva extends these observations by identifying and characterizing subclones which emerge during the course of treatment. This understanding of subclones which persist or emerge despite current novel therapy is key to developing more successful treatment and achieving MRD-Zero--the primary goal of the Black Swan Research Initiative (BSRI)

Quite a number of abstracts touch on the comparison of various methods to most accurately assess MRD-Zero. Another key abstract from Spain on this topic (#1848) compares flow and molecular techniques. Different aspects of risk and response assessment are covered in abstracts #762, #1841, #1842, #1868, #1878, #1902, #1936, #3126, #3152, #3223, #4290, #4647. Although DNA methods may be slightly more sensitive, a new flow technique may prove to be equally, if not, more sensitive, and has the advantage of allowing identification and molecular study of any residual clones. Hearing all the details at ASH will be very important. So much more to learn!

An important report (abstract #1936) from the Bologna team shows that 29% of patients who appear to be in complete response by other methods of assessment have positive PET/CT scans. Thus, follow-up imaging is essential to confirm the residual disease status. Another abstract (#762) shows that early improvement in the serum heavy/light chain ratio (HLCR, Hevylite) predicts for a high likelihood of subsequent development of MRD-Zero.

Understanding the Biology of Myeloma

In the category of understanding the biology of myeloma better, I draw your attention to a few abstracts. A collaboration between Washington University and Mayo Clinic researchers (abstract #397) has revealed that in mice predisposed to myeloma, one particular gene (Samsn 1) is missing in all cells (called a germline mutation), which results in both B cells (precursors of myeloma cells) and microenvironmental cells such as macrophages and osteoclasts being primed for activation. Another abstract (#3116) also suggests that we take a closer look at predisposing and triggering factors for MGUS and myeloma. 

The team of French researchers from Nantes shows that in 22.7% of patients with MGUS and myeloma, the monoclonal protein reacts against infection: specifically hepatitis C, Epstein-Barr Virus (EBV), and the stomach infection H. Pylori. This raises the possibility that infection can trigger initial disease and possibly relapsing disease. Clearly further studies are required. Another aspect is obesity, which is known to be linked to the onset of both MGUS and myeloma. A large epidemiologic study (abstract #1872) shows a strong association between increasing body mass index (BMI) at age 20 years and a younger age at diagnosis in African-Americans with multiple myeloma. Definitely food for thought!

Subtypes and Categories of Patients

Considering different subtypes and categories of patients with myeloma and related diseases, there are several abstracts: young patients (< 40 years: abstract #3226); older patients (abstract #687); IgD myeloma (#s 1880 and 1935); IgM myeloma (#1881); plasma cell leukemia (#761); extramedullary disease (EMP; #s 1896, 3141, and 3188); central nervous system involvement (abstract #3118); patients susceptible to very early death in ≤ 2 months (#3195) and those patients in remission for ≥ 6 years (abstract #3366). A small, but important point in abstract #3195 is that patients at risk of death within the first 2 months of the myeloma diagnosis are those with unrelated serious health issues. With the advent of novel therapies, it is only months to years later that the impact of high-risk myeloma features is seen as a challenge in controlling progressive or relapsing disease: a reassuring point.

As far as molecular risk features, there are fewer than the usual number of abstracts dealing with this topic at ASH 2013: abstract numbers 399, 529, 530, 1846, 1855, 1856, 1992, 3092, 3108, 3111, 3114, 3121, and 3147. There are two key practical points. In abstract #529, it is noted that poor risk features (such as FISH t(4;14) or -17p) will prevail even if there is hyperdiploidy (extra chromosomes: normally considered to be a good-risk feature). Thus the presence of hyperdiploidy does not counterbalance poor-risk features. A related, and somewhat frustrating point (in abstract #1992), is that the 1q21 FISH abnormality does confer poorer risk, but is not part of the standard FISH testing panel!  So, back to the drawing board again to have a new recommended FISH testing panel.

And there you have it for now: many interesting abstracts, some which I predict will prove to be very important, and others where we are waiting to hear more at the time of the ASH meeting in New Orleans in December.

