MMRF Efforts Attack the Disease From Every Angle; "Transformation" on the Horizon

In 1996, Kathy Giusti was a 37-year-old rising star in the pharmaceutical industry, with a young child. When she learned she had multiple myeloma, the news floored her. Not only did she not resemble the typical profile of someone with this rare blood cancer, but she quickly discovered that treatments for the disease had barely

progressed in 40 years.¹

Neither the projected 3-year life expectancy nor the state of treatment were acceptable to Giusti, and she took action. With her twin sister, Karen, who would become her donor for a life-saving stem-cell transplant, the pair founded the Multiple Myeloma Research Foundation (MMRF).² Since 1998 MMRF has raised more than $250 million,³ and from 2003 to 2007 the foundation helped win FDA approval for 4 drugs that are mainstays of current multiple myeloma therapy: bortezomib, lenalidomide, thalidomide, and doxorubicin.⁴ More recently, MMRF offered research support for

carfilzomib.^2,4

By bringing the same principles she learned in her business career to finding treatments for multiple myeloma, Giusti has beaten the odds, in scientific and personal terms. She’s lived with the disease for 18 years, and the organization she founded has helped trim approval times for a host of treatments, in turn increasing the average survival from 3 to 8 years.

It’s an important time for the foundation and for those who study and treat persons with the disease, said Walter M. Capone, who in December 2013 became MMRF president after several years as chief operating officer. Capone, who came to the organization after years in the pharmaceutical sector, said he expects the next few years to resemble the shift he witnessed from 1996 to 1998 in HIV treatment, with the arrival of both new drugs—protease inhibitors and non-nucleoside analogue inhibitors—and new viral load detection tests. The ability to both detect HIV more accurately and attack it through multiple channels, Capone said, ended the disease’s status as a certain death sentence. By 2012, HIV qualified as a

“chronic condition” under the Affordable Care Act.⁵

Multiple myeloma treatment is headed in the same direction, he said. “This couldn’t be a more exciting time…the advances that are going on are going to be quite significant and transformational,” Capone reported. Although the declaration of a “cure” for multiple myeloma is well in the future, doctors are much closer to finding one than when the MMRF started.

Researchers still don’t completely understand what sets the disease in motion, but they know that in a healthy person a delicate balance properly regulates the transition of B lymphocytes into plasma cells as they leave the bone marrow. When the immune system is damaged, this process produces oncogenes instead. Healthy blood cells get crowded out, causing a host of health

problems such as fatigue, kidney damage, and calcium deposits. The skeletal system is compromised, and multiple myeloma patients may suffer broken bones from no obvious cause.

The MMRF sees progress in how multiple myeloma has expanded its presence on the scientific agenda. Advances have taken center stage at recent meetings of the American Society of Hematology⁴ (ASH) and the National Comprehensive Cancer Network (NCCN). At NCCN’s spring meeting, Kenneth C. Anderson, MD, director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute, and chair of the steering committee for the MMRF’s scientific arm, the Multiple Myeloma Research Consortium, proudly told his colleagues, “I want you to get excited about the future…we think we’re about to get a monoclonal antibody or two.”⁵

A central feature of multiple myeloma, and a challenge of treatment, is how the disease behaves differently from patient to patient. Even in a given person, it must be attacked on multiple fronts. Thus, the MMRF supports research into many different types of drugs, while also spearheading the science that examines myeloma’s genetic underpinnings. In the necessary diversity of

approaches, “It’s like an investment portfolio,” said Capone. Drawing on the HIV comparison, he foresees breakthroughs in both the diagnostic and therapeutic areas: next-generation

sequencing and circulating tumor cell detection strategies, as well as whole new classes of drugs. There are elotuzumab and daratumumab, the antibodies that Anderson referenced at NCCN.

