We are international
Donate

Recently in Dr. Durie's Blogs Category

ASH2014.jpg

To prepare for the upcoming 56th annual meeting of the American Society of Hematology (ASH), which will be held in San Francisco Dec. 6- 9, the IMF's Medical Editor Debbie Birns and I poured over 800-plus scientific abstracts related to myeloma that will be presented at the event.  While this year there doesn't appear to be the sort of news that will reset the needle in the myeloma landscape, a few trends stand out.

Targeting specific populations: After years of excellent outcomes with the novel therapies, researchers are now looking to fine-tune treatment protocols to maximize effectiveness in specific categories of patients. Studies presented this year consider patients who are young (#2059), elderly (#178; #81) with renal impairment (#2112) , African-American (#2030), obese (#2048), long-term survivors (#2019), and those with co-morbidities (#1301; #2136). This year there are also data in patients with both amyloidosis (#35) and POEMS syndrome (#36).

Diagnostic testing and monitoring protocols: Numerous studies to be presented at ASH 2014 examine the diagnostic efficacy of myeloma tests, including PET-CT (#3371; #3382), Freelite (#180), Hevylite (#3383), and sensitive Flow-MRD monitoring (#3390), among a total of nine abstracts dealing with MRD assessment.

New combinations: Fine tuning of novel combinations is an important aspect as noted above. Perhaps the most important presentation at ASH this year is the "ASPIRE" trial dataset which compares Kyprolis Rd with Rd alone (#79) in the 1-3 relapse setting. The more frequent and deeper responses with KRd will be discussed. Other novel combinations include Kyprolis given once/week (#175) as part of the KCd regimen (Kyprolis/ Cytoxan/ Dex) and reduced dose RVD (Revlimid/ Velcade/ Dex) so called "RVD Lite" for elderly patients (#3454). A new interesting combination is alternating VMP with Rd which is also very active in the elderly population (#178).      

Pipeline drugs:  A Phase 1-2 study (#82) of the oral proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone shows promise in newly diagnosed patients. Separate abstracts show benefit with Ixazomib used as maintenance (#82) and in patients with amyloidosis (#3450). Also presented will be data on selinexor (#4773), elotuzumab (#4762), ibrutinib (#31), oprozomib (#34), panobinostat (#32; #33) and the anti-CD 38 agents daratumumab (#84; #178; #3474) and SAR 650984 (#83; #4729).

SNAPSHOT OF IMF ACTIVITIES AT ASH 2014

While in San Francisco, the IMF will host several educational events, three of which will be live-streamed for viewing by those unable to attend the ASH meeting. I strongly recommend tuning in to learn first-hand what myeloma researchers are identifying as the most compelling data presented.

Critical Issues Need Answers:
Providing Best Options for Myeloma Treatments in 2014
Friday, December 5, 2014
12:00 pm PT
www.ash2014symposium.myeloma.org (live and archived)

The symposium will have a unique program format that includes "point-counterpoint" presentations and interactive case discussions. Each point-counterpoint session will begin with an initial clinical question followed by the presentation of two alternative views. Topics to be considered:

- When to Treat Patients With Smoldering Myeloma
- Assessing Response and Minimal Residual Disease Following Induction Therapy
- Incorporating Maintenance Therapy into Treatment Strategies
- Best Choices of Salvage Therapy in Relapsed/Refractory Myeloma

News Briefing:
The Latest on Blood Cancers - From Advances to Patient Advantages
Sunday, December 7, 2014
8 pm PT
www.myeloma.org (live and archived)

I will serve as moderator for this event, hosted by the IMF, the MDS Foundation on behalf of the MDS Alliance, the Lymphoma Research Foundation and the National Patient Advocate Foundation. A panel of leading blood cancer experts, advocacy organizations and patients will put ASH data into perspective, showcasing how scientific advances help patients.

