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Top 10 Discoveries Of 2013 In Multiple Myeloma

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Published: Jan 25, 2014 9:58 am

Last year, 2013, was a great year for myeloma research.

We had a number of important discoveries that will impact diagnosis, moni­tor­ing, prognosis, and treatment of the disease. Some new findings provide us with a better understanding of myeloma biology and mecha­nisms of drug resistance, while others present information that immedi­ate­ly impacts how patients are man­aged.

Collectively, these discoveries represent a significant advance to­wards our goal of curing myeloma.

I present here my list of the top 10 most compelling scientific findings and discoveries of 2013 in the field of multiple myeloma.

I have tried to highlight the specific reason why each of these discoveries merits a place in this list. Some, especially the top five, have implications that I think extend beyond the actual finding, and I have provided this perspective as well.

#10 Clinical, genomic and imaging predictors of myeloma progression from asymptomatic mono­clon­al gammopathies (SWOG S0120) by Dhodapkar and colleagues: Blood, October 21, 2013, vol. 123, no. 1, 78-85.

This study conducted by the Southwest Oncology Group (SWOG) looked at 331 patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering (asymptomatic) multiple myeloma (SMM).  These are both diseases that can progress to multiple myeloma.

We have known for many years that there are several distinct subtypes of multiple myeloma that differ in terms of chromosomal abnormalities.  The major finding in this study was that the main genetic subtypes of myeloma were already present at the smoldering stage. Further, a gene expression profiling-based method of classifying these subtypes was also able to predict the risk of progression from smoldering myeloma to multiple myeloma.

Since we have started to look at ways to intervene early in the smoldering myeloma stage, the results of this study are timely and valuable.

#9 Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile by Paiva and colleagues: Blood, November 21, 2013, vol. 122, no. 22, 3591-3598.

The Spanish myeloma group is well known for their cutting-edge techniques in multi-color flow cytometry to analyze and profile myeloma cells. In this study, they applied these techniques to determine if circulating myeloma tumor cells in the blood differed from myeloma cells in the bone marrow.

They found that circulating myeloma cells represent a unique subgroup of bone marrow myeloma cells, and that, curiously, these myeloma cells preferred to escape the confines of the marrow to enter the circulating blood at night when the patient was asleep! The paper provides the specific features of these cells.

These findings will help us understand how myeloma evolves over time from a disease limited to bone and bone marrow to one that goes to other tissues and organs, and eventually even to leukemia in some pa­tients. They will also provide us with the information we need to detect these aberrant cells in the blood as we pursue eradication of minimal residual disease (MRD).

#8 SAR650984, a CD38 monoclonal antibody in patients with selected CD38+ hematological malig­nan­cies – Data from a dose-escalation Phase I study by  Martin III and colleagues: Blood, October 21, 2013, vol. 122, no. 21, abstract 284 (see related Beacon news and presentation slides courtesy of Dr. Joseph Mikhael).

SAR650984 is an antibody that targets a protein called CD38 on multiple myeloma cells. Data from a Phase I multi-center trial of this agent in blood cancers was presented at the annual meeting of the American So­ciety of Hematology in December 2013.

Of the 39 patients treated, 34 had multiple myeloma. Among 24 patients with myeloma treated at a dose of 1 mg/kg or higher, 25 percent responded; and at a dose of 10 mg/kg or higher, 31 percent responded to treat­ment.

This is a remarkable finding because only a small number of drugs have shown “single-agent” activity in multiple myeloma – on their own without adding other drugs like steroids or Velcade (bortezomib) or Rev­limid (lenalidomide) to boost the response. In this regard, SAR650984 joins daratumumab, another CD38 antibody that has also shown single-agent activity.

Of note, other new drugs that have shown single-agent activity in myeloma include filanesib (ARRY-520, a kinesin spindle protein inhibitor), cyclin dependent kinase inhibitors (for example, dinaciclib), indatuximab ravtansine (BT062, an antibody targeting CD138), and afuresertib (GSK2110183, an oral Akt inhibitor).

#7 Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications by Bjorklund and colleagues: Leukemia, June 13, 2013, doi: 10.1038/leu.2013.174

One of the big frustrations in multiple myeloma is that resistance to treatment emerges right when things seem to be going just fine. This has been a major roadblock to finding a cure. In order to cure myeloma, we need to be able to understand how myeloma cells are able to find a way around some of our most capable drugs.

In this study, myeloma experts from the MD Anderson Cancer Center identified the protein CD44 as a me­di­a­tor for the development of resistance to Revlimid in myeloma. Resistant myeloma cells had higher than normal levels of CD44 on their surface, which then allowed them to bind to bone marrow stroma and avoid killing by Revlimid, a process called cell adhesion-mediated drug resistance (CAM-DR).