Please remember the IMF's various educational programs at and from ASH: live-streaming of the Satellite Symposium on Friday, December 6th, and the Conference Series on Monday, December 9th, blogs/Twitter ongoing, interviews with lead investigators immediately after ASH, and post-ASH highlights in January 2014!

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.

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The ASH 2013 abstracts were released on November 7th.  As usual, there are a staggering number of myeloma abstracts: this year, 830. The IMF team has been reviewing them studiously, trying to identify what is new, interesting, and important. We have identified 131 abstracts worthy of specific comment: 38 oral presentations and 93 posters.

The first key point is that a myeloma abstract is one of the top "plenary session" abstracts for ASH overall this year. Abstract #2 (I believe this may be its priority ranking for 2013 ASH) will be presented by Dr. Thierry Facon of the Intergroupe Francophone du Myelome (IFM) and details the results of a Phase III trial involving 1,623 patients over age 65 years (a huge study) which compares lenalidomide (Revlimid® [R]) low-dose dexamethasone (d), given until disease progression (ARM A) with Rd give for 18 cycles (ARM B) with the combination of melphalan, prednisone, andthalidomide (MPT) for 12 cycles (ARM C).  

This study thus compares two drugs (Rd) - with and without maintenance - with three drugs (MPT).  According to the abstract, there is a 28% reduction in the risk of progression with the Rd (ARM A) versus MPT (ARM C), which is statistically significant. There was also a trend toward survival benefit: 22% reduction in the risk of death.  A topic of keen interest is also the rate of second primary cancers (SPMs).  The question has been whether SPMs are more linked to Revlimid use versus melphalan, as for example, in the MPT regimen. The hematologic SPMs were 0.4% with Rd in ARM A versus 2.2% in ARM C, which certainly trends toward more SPMs with melphalan exposure versus Revlimid. The solid tumor SPMs were 2.8% in both arms, which is now considered to be an expected rate for myeloma patients. I am sure we will hear more at the ASH presentation. Of added importance, it is widely speculated that these results can lead to the approval of the Rd doublet as frontline therapy both in Europe and in the US. This approval is particularly important outside the U.S., where drugs can only be prescribed strictly within the labeled indication.

Of the 131 interesting and important abstracts we have identified this year, 43 involve the approved novel agents thalidomide, lenalidomide (Revlimid), bortezomib (Velcade), pomalidomide (Pomalyst) and carfilzomib (Kyprolis). For thalidomide, aspects presented will include thalidomide consolidation (#537), which improved both progression free (PFS) and overall survival (OS), and thalidomide combined with dose escalation of carfilzomib (#688), which proved to be a rapidly effective regimen for newly diagnosed myeloma. For lenalidomide, there are multiple aspects presented and discussed in numerous abstracts.  

An overarching topic, already touched upon with abstract #2, was the benefit of lenalidomide for maintenance and/or as ongoing continuous therapy. Data include the follow-up of the IFM lenalidomide maintenance trial post autologous stem cell transplant (#406), which again showed PFS but not OS benefit, and a meta analysis of lenalidomide maintenance (#407), which assesses PFS, OS, and SPM rates overall. An additional concept explored in the maintenance phase of the MM-015 update (#405) from the Torino team is the value of lenalidomide maintenance considering "PFS 2," which refers to the length of the second response in patients relapsing, with or without prior lenalidomide maintenance. The PFS 2 was markedly improved in the melphalan prednisone Revlimid arm (MPR-R) with Revlimid maintenance versus the melphalan prednisone alone (MP) arm. This added piece of information is now being considered as part of the drug approval process, especially by the European Medicines Agency (EMA). 

For bortezomib (Velcade), there are several important observations.  First, in abstract #1968, the cumulative dose of administered Velcade in the VMP (Velcade, melphalan, and prednisone) arm of the Phase III VISTA trial is directly linked to improved overall survival outcomes. This is a key educational point in the use of Velcade, which has become much better tolerated with the subcutaneous (SQ) route of administration. Another important abstract (#3187) evaluated cardiac issues (such as heart failure) in myeloma patients in a retrospective analysis of bortezomib (Velcade) trials. Use of Velcade was associated with a low rate of severe (grade ≥ 3) heart failure in both newly diagnosed (2%) and refractory (1.9%) patients. This rate is not statistically different from the expected background rate. 

