COMMENTARY

Infection Prophylaxis, Immune Therapies Lead Practice-Changing Myeloma Research at ASH 2017

S. Vincent Rajkumar, MD

Disclosures

February 06, 2018

Hello. I'm Vincent Rajkumar, professor of medicine at the Mayo Clinic in Rochester, Minnesota. Welcome to Medscape Oncology Insights, coming to you from the 2017 American Society of Hematology (ASH) annual meeting. Today we will be discussing some of the highlights from the myeloma sessions at the meeting.

As you are well aware, there has been a dramatic amount of progress made in multiple myeloma in terms of preventing progression from asymptomatic to symptomatic disease, treatment of newly diagnosed patients, treatment of relapsed multiple myeloma, and improvements in supportive care. At this year's ASH meeting, we saw several abstracts that addressed each of these stages.

Smoldering Multiple Myeloma

There were at least two strategies trying to prevent or delay progression from the smoldering state to the multiple myeloma stage. One was an abstract by the Spanish Myeloma Group[1] that looked at a fairly intensive approach. Here the idea was that if we deliver very intense therapy to the early asymptomatic stage, can we even cure the disease?

They employed carfilzomib, lenalidomide, and dexamethasone as induction followed by high-dose therapy/autologous stem cell transplantation; carfilzomib, lenalidomide, and dexamethasone consolidation; and then maintenance therapy. They found a 100% response rate, with 50%-60% of patients reaching a minimal residual disease-negative state. Only time will tell whether this kind of an approach can really make a difference or not. This is a phase 2 study, so it's the first step in many clinical trials to follow.

On the other hand, there is another strategy designed more to control the disease rather than to cure it. The control strategy takes advantage of single agents that have a very good safety profile and very high activity. The goal here is to delay the onset of symptomatic disease by many years.

In an abstract presented by Dr Craig Hofmeister,[2] researchers used single-agent daratumumab for smoldering multiple myeloma and showed good tolerability and very good response rates in this stage.

Newly Diagnosed Disease

We've traditionally been using a regimen of bortezomib in combination with lenalidomide and dexamethasone for induction followed by stem cell transplant in the newly diagnosed disease stage. The question is: Can you improve on this triplet?

Here again the Spanish Myeloma Group has taken the lead, presenting an abstract[3] comparing a four-drug regimen of daratumumab plus bortezomib-melphalan-prednisone versus bortezomib-melphalan-prednisone. This trial showed a significant improvement in progression-free survival with the full drug regimen.

Again, only time will tell whether this translates into an overall survival benefit. We hardly use melphalan-prednisone in the United States and in many other countries, so more data are needed to indicate whether this kind of a result can be replicated in studies that use more traditional initial therapy regimens. Nevertheless, this is very promising.

The addition of a monoclonal antibody to frontline therapy seems feasible, safe, and also to be associated with very high response rates and progression-free survival rates.

Relapsed Multiple Myeloma

In terms of relapsed multiple myeloma, we've had a number of new drugs approved recently: carfilzomib, panobinostat, pomalidomide, and ixazomib.

At this meeting, the energy is on new treatments, and immune therapies are at the forefront. One approach is to use chimeric antigen receptor T (CAR T) cells, which are modified T cells that target specific antigens. One of the CAR Ts with results reported here was bb2121, which targets B-cell maturation antigen (BCMA), present universally on plasma cells. The study[4] shows an extremely high, almost universal, response rate in relapsed/refractory patients treated with this CAR T.

The question is: If you can use a CAR T against BCMA, can you also use a monoclonal antibody and derive similar benefit? A conjugated monoclonal antibody was studied by a group led by Dr Suzanne Trudel, who reported the results[5] at this year's meeting. Here, the use of a single-agent monoclonal conjugated anti-BCMA antibody was associated with 60% response rate in the relapsed setting; very promising.

Several other drugs are being tested in this field. We have a lot of promise in the treatment of relapsed/refractory myeloma.

As improvement occurs in relapsed disease, I also expect that some of these agents and regimens will slowly migrate to the maintenance setting or even into the treatment of newly diagnosed myeloma.

Reducing Complications

Finally, no matter what advances you make in myeloma therapy, we do lose patients, oftentimes to infections and other complications. There was a seminal abstract[6] at this year's meeting by a UK group that looked at a simple intervention of prophylaxis with once-daily levofloxacin for 12 weeks that was associated with the initial therapy of multiple myeloma.

The researchers found that for patients who received levofloxacin, there was a significant decrease in the incidence of infections in the first 12 weeks, as well as an improvement in overall survival. This is very important for myeloma patients as it shows that we can save lives by just using routine prophylactic antibiotics.

In the same abstract, they also reported that they further lowered the incidence of infections by adding thrice-weekly trimethoprim/sulfamethoxazole (TMP/SMX), a drug we routinely use to prevent pneumocystis. They had some patients who received TMP/SMX and some who didn't. When they compared the groups, they found that the combination of levofloxacin plus TMP/SMX was able to improve the infection rate and reduce the number of serious infections and hospitalizations. I expect this to have a major impact on the treatment of myeloma.

Tandem Transplantation

Besides the data I've mentioned, there were multiple other interesting abstracts presented at this year's meeting. We have had a long debate for many years on the role of tandem transplantation; that is, doing two transplants instead of one for the treatment of myeloma.

There was a study presented by an Italian group[7] that shows that when you use two transplants, improvements occur not only in progression-free survival but also overall survival. Again, I have to caution the audience that I'm not sure what this will mean for the vast majority of patients in the United States because many of the new drugs were not available universally to patients studied in the Italian trial. Time will tell.

We did do a similar trial in the United States with one versus two transplants, and those results are still being analyzed. An updated follow-up of that study will tell us more about the role of double transplant.

There are also many investigators exploring improvements in conditioning regimens for stem cell transplant. Can we, instead of melphalan 200 mg/m2, use busulfan plus melphalan or bortezomib plus melphalan? Again, time will tell whether they make a difference in the outcome of myeloma patients.

Overall, this was a wonderful ASH meeting with many new abstracts showing promising data for the treatment of myeloma patients. As a result, I think that the overall survival of patients with multiple myeloma will continue to improve over the next several years.

Thank you so much for joining me. This is Vincent Rajkumar speaking from ASH 2017 in Atlanta, Georgia. Thank you.

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