Making Sense of Treatment:
The International Myeloma Working Group (IMWG) Conference Series
Monday, December 8
8 pm PT
www.imwgconferenceseries.myeloma.org (live and archived)

I will moderate and join with my colleagues and IMWG members Drs. Joseph Mikhael, Dr. Ola Landgren and Dr. Antonio Palumbo to tackle the key questions currently facing myeloma doctors and patients in light of the latest research presented at ASH.

DurieBlog_Stemcellv2.jpgMore than two dozen experts from around the world gathered in Minneapolis, Minn. Oct. 27, 2014 to assess the current landscape for autologous stem cell transplant (ASCT) as an option for myeloma patients who have relapsed. "Salvage" transplant--despite its rather gruesome-sounding name--offers an effective treatment choice for patients who have had a positive prior response to transplant.

During this era of novel therapies, salvage transplant has become an overlooked option. Presentations at the recent meeting, held under the auspices of the American Society of Blood and Marrow Transplantation (ASBMT), the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Workshop, the National Marrow Donor Program, and the International Myeloma Foundation, suggest that it is time to take a second look at the uses and recommendations for salvage transplant--both the name, perhaps, and the process.

We know that transplant has clear benefits as a high dose consolidation therapy for patients in the frontline setting, as described in the 2011 publication in the journal Blood, International Myeloma Working Group (IMWG) consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation.  The Minnesota workshop provided a wonderful opportunity to re-examine of the merits of second transplants as well.

The workshop was co-chaired by Dr. Sergio Giralt (Memorial Sloan Kettering Cancer Center) and Dr. Ed Stadtmauer (University of Pennsylvania School of Medicine, Abramson Cancer Center) representing the Center for International Blood & Marrow Transplant Research (CIBMTR) and the BMT CTN, and myself, representing the IMF and the IMWG. Other organizing committee members were Drs. Hari Parameswaran, Phillip McCarthy and Marcelo Pasquini.

Two of the key presentations during the workshop were:

Dr. Stadtmauer's excellent overview of the role of salvage ASCT. The data from the International Bone Marrow Transplant Registry (IBMTR) were compared with other reported studies. Outcomes correlated with the length of the first remission with ASCT, as well as the depth of response with both the first and second (salvage) transplants. To put the results in perspective with regard to other potential therapies for relapse patients, average remissions were about 1 year and subsequent overall survivals approximately 2-4 years.

Prof. Gordon Cook's (University of Leeds, UK) presentation of the results of his Myeloma X Trial. Salvage transplant with melphalan 200mg/m2 (ASCT) was compared with simply Cytoxan by mouth (400 mg/m2 once/week for 3 months). Starting in 2008, 174 patients were randomized. The full results were published recently in Lancet Oncology. It was very helpful to see the benefit of salvage ASCT in this randomized setting. The data also confirmed the importance of length of prior remission and depth of response.

After breaking into four work groups, workshop participants presented their ideas and recommendations, which included:

  • A need to summarize current knowledge
  • Risk stratification of patients at relapse
  • Assessment of the role of minimal residual disease (MRD) measurement after ASCT in the relapse setting
  • Studies of ASCT at different time points
  • A need for comparative effectiveness research (ASCT at relapse versus other options)

With priorities agreed upon by all of the workshop participants, the meeting concluded with a commitment to prepare guidelines promptly under the auspices of the IMWG and also to set up several planned studies. The IMF team of Lisa Paik, Diana Wang and myself were very pleased to be in attendance and will be working closely with the transplant team members to ensure rapid progress to achieve the planned outcomes. In addition, follow up meetings will occur as feasible at the Annual Meeting of the American Society of Hematology (ASH), the IMWG Summit and other venues.  