This study not only provides us with a mechanism for resistance to Revlimid, but suggests that we may be able to overcome this problem by using drugs that specifically target CD44.

#6 Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor re­sistance in multiple myeloma by Leung-Hagesteijn and colleagues: Cancer Cell, September 9, 2013, Volume 24, Issue 3, 289-304.

As with Revlimid, resistance is also a major problem that emerges during therapy with Velcade.

In this multicenter study, researchers identified the presence of a subgroup of primitive cells in myeloma that are able to evade killing by proteasome inhibitors such as Velcade.  These included Xbp1s negative pre-plasmablasts and earlier stage CD20+ B cell progenitors that appear to survive despite therapeutic doses of Velcade. They found that Xbp1 was required for the maturation of precursor cells to mature myeloma cells that secrete monoclonal protein, and that its absence contributed to resistance to proteasome inhibition.

This study and the earlier one on Revlimid resistance are critical to our understanding of how and why resistance develops to our treatment regimens in myeloma, and they enable us to identify and overcome barriers to the goal of curing myeloma.

#5 A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly di­ag­nosed symptomatic myeloma with an MGUS-like signature and long-term disease control by Paiva and colleagues. Leukemia, October, 27, 2013, 2056–2061 (see related Beacon news).

I have earlier written about the limitations of complete response as a treatment goal in myeloma (see my Beacon column on the subject). For example, the monoclonal (M) protein that is detected in the blood of myeloma patients may come from both the true myeloma clone, as well as the precursor MGUS clone. Thus, some patients with residual M-protein after treatment may in fact have only residual MGUS cells remaining. They may technically not have achieved a complete response but yet have extremely long survival.

In this study, the Spanish myeloma group examined 698 patients with newly diagnosed myeloma. They found using sophisticated multicolor flow cytometry that 8 percent of patients had an MGUS-like profile at baseline. These patients had excellent survival; about 65 percent were alive at 10 years, higher than other myeloma patients. Further the survival was similar whether or not they achieved a complete response.

The study identifies one subset of patients with myeloma who have excellent outcomes regardless of wheth­er or not they achieve complete response.  Further, in my opinion, the study strengthens the argument that the real goal of myeloma therapy should be to try and eradicate residual clonal malignant cells; trying to eradicate residual clonal premalignant (MGUS) cells may not only be unnecessary but also places patients at the risk of needless toxicity.

#4 Shared by:
Progression in smoldering myeloma is independently determined by the chromosomal abnor­mal­i­ties del(17p), t(4;14), gain 1q, hyperdiploidy, and tumor load by Neben and colleagues: Journal of Clinical Oncology, December 31, 2013, vol. 31, issue 34, 4325-4332 (see related Beacon news); and
Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma by Rajkumar and colleagues: Leukemia, August 2013, vol. 27, issue 8, 1738–1744 (see related Beacon news).

Two studies occupy the top 4 spot. They have strikingly similar conclusions: The risk of progression in smoldering multiple myeloma is significantly different based on the underlying cytogenetic subtype of the disease. The highest risk of progression was seen with smoldering multiple myeloma and either t(4;14) or del(17p) abnormalities, while smoldering multiple myeloma with trisomies had intermediate risk.

On the surface, the studies are important in the specific prognostic value they provide based on the under­ly­ing chromosomal abnormalities. But on a higher level, they provide additional supporting data that what we call myeloma is not one disease, but a collection of cytogenetically distinct entities. We previously knew that the clinical presentation, response to therapy, and outcome are affected by the underlying cyto­ge­net­ic sub­type, and we now know that the risk of progression from premalignancy to malignancy is also different.

#3 Novartis investigational compound LBH589 significantly extended time without disease pro­gres­sion in Phase III multiple myeloma study: Novartis media release, December 6, 2013.

The Phase 3 PANORAMA-1 (PANobinostat ORAl in Multiple MyelomA) trial  compared panobinostat (LBH589) in combination with Velcade and dexa­meth­a­sone (Decadron) versus Velcade and dexa­meth­a­sone alone in patients with relapsed or relapsed and refractory multiple myeloma.

The study found that the addition of panobinostat significantly prolonged progression-free survival compared to Velcade and dexamethasone alone. Although specific data are not yet available, this is of major im­por­tance to the field since it identifies a new class of anti-myeloma therapy.

I have been quite skeptical that drugs with zero to minimal single-agent activity are of value in myeloma. If the results hold out, this trial will disprove my assumption. It opens up the possibility that there may be drugs without meaningful single-agent activity that nevertheless prove to be of clinical benefit when combined with other active drugs.  In that sense, this is indeed remarkable news.

#2 Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma by Mateos and colleagues: New England Journal of Medicine, August 1, 2013; vol. 369, issue 5, 438-447 (see related Beacon news).

