We read, hear and see so much negative news that it is important to remember that good things are happening too. That includes getting closer to finding a cure for myeloma.

But what does “a cure” really mean?

The outlook on response, remission and survival is already very bright for many patients diagnosed in 2019 and beyond. Over 90 percent of patients will respond well with initial therapy. First remission will be in the four-year range. And overall survival for good responding patients (VGPR or better) is more than eight years. Then there is the impact of new immunotherapy and additional novel approaches.

When does remission become cure?

Achieving minimal residual disease (MRD) negative is the subject of much discussion. Bone marrow samples that show zero out of a million myeloma cells remaining are predictive of long remission and very good survival. But what about cure? This is the next step in the research: If MRD negative persists at one year, this is excellent. If it persists at three and five years, even better. But this is not an absolute guarantee of permanent success, or the fabled cure.

It is important to take a step back and understand what we know about long survival in myeloma patients:

1. Excellent response, including MRD-negative status, is a definite indicator of best outcomes.
2. A study from the University of Heidelberg showed that half of patients who had survived 20 years and beyond had residual disease. But these patients were still in remission and doing well. They had achieved a new equilibrium. Their immune system could control residual myeloma and, thus, prevent relapse. This immune status is now the focus of intense study.
3. Some MRD-negative patients become MRD-positive with relapsing disease. This resistant disease pattern is the subject of intense study.
4. Long survival can occur with and without negative MRD status, and negative MRD status may not be permanent.

What is a useful definition of cure today?

A good way to define cure right now is when patients live with a good quality of life and succumb to something other than myeloma—such as old age, vascular disease, or other common illnesses of the elderly. By this definition we are well on the way to curing many myeloma patients, with the prospect of curing many more in the future.

It is worth noting that even with older therapies, long-term follow-up showed survival at 20 years as 14.36 percent, not zero. So, with our new Cure trials we are not starting at rock bottom.

Learning from HIV and hepatitis C treatments

As in myeloma, AIDS researchers have long sought a cure. Fortunately, ongoing triple therapy for AIDS has achieved long-term disease control. Without maintenance treatment, researchers found, HIV rapidly rebounds, the result of reservoirs of infection. These reservoirs are primarily found in macrophages, where the virus hides.

A key advance in HIV treatment came from understanding that without triple therapy, infection came roaring back. Triple therapy can overcome the many mutants that emerge given the chance. Mathematical modeling showed that single or double therapy was not enough to prevent emergence of mutant virus. Triple therapy provides long-term disease control and, essentially, cure status for most patients.

If this is starting to sound familiar, it is because this is exactly what we face with myeloma therapy. The questions that arise in myeloma are therefore parallel to those in HIV:

• Is there a hidden reservoir, despite apparent MRD negativity?
• Is the mutation rate so low in some cases that new clones emerge very slowly over months to years?

All this certainly supports the current strategy to recommend ongoing maintenance. The advantage we have with myeloma is that relapse tends to emerge after months to years versus days to weeks if HIV treatment is stopped.

In patients with hepatitis, it appears that intensive antiviral therapy can eradicate not only the virus, but any potential reservoirs. Might this be possible for some patents with myeloma? This is the first question investigators are asking in the CESAR and ASCENT Cure trials: Will MRD-negative remission be sustained when intensive therapy for HR SMM (high-risk smoldering multiple myeloma) is stopped?

We are studying this question with great caution. But the path forward looks very positive.

Can mathematical modeling identify best strategies to cure myeloma?

Equipped with detailed information about myeloma cell mutations, MRD levels, time-to-relapse, and other factors, “deep learning” or artificial intelligence could help to refine approaches to treatment in the future. At the June 2019 International Myeloma Working Group Summit in Amsterdam, the keynote address by Dr. Casey Greene will address this topic. As for viral diseases, combinations of drugs (like triple therapy) will be necessary, and must be administered in a tailored fashion to achieve best outcomes.

Myeloma news briefs

• A company called Chemiocare has announced it will produce a patch to deliver lenalidomide (Revlimid is the oral formulation) through the skin, using what it calls “permeation-enhanced transdermal technology (PETT).” The company hopes to improve lenalidomide’s safety and efficacy. This could be a convenient approach if it turns out that sustaining chronic disease control requires ongoing lenalidomide treatment. Obviously, further research is required.
• In a recent study it was reported that high doses of vitamin C selectively attack myeloma cells and may enhance the efficacy of other therapies, such as high-dose melphalan, used as part of ASCT (autologous stem-cell transplant). Something to keep an eye on!

Environment news briefs

Long-term myeloma survivors need a healthy planet to inhabit. Again, with so much in the news about the horrors of climate change, it is encouraging to note positive news.

• Instead drinking from environmentally harmful plastic bottles, runners in this past Sunday’s London Marathon hydrated with water-filled seaweed pods that biodegrade in six weeks.
• A low-tech approach to fighting climate change is to plant more trees in regions most suited to growth in the changing climate. The idea, which is called “assisted migration,” is being tested by foresters in Rhode Island. Southern trees, such as persimmon and shortleaf pine, are thriving among the state’s native oaks and pines.
• Those of you worried about the state of coral reefs can rest easy. During coral's free-floating larval stages, it can travel by ocean currents to areas along the coast that better suit it and create new reefs, researchers report.
• The bacteria found in ancient Irish soil can halt the growth of so-called “superbugs.” This provides new hope for tackling antibiotic resistance. It is also good news for myeloma patients, for whom recurrent infections can often be a problem.

The bottom line

There are many good and positive things happening in the world. We just need to look beyond the headlines to find positive information that really matters.

---

Dr. Brian G.M. Durie co-founded and now serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.