So, as always, 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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

DurieBlog_PanaV2.png

Today's Oncologic Drugs Advisory Committee (ODAC) hearing convened in an optimistic fashion with many in the myeloma community expecting there would be a recommendation for approval of panobinostat, an HDAC inhibitor used in combination with Velcade and dexamethasone. Publicly available data indicated a 3.9 months progression-free survival (PFS) or remission duration benefit with the three-drug panobinostat combination in patients who had been treated with 1-3 prior therapies. Note was made of significant toxicities, including low blood platelet levels (56.7%), diarrhea (25.4%), and fatigue (24.6%). However, going into the hearing, it was felt that the benefits outweighed these types of toxicities. From the myeloma patient perspective, there was the hope that panobinostat--representing a new class of drugs, the HDAC inhibitors--would be added to the myeloma treatment armamentarium. IMF staff and team members were at the ODAC hearing to affirm the continued unmet need for new drugs to treat myeloma.

Unfortunately, the presentation by Barry Miller, FDA Senior Clinical Analyst, dashed these hopes and expectations rather quickly. Miller pointed out that "missing data" was the main reason the FDA staff asked for the ODAC review. A large amount of data was unavailable or "censored," often because patients withdrew from the trial. The question was "Why?" Did the patients withdraw for incidental reasons (minor problems, trial logistics, etc.) or major toxicities, or even unexpected on-trial deaths?

As pointed out by Dr. James E. Liebmann (ODAC panelist from University of Massachusetts Memorial Medical Center), there was a disparity in "on-treatment deaths" in the panobinostat arm of the trial. The uncertainties about "censoring" apparently had led to four separate estimates of the PFS duration: 3.9 months (the duration reported); but also 2.2. months; 3.7 months, and 1.9 months. The FDA's own analyses gave a PFS difference of 2.2. months (9.9 months versus 7.7 months): rather disappointing compared to the 3.9 months provided by Novartis and their IRC (Independent Review Committee). IRC member Dr. Paul Richardson was unable to explain the reasons for the censoring to the satisfaction of the ODAC reviewers. Dr.  Richard Pazdur (Director of the FDA Office of Hematology and Oncology Products) himself raised the issue of censoring as an important concern.  

Ultimately, Dr. Richard Pazdur summarized what appeared to be the prevailing opinion of the ODAC reviewers.

            "PFS is not the question, there's clearly some benefit. ... The question is what is the magnitude of benefit and does it warrant the toxicity."

This perspective reflected the vote of 5-2 against a recommendation to the FDA to approve panobinostat. Dr. Liebmann also summarized the difficulties faced by the panel when confronted, as they were, by patient advocates (Robin Tuohy, Michael Tuohy and Diane Moran) including a woman who had benefitted for five years on panobinostat. He said, "First, this is a very difficult decision... this agent does have some activity ... and can be useful in this disease. But, "I think the toxicity outweighed the marginal benefit in PFS."

He went on to say that we should not give up on the drug or class of drugs, and certainly this is the case. Although it seems very unlikely that the FDA will go against the ODAC recommendation, it may still be possible that Novartis can answer the questions that were raised.

This is certainly a wake-up call for the myeloma community. What are the expectations for new drugs moving forward? Do we need to set the bar higher and try to achieve a much greater benefit, especially in the setting of important toxicities? My sense is that all involved will be recalibrating and setting their sights on longer remissions and lesser side effects - key needs for myeloma patients everywhere!

Stay tuned and we will keep you posted as many new drugs move forward in trials and hopefully give the benefits we all want to see. 

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

IMWG+tagline 2014-lyrs_a1_Thumb.jpg

For some time, members of the International Myeloma Working Group (IMWG), the IMF's research division, have been trying to identify and describe a group of patients without CRAB features.  Finally, Dr. Vincent Rajkumar, my co-chair in this project, has succeeded in bringing together the data, plus ideas and opinions from the IMWG members, to create new diagnostic criteria for myeloma. The criteria define a new "Pre-CRAB" group of patients who need treatment. A paper detailing the IMWG's updated criteria was published today in the journal Lancet Oncology.