Capone also sees promise in the histone deacetylase inhibitors, which are being studied in combination with bortezomib and dexamethasone in patients with relapsed myeloma.⁶

Capone also pointed to Millennium’s late phase 3 trials on what would be the first oral proteasome inhibitor. Results presented at ASH 2013 in New Orleans showed a combined complete response and very good partial response rate of 76% (46/62), and a 94% overall response rate (58/62 ≥ partial response.)⁷

The Genetic Foundations

MMRF’s most ambitious project to date may be its CoMMpass Study, an effort to track 1000 multiple myeloma patients for at least 5 years each.⁸ Patients enrolled in the study will provide

a tissue sample when they are newly diagnosed, and then provide additional samples each time their disease relapses. The goal is to examine how each patient’s molecular profile affects

the progression of the cancer, with the hope of not only tailoring treatment for that individual patient but also developing an increasingly rich database, one that will propel the discovery of more effective targeted therapies with each passing year.

CoMMpass patients come from a variety of treatment settings, and its data are open to clinicians and researchers. All this is by design, Capone said, to facilitate clinical trials and to aid treatment for patients far from academic research centers. When asked if MMRF had a position on whether pharmaceutical or diagnostic testing companies should share patients’ genetic data,

Capone strongly supported making data available for all researchers: “I’ve got a particularly strong emotional and practical position,” he said. “It’s the patients’ data,” and, thus, does not belong to any one company.

“The fact that industry in its various forms might to try optimize it, well, that’s only wonderful if it’s for the patients’ benefit. When that becomes secondary and subordinated, that’s a fundamental

problem. And that’s why we put the data on a public portal.”

MMRF’s efforts in genomics predate the 2011 launch of the CoMMpass study. In 2005, the foundation started its Multiple Myeloma Genomics Initiative, which gathered 250 tissue samples

for study.⁹ Those efforts bore fruit in March 2011 with the publication of an article in Nature.¹⁰ Researchers examining the first batch of tumor genomes collected by the MMRF observed

mutations of the kinase BRAF in 4% of the patients, suggesting that BRAF inhibitors should be studied in multiple myeloma patients in clinical trials.¹⁰

As a result, new therapies that have been highly successful in treating metastatic melanoma patients—vemurafenib, trametinib, and dabrafenib—are now at various trial stages for multiple myeloma patients with BRAF V600E and V600K mutations.^11-14

Is Screening in the Future?

The diversity or heterogeneity of multiple myeloma means that what works in one patient might fail in another. As Giusti discovered shortly after she was diagnosed, that’s what kept pharmaceutical companies from investing in multiple myeloma for so long.

The rise of genomic research is the game changer. It offers the ability to build clinical trials around therapies that have already worked in other cancers, or to include multiple myeloma patients

in trials for new therapies aimed at a particular mutation seen in many cancers.

This is already happening with the BRAF mutations. But as this strategy unfolds, it will mean attacking the disease on many fronts. That will mean many drugs. And that could get very expensive.

A panel convened recently by The American Journal of Managed Care (see related story, below) discussed the cost implications for payers as multiple myeloma patients live longer with the disease.

One clinician, Jack Goldberg, MD, of Penn Presbyterian Medical Center in Philadelphia, said it was essential to get better at treating the disease earlier. Not everyone agreed that screening for

multiple myeloma made sense, since it might not be treated right away, causing patients undue stress.

Capone, however, sees a future for screening among persons older than 60 years. Screening could become routine, just as colonoscopies and prostate-specific antigen (PSA) tests have, he said. Identifying biomarkers for multiple myeloma, and certainly catching more cases at the “smoldering” stage, while figuring out ways to prevent full-blown disease, makes tremendous

sense.

EBO

“From an intervention standpoint, therapies that involve the priming of, or strengthening of, the immune system to identify and mitigate aberrant cell development offer the best benefit for patients,” Capone said. “It’s much less expensive to treat it early.” References

1. Carpentier F. Cancer can’t stop me: Kathy Giusti’s mission to cure multiple myeloma. Parade. http://parade.condenast.com/37077/francarpentier/25-kathy-giusti-misson-to-curemultiple-myeloma/. Published February 25, 2010. Accessed June 2, 2014.