Treatment has not been recommended for patients with smoldering multiple myeloma because these pa­tients are asymptomatic and there was concern that therapy would do more harm than good. Earlier ran­dom­ized trials failed to show a survival benefit.

However, it is time to reexamine this paradigm. First, we have better drugs; second, we are able to identify patients with smoldering multiple myeloma who are at higher risk of progression.

Employing these two strategies, the Spanish myeloma group studied 119 patients with high-risk smoldering multiple myeloma. Patients were randomly assigned to treatment with Revlimid plus low-dose dexa­meth­a­sone versus observation. They found that the time to progression to myeloma was significantly longer in patients treated with Revlimid-dexamethasone. More importantly, overall survival was also sig­nif­i­cant­ly longer with Revlimid-dexamethasone.

This study shows that early treatment of patients with high-risk smoldering multiple myeloma may be an effective intervention that can prolong overall survival. It is a landmark finding in that it is the first time we have found that early intervention can prolong life in myeloma, and it changes the existing paradigm. There are caveats though, including identifying which patients need therapy, and we still encourage most patients with high-risk smoldering multiple myeloma to consider enrollment in clinical trials such as the ECOG E3A06 trial of Revlimid versus observation.

#1 Initial Phase 3 results of the FIRST (frontline investigation of lenalidomide + dexamethasone versus standard thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) pa­tients (pts) ineligible for stem cell transplantation (SCT) by Facon and colleagues: Blood, October 21, 2013, vol. 122, no. 21, abstract 2 (see related Beacon news).

Melphalan (Alkeran) has always been the mainstay of treatment of elderly patients with multiple myeloma who are not candidates for stem cell transplantation. Despite being one of the most active agents in this disease, melphalan does have drawbacks including its effect on stem cells and that it increases a patient’s risk of developing myelodysplastic syndrome or secondary leukemia.

Revlimid plus low-dose dexamethasone (Rd) has been shown to be a well-tolerated regimen and is widely used as a doublet or in combination with other drugs in regimens such as VRd (with Velcade) or KRd (with Kyprolis (carfilzomib)).

In this study, one of the largest randomized trials in myeloma, 1,623 patients were randomized to MPT (mel­phalan, prednisone, and thalidomide (Thalomid)) for 18 months, Revlimid-dexamethasone for 18 months, or Revlimid-dexamethasone until progression.  The results of the study were presented in the plenary ses­sion of the annual meeting of the American Society of Hematology in December 2013.

The study found that overall survival was significantly longer with Rd given until progression compared with MPT; no significant difference in survival was apparent as of now between the two Rd arms. There was no increase in risk of second cancers. Besides the compelling result that a well-tolerated doublet can prolong survival in elderly patients with myeloma, the study shows that when there is effective therapy, overall survival improvement can still be demonstrated in myeloma. It also provides support to numerous ongoing trials that have used the Rd backbone in other combinations in the frontline setting, anticipating this result at least in part.

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As with any list compiled in this fashion, there will be articles that others will feel that I should have included instead of the ones I picked. And I am sure there can be disagreement on the order of the top 10. Despite these considerations, I feel that this is a worthwhile exercise, since it brings hope to those of us in the field and informs the patients we serve of the progress that is being made by a truly global team of researchers.

Dr. S. Vincent Rajkumar is a professor of medicine and chair of the Myeloma Amyloidosis Dysproteinemia Group at the Mayo Clinic in Rochester, Minnesota. His research focuses on clinical, epidemiological, and laboratory research for myeloma and related disorders.

Photo of Dr. S. Vincent Rajkumar, professor at the Mayo Clinic.
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14 Comments »

  • Nancy Shamanna said:

    Thanks for this interesting article, Dr. Rajkumar. There seems to be good news for patients with all stages of monoclonal proteins -- MGUS, SMM, and active myeloma. I found the studies on getting around resistance for Revlimid and Velcade (#6, #7), and also the studies on the antibodies, such as the one that attacks the CD 38 protein on MM cells, to be really encouraging. If I need more help in the future with drug resistances, having already been treated with Velcade and Revlimid (and yet not resistant), maybe these new therapies would be really helpful!

  • Barb Sarbaugh said:

    What a nicely summarized and clearly stated article! Thank you, Dr. Rajkumar. I have heard and seen other presentations of the latest information about research, but none presented as well as yours, with the findings and their importance to us as patients, side by side.

  • Steve said:

    Thank you Dr. Rajkumar!

    As usual, your analysis is always insightful. That said, I was hoping that you might have included the discovery of the so-called myeloma stem cell in your list of top ten. Perhaps you, or maybe even your Mayo Clinic colleague Dr. Keith Stewart, might be able to comment on that subject sometime in the near future?

    Best,

    S.