This step forward has many important implications, not the least of which is the expectation that earlier treatment will lead to better outcomes!  This is the central idea of the IMF's signature Black Swan Research Initiative, in which early treatment is combined with close assessment of low levels of residual myeloma--minimal residual disease (MRD) testing--to push for therapy to achieve an MRD negative status that can lead to a cure.

The IMWG's updated criteria represent no less than "a paradigm shift in myeloma," said Dr. Rajkumar in a video interview.  "We are now willing to treat myeloma before symptoms happen. This is a big deal."  To read the IMF's announcement about the IMWG's updated criteria CLICK HERE

DurieBlog_Cure.jpg

In a recent paper in the journal Blood, Dr. Bart Barlogie and his team at the University of Arkansas in Little Rock claim they are "Curing myeloma at last: defining criteria and providing the evidence." This is a bold statement.  I would argue that while the paper provides a statistical/computer model, achieving and documenting true cure demands a follow-up of individual patients and cannot be predicted by a computer model.

But let's examine the approach taken here more closely to see why. In order to comment intelligently on this paper, one must search through the details of the methods used to define cure and provide the "evidence."  The term "cure fraction" is used in the paper.  It is derived from a combination of relative survival estimates (myeloma patient survival versus a patient without myeloma) and a complex computer model derived from a statistical approach used in 1982 for breast cancer. Is this a valid statistical approach to derive a "cure fraction"?  The authors of this statistical paper emphasize the constraints of the approach.  Two risk groups are required for the statistics to work.  Dr. Barlogie divides his patients into "high" and "low" risk so that this approach can be applied, but as readers are probably aware, the Mayo Clinic mSMART approach divides patients into three risk groups.  Which is correct or better?  We don't know.

After careful review, it appears that the "cure fraction" from the Little Rock "model" is considered to be: patients with "high risk" disease by gene expression profiling (GEP) who remain in complete remission (CR) for > 5 years and "low risk" patients by GEP who stay in CR for > 10 years.  Are such patients cured?  Clearly they are doing well, but the risk of relapse is not zero.  The label of "cure" is still just a statistical prediction, which is treatment and model dependent.  The outcome for each individual patient is determined by individual staging and prognostic factors, as well as non-myeloma related co-morbidities. Although calculating a "cure fraction" using the proposed model does allow comparisons between the different "total therapy" regimens used in Little Rock, it does not affirm that individual patients are actually cured. 

What is more helpful is to offer criteria that can predict a likely very good outcome at the start of therapy and/or early in the disease course.  This is the strategy of the IMF's Black Swan Research Initiative.  Using MRD assessment as a primary tool, it is possible to predict likely long remissions with complete remissions, especially with CR or stringent CR for patients with initial stable response.  Without claiming that patients are necessarily "cured" (meaning that there will never be a relapse even after 10 years), one can predict chronic disease control, which is most helpful to individual patients.  Thus, for example, in a young patient with good risk features--(ISS Stage I), normal F.I.S.H. testing (no t[4;14]; 17p-; 1q+ ), and normal LDH at baseline who achieves stringent CR and flow MRD-negative status--a very good outcome can be predicted.

The total therapy regimens clearly produce excellent outcomes for some patients. But in 2014, most patients and investigators are looking to novel therapy/transplant regimens that can be successful without the automatic double transplant approach plus other elements of the total therapy program.  The pioneering value of total therapy has triggered the search for other ways forward that can occur within the Black Swan Research Initiative, which allows use of MRD assessment to achieve the best outcomes.

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

DurieBlog_ChemoCost.jpg

This past weekend, "60 Minutes" focused on the high cost of cancer drugs. Although the discussion centered on treatments for colon cancer and chronic myelogenous leukemia, it is an across-the-board problem. Lesley Stahl interviewed experts at Memorial Sloan Kettering Cancer Center about the very high cost--$11,000 a month--for a new drug, Zaltrap, to treat colon cancer, versus $5,000 a month for a very similar drug, Avastin. The prolonged survival benefit of 1.4 months did not seem to justify the doubled cost. After a New York Times op-ed that made this point was published, Sanofi, the manufacturer of Zaltrap, immediately agreed to cut the cost in half! This rapid reaction prompted a chain of other reactions revealing the complexities involved in determining current cancer drug pricing.