Other interesting abstracts include numbers 1940 and 1969, which report upon the combination of Velcade with pomalidomide and dexamethasone in relapsed myeloma. This is clearly a very active and well-tolerated regimen. Follow-up data are reported on other Velcade combinations, including Velcade/Cytoxan/dexamethasone [CyBord] versus Velcade/Revlimid/dexamethasone [VRd] (#3178), CyBord long-term follow-up (#3192), VTD long-term follow-up (#3221) and Velcade combinations in the elderly with or without autologous stem cell transplant (#3344).  Key points here include the impressive efficacy of CyBord (versus VRD: #3178) with a substantially lesser cost and the sustained longer-term benefit of the CyBord regimen (#3192).

Pomalidomide is covered in several abstracts, basically confirming the efficacy in the relapsed/refractory setting (#408, 686, 689, 690, 1979, 3185, 3191, and 3198).  Points of note include efficacy with high-risk features, such as 17p- on FISH testing (#689) abnormal cytogenetics (#408) or high-risk GEP (#3191). The combination of pomalidomide with carfilzomib also continues to show considerable promise (#690).  Of interest, the combination of Biaxin (clarithromycin) with pomalidomide plus dexamethasone is also remarkably effective (#1955).

Carfilzomib (Kyprolis) was a part of many trials reported this year at ASH. Combinations showing great promise are carfilzomib/Revlimid/dexamethasone (CRd; numbers, 538, 1939, and 3220), Carfilzomib/Cytoxan/dexamethasone (CCd: #585), carfilzomib/MP (CMP: #1933), and carfilzomib along with Biaxin plus Revlimid/dexamethasone (#3216).  Response rates are high and deep: prolonged benefit is being achieved. It will be very helpful to learn the full details of these exciting combinations at ASH.

Next week: In part two of this ASH preview, I will cover new drug updates as well as a diversity of other topics, including many details about testing for minimal residual disease (MRD) and new molecular/genetic research findings. So stay tuned!

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.

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There is a constant flood of information about food. This is partly because we all eat and someone is always trying to sell us a cookie, organic salad, or whatever we want or crave.  But it is also because there is a lot of new and important information, which can guide our decisions.

Enter exhibit number one.  A new study in rats purports to show that the cream in Oreo cookies is as addictive as cocaine!  Can that possibly be true?  The study has certainly raised much controversy.  The study shows that in a common maze-type study the rats went to the side of the maze to get an Oreo versus a rice cake on the other side.  In a separate experiment, rats preferred cocaine to a salt solution - again, possibly not surprising. The key additional part of the study was that the researchers also studied chemicals released in the reward region of the brain: an area called the nucleus accumbens. The chemical activation was greater in Oreo-eating rats than in rats receiving cocaine injections!  

Critics of the study emphasize that this is just one step in assessing truly additive behavior.  But, nonetheless, the results are quite impressive? and people do love, even crave, Oreos.

So is it the combination of high fat, high sugar cream, or maybe some other component, which is producing this effect? This is where the results become broadly important because this is the question about many foods for which craving can become a problem.  For example, why do so many people crave McDonald's French fries?  It is not just the potatoes themselves, but what is added to give the wonderful taste and smell, which is the hallmark of these fries. The flavor comes from a special concoction of chemicals, developed as a result of detailed research.

What is important is that many processed foods are hard to resist, but should really be avoided, with "good food" as a better choice.

So what is new about good food?  The new news is similar to the old news: a Mediterranean style diet is strongly linked to greater health and well being, especially for individuals at midlife into their later years beyond 70 years of age. The elements of a Mediterranean diet considered in this study were nine components: vegetables (excluding potatoes), fruits, nuts, whole grains, legumes, fish, red or processed meats, moderate alcohol, and the monounsaturated fatty acid- saturated fatty acid ratio. A perfect score is nine, if adherence falls within preferred intake levels.  One is a perfect score for each element and zero is the score if one eats too much meat and/or too few vegetables or fruits, for example.  