  • Mike Burns said:

    Thank you, Dr. Rajkumar, for the summary. It was interesting to read your list a few days after listening to Dr.Orlowski's LLS webcast with his list of top findings from ASH 2013. Lots of overlap in what you guys consider to be important, which makes sense. These lists and article summaries are a big help to me, as a patient, in better understanding the disease and research toward improved treatments. Thank you!

  • Angela said:

    Thank you for the clear and insightful analysis. It is wonderful to have a dedicated expert explain what new developments are most important. Daratumumab, the anti-cd38 antibody, received fast track status from the FDA last May. What does this really mean for patients? Will it dramatically reduce the time for approval, assuming the clinical trial data is favorable?

  • R said:

    Doc:

    Speaking as a patient....

    I enjoy the fact that the gains in research are enthusiastically embraced by the medical research community, and it seems that (to use a mountaineering example) multiple assaults on the "summit" of a cure or significant control (Multiple Myeloma/Blood dyscrasias) are underway with vigor.

    The Summit of the Eiger is in sight !

    No more false hopes...

    Thank you.

  • Joe said:

    Hi question could high intensity freq ultrasound kill myloma cells.

  • Manon Veilleux said:

    Thank you Dr.Rajkumar for sharing your research with us!

    I live in Quebec City and have been diagnosed multiple myeloma January 2014 at age of 48. My father just died of another blood disease (CML?) in December 2013 at age 71.

    At first, it scared me because I didn't see the difference, but thanks to the explanations of my Doctor and articles like yours, it allows me to understand better.

    In Canada, we hear very good comments about Kyprolis (carfilzomib), is it a revolution in the States? Does it cure multiple myeloma or is it another effective drug to treat multiple myeloma for the people who resist to Velcade?

    Maybe you won't have the time to answer me, but I sure hope you'll at least receive all my gratitude for your remarkable work and article. Thank you and all the best to you and the ones you love!

  • Chitaranjan said:

    Dear Vincent,

    Do you remember me? i was your classmate in plus two and also a resident of KK Nagar. I was simply amazed at your findings and actually proud of your achievements. I will be much delighted if you will kindly revert back. my email id is chitaranjank@gmail.com

  • Vincent Rajkumar said:

    Thanks to everyone for the kind comments. Steve: The search for the "myeloma stem cell" has been going on for quite some time. A lot depends on what we mean by stem cell; but there is no question immature, "hard-to-kill" precursor cells exist in myeloma, and are involved in relapse despite what appears to be effective therapy. An additional factor is the clonal heterogeneity that allows natural selection of disease resistant subclones. For a good review article on the subject and how complex it is see Abe et al. Stem Cells. 2014 Jan 22. If you need a copy of the article email me.

    Yes. Fast track review will speed up development, but the timeline still depends on the type of pivotal study and the magnitude of the clinical benefit. Given than anti-CD 38 monoclonal antibodies have single-agent activity, I hope that they are successful in regulatory studies.

    I do not know much about high intensity frequency ultrasound- but in general since myeloma is a systemic disease even highly effective locally administered modalities like radiation are mainly used in disease palliation, emergencies, and/or symptom relief.

    As far as carfilzomib (Kyprolis) goes, it is at this point another effective drug to treat patients resistant to Velcade and other treatments. A lot of studies are underway in all stages of the disease, and I am confident that it will be approved in Canada soon.

    As with Velcade, there is a learning curve on how best to use the drug, including the optimal dosage. I think as we optimize this, the proportion of patients resistant to Velcade who respond to Kyprolis will be higher than what was seen in the regulatory phase II study that was used to secure FDA approval in the US.

  • Judy Wirtz said:

    I have or had 4;14 & 13 abnormalities. After the initial induction therapy of RVD before a transplant, the abnormalities disappeared. Has anyone ever seen this happen after biopsy and cytogenetic analysis. Thank you

  • Elizabeth Eden said:

    There are articles out about harvesting, modifying and re implanting T cells to combat myeloma and other blood disorders. Any news?

  • Myeloma Beacon Staff said:

    Hello Elizabeth,

    This article that was published as part of our coverage of December's American Society of Hematology annual meeting may have some of the information you're looking for:

    ASH 2013 Preview: Novel Immunotherapies Under Development For The Treatment Of Multiple Myeloma

    You may also want to ask for insights from other readers in the Beacon's forum. It is not necessary to register to read forum postings or post in the forum.

  • deep - thought said:

    We continue to plan for the best ...

    I take comfort from the fact that real tangible progress is now being made in the treatments available for Myeloma. Hoping that as one treatment's efficacy fades another new treatment will be at hand. One day I hope and know that through the tenacity and intellect
    of the doctors and scientists that a cure will be discovered, even if by chance or serendipitous. The diagnosis of myeloma will be taken onboard like water off a ducks back. Emotionally painless and easily permanently cured by a series of injections.

    Dare to dream fellow patients I hope time is on your side personally. Good luck for the journey.