The basic problem is that many new cancer drugs cost approximately $100,000 a year, and patients may need to take more than one at a time. Few patients can pay such costs directly. This is where the complexity starts. Prices, drug manufacturers argue, are linked to development costs that often amount to several $100 million to as much as $1 billion.

Dr. Hagop Kantarjian from MD Anderson Cancer Center in Houston takes issue with this argument. He examined the costs for the spectacularly successful drug Gleevec, to treat and control chronic myelogenous leukemia with indefinite, continuous use. The cost for Gleevec in 2001 was $28,000 a year. The development costs were recouped within the next decade. The Novartis Corporation has now earned a total of approximately $45 billion from Gleevec alone. The problem is that the cost of Gleevec is now $92,000 a year. What justifies that increasing cost over time? And what justifies the fact that patients in the US routinely pay 40-80% more for their drugs than do their European, Canadian and Australian counterparts?

The major justification offered by a representative of the pharmaceutical trade group on "60 Minutes" is that continued expensive research and innovation are required to develop new and better drugs. Who should pay for that innovation? Certainly not desperate cancer patients who are struggling to pay for lifesaving therapies.

After watching the interviews on "60 Minutes" I concluded that a financial structure that allows pharmaceutical firms to recoup the original investment and rewards them for their risk is fine. The system, however, must price those lifesaving drugs in a way that respects the needs of patients. I believe that the funding of additional and new innovation should be the focal point of a separate dialogue: How can we reduce drug costs and also make drugs available in a more realistic fashion in the global marketplace?

An honest dialogue would require all parties to come to the table - patients, manufacturers, legislators, government entities such as Medicare (which currently, by law, must pay full price for drugs), large hospitals and clinic groups (which negotiate discounts), insurers, and physician care providers (who are largely caught in the middle of complex buying arrangements). This must not be a blame game. Faced with an explosion in cancer drug costs, I believe there is enough momentum to find equitable solutions.

Any ideas for solving this problem will be most welcome and, perhaps, can initiate the necessary dialogue. A starting point for the conversation on behalf of myeloma patients might be our next International Working Group (IMWG) Summit, where we can invite all concerned parties to address this issue. 

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

DurieBlog_SavePlanet.png

In recent weeks, you may have seen full-page newspaper ads signed by 160 award-winning scientists from around the world pleading for funding to help save the planet in the face of climate change. This week, the United Nations convened what the New York Times called "the largest gathering of world leaders ever devoted to climate change."  The need is clear, but momentum  to take action has been strangely lacking.

Toxic chemicals not only affect our planet, they affect the humans who inhabit it. On September 10, the IMF held a congressional briefing in Washington DC that presented information about the link between chemicals at the 9/11 sites and cancer. There are clear links between exposure to certain environmental toxins and myeloma, but the cause of myeloma has typically been listed as unknown. There is no momentum to investigate further or try to prevent myeloma.

We have knowledge about environmental toxins that could help make myeloma a preventable disease; there is a long list of chemicals that cause cancer, and there are thousands more--equally or more toxic--in widespread use that have never been tested to see if they cause cancer.

Where is the motivation to use energy and chemicals wisely, and to begin de-contaminating our planet and its people?