This study, which included only women, is consistent with a whole range of other data and reports. Avoiding processed foods and soft drinks is part of the recommendation. Of related interest is news reported in the New York Times that the FDA is proposing to declare partially hydrogenated oils (the source of trans fats) as unsafe. Companies which say they are safe will be required to scale "a high hurdle given the scientific literature," the report states.

So what things do we continue to be unsure about? An important area of uncertainty is Complementary and Alternative Medicine (CAM). This includes everything from St. John's wort to grapefruit juice. Do they give added benefit?  Are they safe to take along with other therapies?  An upcoming conference call on November 13, 2013 led by IMF Nurse Leadership Board Member, Sandra Kurtin, will provide a comprehensive review and update. The bottom line is that there is unfortunately still a lot to learn and all supplement use should be discussed with your doctor or healthcare provider.

And so the new is similar to the old. Avoid processed foods. Try not to get addicted to anything.  Focus as much as you can on fresh, organic produce within the framework of a Mediterranean style diet. And in those quiet moments, try to resist the Oreos!

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF Hotline staff instead. Specific medical questions posted here will be forwarded to the IMF Hotline. Questions sent to the Hotline are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate. To contact the IMF Hotline, call  800-452-CURE, toll-free in the US and Canada, or send an email to hotline@myeloma.org. Hotline hours are 9 am to 4 pm PST. Thank you.

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During the last week of October, I had the pleasure of being a guest speaker at the annual multiple myeloma seminar in Seoul, South Korea hosted by the Korean Blood Cancer Association (KBCA) and the Korean Multiple Myeloma Working Party (KMMWP), a division of the Korean Society of Hematology (KSH).  This was the second time that the International Myeloma Foundation (IMF) had the honor of participating in this meeting to address myeloma patients in Korea, and the opportunity to meet with the team of dedicated physicians and members of the KBCA staff.

More than 250 patients and family members listened to presentations by the KMMWP on transplant, clinical trials, frontline therapy, and relapse. Fortunately, they were also excited to learn about advocacy, which is where I came in. While it has no direct translation in the Korean language, I explained that the word advocacy applies to many activities that meet the dictionary definition of " the act or process of supporting a cause." This can mean educating others about the disease, raising myeloma awareness in the community, or telling your story as a patient to the media or policymakers to illustrate the need for continued innovation in blood cancer and access to treatment for patients in Korea.

The message seemed to resonate with the audience as many patients approached me after the meeting to thank me for my participation and compassion for patients in Korea. I also learned that there is a lot of online advocacy activity already happening through a myeloma patient group affiliated with KBCA, the Korean Federation of Multiple Myeloma Patients (KFMMP).  I had the opportunity to meet with them and learn more about their organization and discuss ways in which we may collaborate to improve the circumstances for patients in Korea. My hope is that there will be much more to report on that effort in the near future.

A brief history of the KBCA:  The Korean Blood Cancer Association is a nonprofit organization that was established in December 1995 in Seoul, South Korea with the mission of supporting patients through education, consulting, support programs, and financial assistance. The association offers various programs that are similar to ours at the IMF and they are run by a compassionate group of patients and social workers.  KBCA also started the Hope Medical Information Center, which is run by nurses and social workers, and offers support programs to patients and their families. It is the only center of its kind in Seoul where patients can come to learn, meet other patients, get emotional support, and participate in a programs including patient mentoring, medical information sessions, yoga therapy, mind healing, and nutritional/cooking classes, to name a few. I was very impressed with the number of classes and programs offered and how they aim to treat the whole patient, physically, mentally, emotionally, and spiritually. 

While we may come from very different parts of the world, it was quite clear that the passion and dedication that we have for the myeloma community is the same from one side of the world to the other, and we will all continue to work tirelessly to support patients and their families battling myeloma.
 
I'd like to sincerely thank the staff at KBCA, HOPE Center, and the members of the KMMWP for your hospitality, your compassion for patients and for the amazing opportunity to be a part of your outstanding work!