New Therapies for Multiple Myeloma Provide Optimistic Outlook

With the approval of four drugs, 2015 was a monumental year for multiple myeloma, and Sundar Jagannath, is optimistic about the years to come.

“Last year, we had four new drugs approved for the treatment of multiple myeloma, including the first-in-class HDAC inhibitor Farydak (panobinostat), two monoclonal antibodies — Empliciti (elotuzumab) and Darzalex (daratumumab) — and an oral proteome inhibitor Ninlaro (ixazomib)," says Jagannath, a professor of Medicine, Hematology and Medical Oncology at Mount Sinai Hospital. “Now is a very exciting period in multiple myeloma. Whichever way I look at it, the next three to five years are going to be very significant for myeloma and we will have better solutions for relapsed patients.”

November 2015 was a watershed month for multiple myeloma, as Empliciti, Darzalex and Ninlaro all received FDA approvals for the disease.

First, the FDA approved Darzalex as a monotherapy for patients with multiple myeloma following at least three prior therapies, based on data from two open-label clinical trials. The CD38-targeted monoclonal antibody demonstrated a 65 percent one-year overall survival (OS) rate and a 29.2 percent objective response rate (ORR) in the phase 2 MMY2002 study. In the phase 1/2 GEN501 study the ORR with single-agent Darzalex was 36 percent, median progression-free survival (PFS) was 5.6 months, and the one-year OS rate was 77 percent in pretreated patients with relapsed/refractory myeloma.

Secondly, Ninlaro was approved in combination with Revlimid (lenalidomide) and Maxidex (dexamethasone) as a treatment for patients with multiple myeloma who have received at least one prior therapy based on the phase 3 TOURMALINE-MM1 trial. The trial looked at 722 patients and demonstrated a median PFS of 20.6 months with Ninlaro plus Revlimid and Maxidex compared with 14.7 months with Revlimid and Maxidex alone.

Finally, Empliciti was approved for use in combination with Revlimid and Maxidex for patients with multiple myeloma following the failure of one to three prior therapies. This approval was based on data from the phase 3 ELOQUENT-2 trial, in which the three-drug combination reduced the risk of disease progression by 30 percet compared with Revlimid and Maxidex alone.

In February 2015, the FDA approved Farydak in combination with Velcade (bortezomib) and Maxidex for patients with multiple myeloma who received prior treatment with Velcade and an immunomodulatory agent, based on a prespecified subgroup analysis from the PANORAMA-1 trial. In the analysis, which looked at 193 patients, the median PFS with the Farydak combination was 10.6 months versus 5.8 months with Velcade and Maxidex alone.

What upcoming advancements are you most excited about in multiple myeloma?

In addition to the recently approved agents, several novel therapies are currently being investigated in multiple myeloma, including checkpoint inhibitors such as Keytruda (pembrolizumab), CAR T-cell therapy and vaccines. In an interview with CURE, Jagannath discusses which emerging agents he is most excited about, sequencing challenges in multiple myeloma and the role for personalized medicine in the disease.Jagannath: There are several new drugs in the pipeline that are going through rapid clinical development. This includes new classes of drugs. At the same time, immuno-oncology is expected to play a major role in multiple myeloma. Also, we now understand that these antibodies that are being approved can be used in combination with other existing drugs effectively and safely.

The future looks even brighter. At the 2015 ASH Annual Meeting, results were presented from a study looking at Revlimid and Maxidex with the checkpoint inhibitor Keytruda. This combination was able to put patients into remission who were refractory to currently approved agents. This means that the therapeutic armamentarium is going to widen, and there is a possibility that immunotherapy may lead to a cure for myeloma.

In the same way, we are excited that CAR T cells against B-cell maturation antigen are coming into clinical trials in multiple myeloma. There was a CAR T-cell treatment of a single patient case report that was published in The New England Journal of Medicine.

With all of these new agents, do you see potential for a personalized medicine approach?

For the first time, we are also exploring vaccines in posttransplant multiple myeloma. People are convinced that they are looking at minimal residual disease. We may be in a situation that the myeloma goes into a deep complete remission. For patients who can maintain deep complete remissions for three or five years, we can then say they are cured. These kinds of assessments are coming into play.Personalized medicine is very tantalizing. We are looking at whole-genome sequencing, exome sequencing, and RNA sequencing. This is evidence that myeloma has multiple clones but, at any one given time when the disease is progressing rapidly, it looks like one of the clones becomes prominent and grows rapidly and, sometimes, could be lethal.

In those cases, we may be able to repurpose a drug that is approved in another tumor type, such as lung cancer or skin cancer. This may be an appropriate therapy for myeloma. In this regard, Zelboraf (vemurafenib) has been shown to be effective for treating patients with myeloma and getting their disease under control.

How will sequencing be determined with these new agents and how may that change going forward?

I do not think the answer is personalized medicine, because there are a lot of different mutations. However, it so happens that the patients with the highest mutational burden and a lot of neoantigens are the patients who seemingly respond very well to checkpoint inhibitors. Therefore, in a way, you have a few mutations that we have a therapeutic target for, or there are too many mutations, a high mutation burden and rapidly progressive disease. Checkpoint inhibitors may be able to work.Myeloma has multiple clones, so it is clear that, for a newly diagnosed patient, we should use a combination of a proteome inhibitor, an immunomodulatory drug and Maxidex.

In the future, we may add a monoclonal antibody to this three-drug combination. These agents are currently in phase 3 trials, and I have a feeling they are likely to be positive trials. That is very important. We are still incorporating transplant into the management of patients.

In the posttransplant area, we are looking at immunomodulatory molecules but, more than that, we are looking at checkpoint inhibitors and monoclonal antibodies, both of which will play a role.

For patients who relapse, we fortunately have another set of drugs. For patients who have failed on Revlimid, for example, we have Pomalyst (pomalidomide). For patients who failed a first-generation proteasome inhibitor like Velcade, they can go on a second-generation proteasome inhibitor such as Kyprolis (carfilzomib).

Then, we have completely new drugs, such as HDAC inhibitors. These are able to make patients who have become resistant to traditional drugs sensitive again when an HDAC inhibitor is added into the mix. That becomes another treatment solution. We also have the monoclonal antibodies.

My feeling is that all of these new drugs have approximately a 30 percent response rate, and duration of control of the disease, on average with all of these agents, is about seven months. No one drug is a home run, although it remains to be seen what CAR T-cell therapy will do in this situation.

Will multiple myeloma eventually become more of a chronic condition?

However, short of that, all of these different drugs are required in order to make the patient live longer and longer. That is important because we are at the watershed period where all these different approaches are coming into play. If any one of them hits a home run, patients who were kept alive with these different drugs may be able to be cured.In myeloma, we have different classes of drugs, so we can switch classes if something doesn’t work. That is why we are able to salvage patients after one, two or three failures.

When you look at clinical trials, many patients coming into the trials have failed one to three, more than three or more than four lines of therapy. Even when the patient has failed all of the currently approved agents, here comes the next agent or, a new class of drugs in the pipeline.