Ever so slowly, the tide is beginning to turn. The Rockefeller Brothers Fund announced this week it will sell assets in fossil fuel companies and invest in cleaner alternatives.  Germany is building massive wind farms off shore to make a meaningful contribution to cleaner energy generation. The European Commission now requires toxicology testing for all new chemicals, and older chemicals are under much tighter review. Reduced use of chemicals is now on the agenda.  And innovative, environmentally sensitive companies such as Pylantis are working to replace petrochemical plastics with non-toxic, recyclable and compost-ready alternatives. Even China has announced a multi-billion-yen program to reduce and shift away from pollution.

study published recently in the journal Nature illustrates the need to eliminate toxic chemicals, not just in the environment, but in our diets as well. According to NPR, the study suggests that for some people, diet sodas may alter "gut microbes in a way that increases the risk of metabolic diseases such as Type 2 diabetes." The change in gastrointestinal microbes leading to diabetes and obesity is also linked to myeloma and other cancers (breast cancer and certain pediatric cancers), again demonstrating that there is a multi-system, multi-step disease causation process. In the case of diet soda, it is potentially a reversible process.

Reversing our exposure to toxic chemicals requires recognition of their effects: agricultural run-off leaks into rivers, lakes, and oceans, and then into fish and into food, causing DNA damage and reducing the strength of the immune system. Inflammation triggers the growth of damaged plasma cells in the case of myeloma, or of other cells, causing other types of cancer.

Cancer prevention requires a multifaceted approach that focuses on eliminating ALL toxic chemicals. Safe chemicals, real food, clean water, and clean energy are critical elements for insuring our good health.  

Is it too late? Let's hope not! We really need our planet--one on which myeloma is decreasing, not increasing.

I invite members of the myeloma community who have an interest in raising awareness about pollution and toxic chemicals to think about what might be done to change the momentum and get rid of the lethargy! I welcome your thoughts!

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

DurieBlog_tensteps.png

So much has been written and said about myeloma this year. But what is the bottom line for important changes in 2014 versus 2013 and before? Here are the high points in the context of the IMF's 10 Steps to Better Care, comprehensive guidelines with diagnostic and treatment information designed to ensure patients receive the best care.

Step 1: Know what you're dealing with. Get the correct diagnosis.

Early diagnosis is the new theme. Now we can start to treat myeloma before anemia or bone and kidney damage emerge.

As a result, quality of life for myeloma patients will improve forever. Triple therapy with KRd (Kyprolis, Revlimid, low-dose dexamethasone) in high-risk smoldering myeloma is producing MRD-negative status (no residual disease as shown using the new flow method) and is undoubtedly the pathway to cure for some patients.

Step 2: Tests you really need.

Sensitive imaging techniques detect very early active disease. Whole-body, low-dose CT should be considered if there is a question of bone disease at diagnosis or relapse. PET-CT picks up active myeloma inside and outside bone.

Step 3: Initial treatment options.

Revlimid/dexamethasone (Rd) on a continuous basis is a new, simple option for ongoing disease control, especially for the elderly and/or unfit/frail patients. Triple therapy with Revlimid/dexamethasone and a proteasome inhibitor gives superior outcomes for fit patients with or without initial auto transplant. FISH testing has become more complex--but we still do not know how to treat high- and low-risk patients differently, beyond individual, careful discussion with your doctor.

Step 4: Supportive care and how to get it.

Despite recommendations to the contrary, I believe it is still very important to limit the use of bisphosphonate therapy (Aredia and Zometa). Osteonecrosis of the jaw is a concern with long-term use. Since novel therapy combinations produce deeper response than in the past, ongoing bone destruction is less often a concern, and any survival benefit with very long-term Zometa use remains questionable.

Step 5: Transplant: Do you need one?

Autologous stem cell transplant (ASCT) is still an important treatment option. About 20% of patients have sustained remissions beyond 3 - 4 years with ASCT. ASCT with high-dose melphalan should be looked at as a consolidation that can provide benefit. It will be some years until we know which patients benefit the most.

Step 6: Response assessment: Is treatment working?

The new flow cytometry MRD test provides important pathways forward both for drug development and to achieve cure. When a new therapy leads to MRD-negative status for a patient, it can indicate that one therapy is decisively better than another. This can save millions of dollars and years in drug development time. As noted above, achieved MRD-negative status is the pathway to cure for the individual patient. You can read my blogs explaining this in more detail here, here, and here.  