2. Giusti K. Don’t forget your re-birthday. Multiple Myeloma Research Foundation website. http://www.themmrf.org/about-the-mmrf/powerfulnews/mmrf-blogs/don-t-forget your-re-birthday.html. Published January 25, 2011. Accessed June 5, 2014.

3. Multiple Myeloma Research Foundation (MMRF) supports Tom Brokaw and all patients through their journey with multiple myeloma [press release]. Norwalk, CT: Multiple Myeloma Research Foundation; February 11, 2014. http://www.themmrf.org/about-the-mmrf/powerful-news/press-releases/mmrf-supportstom-brokaw-and-all-patients through-their-journey-with-multiple-myeloma.html.

4. Results: new therapies. Multiple Myeloma Research Foundation website. http://www.themmrf.org/about-the-mmrf/results/newtherapies.html. Accessed June 5, 2014.

5. HIV/AIDS qualifies as a “chronic condition” under ACA, scoring major victory in fight against HIV/AIDS [press release]. San Francisco, CA: Forum for Collaborative HIV Research; November 29, 2012. http://www.hivforum.org/forumnews/press-releases/769-hivaids-qualifies-asqchronic-conditionq-under-aca-scoring-majorvictory-in-fight-against-hivaids.

6. Blake E. Addition of Zolinza slightly improves Velcade treatment for relapsed melanoma patients. Myeloma Beacon. http://www.myelomabeacon.com/news/2013/10/1 /zolinzaslightly-improves-velcade-treatment-for-relapsedmultiple-myeloma/. Published October 16, 2013. Accessed June 5, 2014.

7. Walker T. Updated data with oral proteasome inhibitor reported in newly diagnosed multiple myeloma patients. Formulary Journal. http:// formularyjournal.modernmedicine.com/formulary-journal/news/updated-data-oralproteasome-inhibitor-reported-newly-diagnosedmultiple-myel?page=full. Published January 9, 2014. Accessed June 5, 2014.

8. The Multiple Myeloma Research Foundation (MMRF) and the U.S. Department of Veterans Affairs (VA) create unprecedented private/public partnership to advance the development of personalized medicine [press release]. Norwalk, CT, and Washington, DC: Multiple Myeloma Research Foundation and US Department of Veterans Affairs; November 26, 2012. http://www.themmrf.org/about-the-mmrf/powerful-news/pressreleases/mmrf-landmark-commpasssm-studyexpands-to-include-va-sites.html.

9. Genomics backgrounder. Multiple Myeloma Research Foundation website. http://www. themmrf.org/assets/research-programs/genomics-initiative/genomics backgrounder.pdf. Accessed June 5, 2014.

10. Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471(7339):461-472.

11. Lohr JG, Stojanov P, Carter SL, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25(1):91-101.

12. Bohn OL, Hsu K, Hyman DM et al. BRAF V600E mutation and clonal evolution in a patient with relapsed refractory myeloma with plasmablastic differentiation. Clin Lymphoma Myeloma Leuk. 2014;14(2):e65-e68.

13. ClinicalTrials.gov. A study of trametinib and GSK2141795 multiple myeloma. National Cancer Institute. http://www.cancer.gov/clinicaltrials/ search/view?cdrid=753717&version=HealthProfessional&protocolsearchid=11368643. Updated May 9, 2014. Accessed June 5, 2014.

14. ClinialTrials.gov. Efficacy and safety of the combination therapy of dabrafenib and trametinib in subjects with BRAF V600E-mutated rare cancers. https://clinicaltrials.gov/ct2/show/NCT02034110?term=%22dabrafenib%22+and+%22myeloma%22&rank=1. Updated May 29, 2014. Accessed June 5, 2014.