Step 7: Consolidation and/or maintenance.

Consolidation and maintenance are both ways to achieve a better response, either within a few months or with ongoing therapy. The clear benefits still need to be balanced against quality of life issues and costs--and discussed with your doctor on an individual basis.

Step 8: Keeping track of the myeloma: Monitoring without mystery.

The HevyLite test provides a new blood (serum) test to accurately measure response at a very low level. It is a more sensitive and precise test for low-level monitoring versus the IFE (immunofixation electrophoresis) test, especially for IgA myeloma.

Step 9: Relapse: Do you need a change in treatment?

It remains important to assess possible relapse very carefully. Maybe one lab test is just a mistake? Double check. Are there CRAB features?  Is new treatment really needed? If new treatment IS needed, can a prior successful therapy work again? Discuss the options with your doctor.

Step 10: New trials: How to find them.

It is exciting to see truly new types of therapy having an impact! Anti-CD38 antibodies will definitely have a role. The striking response with measles virotherapy is a breath of fresh air in thinking about myeloma. If virotherapy really works, could a single shot cure the disease despite all the mutations and risk features we keep hearing and reading about? Perhaps. And wouldn't that be amazing? So let's see what happens with the new virotherapy trials Dr. Stephen Russell and the Mayo Clinic team are starting this fall. The first patient who received the massive dose of measles virus is still doing well.

As always stay tuned for updates: we have ASH 2014 to come!

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

MyelomaPersonalized.png

Recently there has been discussion among some myeloma patients concerning the need for fully personalized myeloma treatment. Is there a benefit to this type of approach? Intuitively, the answer is "yes."  But I would argue that "no" is the better answer.

Let me explain. Yes, there are many variants of myeloma which could be considered individually and personally. These include secretory myeloma (IgG, IgA, IgD: Kappa/Lambda only --- ) ; non-secretory myeloma, plasmacytoma, plasma cell leukemia, extramedullary disease and more. But there is a fundamental similarity in biology. Immunomodulatory drugs (IMiDs) (e.g. Revlimid and Pomalyst) combined with proteasome inhibitors (e.g. Velcade and Kyprolis ) produce excellent responses for most subtypes of disease. Even in the relapsed/refractory setting, Kyprolis/Pomalyst/DEX produces responses (>/= PR in 70%), including in patients with high-risk 17P- disease. Long remissions occur for many patients.

Thus, although it is now known that myeloma cells have hundreds of mutations in different subclones, most of these are wiped out by newer novel combinations. The subclones which persist or recur are the ones which require special attention.

Fortunately, a new Flow MRD test, which is highly sensitive and can be used to identify and sort residual clones, is ideal for studying such resistant subclones. A vital element of the IMF's Black Swan Research Initiative is studying the patterns of resistant disease--which are already emerging--and using this knowledge to guide treatment selection.  Figuring out how to mop up disease that remains after initial therapy is much more manageable, in my view, than attempting to individually tailor treatment at the outset.

It appears that broadly applicable relapse therapies can be developed. Studies from single cells or clones from individual patients provide clues for successful approaches that can be applied broadly to others with similar subclones.

The opposite approach of attempting to target each of many, many individual mutations is truly challenging and, I believe, ultimately not feasible. There are too many individual mutations and too much time and expense needed to develop multiple targeted therapies.

If key so-called "driving mutations" can be found, this will be the answer for new drug development. But, again, these therapies will be broadly applicable to treat patients with resistant disease and/or combined with current treatments to start curing patients! The anti-CD38 antibody therapies are examples of this type of more broadly applicable agent that can significantly contribute to better outcomes.

So, although studies of individual patients are extremely helpful, the goal is to have broadly applicable therapy--to "lump and not split" and learn more from treating larger numbers of patients together, not separately. Myeloma can be divided into apples and oranges and maybe even pears, but not a complete fruit cocktail, which would be counter-productive from the standpoint of both diagnostics and treatment.

The argument against fully personalized therapy is therefore very important in the way that myeloma research moves to achieve the best results for all patients in the most rapid fashion.

Stay tuned as the Black Swan Research project moves research in this direction!

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

DurieBlog_MRD.jpg

After more than10 years of progress in myeloma treatment due to the introduction of the novel therapies, researchers now need to know how to eliminate the myeloma cells that remain after current therapies. Today, we are on the brink of having a test that will help us have a clear plan to eradicate residual disease.

The new highly sensitive and extremely accurate flow cytometry test developed with the support of the IMF's Black Swan Research Initiative by Spanish researchers is that test.

It is proving itself to be the most affordable, most sensitive, most easily accessible MRD test yet, and earned near-unanimous acclaim from researchers at a flow workshop co-hosted by the IMF at Memorial Sloan Kettering Cancer Center (MSKCC) in July, as I reported in my blog here.  Asked by an audience member, "Can one of the fluorescent dyes (fluorochromes) used in the FLOW MRD test be changed or improved?" Dr. Alberto Orfao, the FLOW MRD test developer from Salamanca, Spain, said, "Of course - possibly yes!" But these types of tweaks can be never ending, added Dr. Orfao.

 "Do we have a test right now which is working very well? The answer is: YES," said Dr. Orfao. "It is standardized, reliable and sensitive enough at the 10-5 level. Nothing more is needed. It is time to stop tweaking and move forward with full validation in patient trials!"

As readers of this blog are no doubt aware, some in the myeloma community argue that we need a DNA sequencing [molecular] test for MRD in the bone marrow. The main potential advantage of the molecular test, they contend, is greater sensitivity versus flow. However, the new flow method is now equally sensitive and provides excellent prediction of very good patient outcomes. I would add that a more sensitive test might encourage overly aggressive, unnecessary treatment, causing more harm than good!

To be sure, careful comparisons of molecular and flow testing are essential. But after careful consideration of all the pros and cons of each method, the IMF's Black Swan Research team has chosen Flow MRD as the primary MRD detection method--as the benchmark for comparison with other methods.

On the pro side, an important benefit of the new flow method is that it utilizes a stored computer database of all possible myeloma clones or subclones for instant comparison and classification. All myeloma clones or subclones can be identified by flow methodology at any point during the course of the disease. Conversely, the DNA "dominant clone" approach risks missing minor subclones, which take over later in the disease. If residual subclones are identified, these can be characterized and sorted one by one with the flow method for detailed studies, including full sequencing of the DNA.  Applying DNA technology in this combined flow/ molecular fashion is simple and very informative.

The new flow method allows careful measurement of myeloma at the very low levels of disease needed to predict excellent outcomes and enhance treatment for some patients to achieve an MRD-Negative status.

Since the flow test is standardized, widely available and cheap, there is no longer a need for another method such as the molecular method, which has a number of disadvantages. One limitation of the molecular method is that the bone marrow from the time of diagnosis (or a new relapse) is needed to identify the "dominant or main clone" for future monitoring. In my opinion, the molecular method has other disadvantages. It is more expensive--estimates range between $750 and $1,000 (compared to between $100 and $150 for the new flow test)--and cannot be performed at the local center. To those who would argue for using both the molecular and flow tests, a practical point to keep in mind is that "splitting" bone marrow samples into two parts, one for flow and one for molecular, is not ideal. For the best results, the flow test needs the maximum number of myeloma cells from the "first pull" from the bone marrow aspiration sample to give the most accurate results.

Thus, although it is important to compare the flow and molecular methods in some trials, it seems likely that flow is all that we need! Moving forward, there can be some "fine-tuning," with the addition of the Hevylite ratio test as a quantitative replacement for immunofixation (IFE) and whole body PET/CT to directly evaluate myeloma disease outside the bone marrow.

So stay tuned as the Black Swan Research Initiative moves rapidly forward to achieving chronic disease control and a cure!

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 InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.