The FDA and International Myeloma Society (IMS) recently hosted a joint meeting to discuss the myeloma treatment landscape and explore how new myeloma drugs are approved.

The goal was to have a joint discussion about the status of myeloma care and work through the challenges that come with change.  

The FDA has been extremely helpful in approving myeloma therapies for patient access. However, as patients achieve longer life, how clinical trials are designed may need some adjusting. 

The meeting included many leaders in the myeloma space and significant time was provided for Q&A from both live and virtual attendees. The meeting was a significant event for patients and researchers wanting faster cures. 

A Remaining Unmet Need

Nikhil Munshi, MD from Dana Farber Cancer Institute provided the introduction to call out the fact that there is still significant need for new myeloma treatments. He noted the growing 170,000 living myeloma patients in the United States and the annual 35,780 patients diagnosed annually with over 12,000 deaths per year. He also stated the fact that only 18% of myeloma patients are still alive by the time they receive their 5th line of therapy, stressing the need to re-think how approvals are currently done. In the UK, only 15% of patients are alive after their 3rd line of therapy.

He asked the important question, "How do we move faster?" 

He invited an ongoing collaboration between IMS, FDA, academia and pharma for patients. Interestingly, that call for collaboration didn't include the involvement of patients, which I believe it should. 

Bindu Kanapuru, MD from FDA noted the significant progress that has been made in the last 7 years for drug approvals and reviewed why there are fewer drugs in place for the newly diagnosed patients, because most new drugs are always tested first in the relapsed/refractory setting for safety reasons and comparisons to existing standard of care options. 

The Lines of Therapy Debate

Ken Anderson, MD of Dana Farber Cancer Institute said that there have been 19 new drugs approved in myeloma over the last 20 years, and many of these approvals have been performed via the FDA's accelerated approval process. He reinforced the idea that this mechanism for earlier approvals is still essential. 

However, many clinical trials are designed to study a drug only after a certain number of "lines of therapy." For example, the recent approvals for both CAR T products Abecma (BMS) and Carvykti (J&J) were approved for patients who had received at least four prior lines of therapy. 

He stressed that using the number of prior lines of therapy doesn't really work any more because many patients have used at least 4 different drug classes (IMiDs, proteasome inhibitors, CD-38 monoclonal antibodies and steroids) in their first line alone. He suggested that using drug class exposures, a patient being refractory to a drug or drug intolerance instead would be a better method. He noted that when approvals aren't provided until the fourth line of therapy, patients have exhausted most myeloma therapies by the second line and doctors are at a loss for what to use for 3rd and 4th line to be able to meet the criteria. 

As an example, you could design a clinical trial that included patients who had already received daratumumab, bortezomib and lenalidomide, a CD-38 monoclonal antibody and were also refractory or intolerant to lenalidomide. In that example, it would not matter how many prior lines of therapy they received, just what is still working or not working for these patients. 

Using drug sensitivity as a measurement in today's myeloma clinic, Dr. Anderson said that many patients are still not experiencing good outcomes. 

Many panel members commented that using lines of therapy causes disparity issues in clinical trial evaluation and there was general consensus from the academic community that prior drug exposure was much easier to determine as inclusion criteria. 

From multiple FDA speaker comments, FDA was hesitant to get away from lines of therapy completely with Dr. Kanapuru saying that prior approvals have included lines of therapy but it doesn't have to be an all or none approach. 

Dr. Munshi suggested that there was a large need to decrease dependence on lines of therapy and Dr. Anderson agreed that there was significant need to address disease bilogy and not lines of therapy. He said that a patient exposed to three classes of drugs and refractory to their last line of therapy represents a very challenged patient.

Single Arm Vs. Randomized Trials

FDA speakers made repeated comments that they prefer randomized trials with a study arm and control arm compared to single arm trials. Dr. Baines suggested also using randomized trials in earlier lines of therapy. 

Dr. Munshi suggested that doing a randomized study for a new drug wasn't always possible because you are testing a variety of doses for safety. FDA suggested that it requires confidence in dosing and safety parameters. They are very interested in having companies come to them with better dose optimization processes. To FDA this means more dose levels tested in more groups, which means more arms in the trial. This idea is still a significant challenge for companies and academic institutions. 

Vincent Rajkumar, MD of Mayo Clinic said that the need to always have randomized trials and required Phase III trials can represent an additional 2-years of research, putting lives at risk.

An additional barrier for randomized trials is adding a "control arm" that patients actually want to join and will be effective, especially if they have relapsed after having many of those standard of care treatments. This whittles down the available number of patients who are eligible to join. 

Sundar Jagganath, MD of Mount Sinai said that getting patients into the trials has been difficult. If safety and efficacy is known, can they shorten the process? FDA reiterated that they still need randomized trials. They suggested smaller, randomized trials with shorter end points. 

A Higher Bar for Response Rates?

Dr. Anderson also noted that historically FDA was approving drugs that were seeing better overall response rates (ORR) compared to standard of care in the 25-35% range. Drugs like bispecific antibodies or CAR T therapies are seeing 60-100% overall response rates. But if FDA sets this as the new standard, it will make new drug development more difficult. Carfilzomib, pomalidomide and daratumumab are all myeloma drugs approved as single agents with 25-35% ORR rates. 

Dan Vogl, MD of University of Pennsylvania suggested that when it comes to patients who aren't doing well on therapy, a 20-30% ORR has to be "good enough" because it surely beats the alternative of not having another option. 

Using Real World Data In Clinical Trials

I asked a question about the use of real-world data as comparator arms in clinical trials. If complete data sets were available, would that alleviate the need to have a control arm? This would propel clinical trials forward faster. A team member from COTA asked a similar question with the comment that by the time companies get a data readout because trial recruitment was delayed, the trial data is no longer useful. 

FDA said that they still wanted randomized trials to be run and suggested that companies should use real-world data to design their trials prior to coming to FDA. According to FDA, real-world data can help identify the "natural history" to plan a subsequent trial. 

I personally believe that with the right data sets, we can show proof of concept on this idea. 

Opening Inclusion Criteria for Trials

Andrea Baines, MD from FDA talked about the need to expand clinical trials to additional patient populations such as older patients, extramedullary patients, plasma cell leukemia patients, Black patients and high-risk patients. How can trials be designed to represent all patients? This would enable testing of risk and benefit for all patient types. 

Having more diverse patients included in trials may make it harder for a company to see if their drug works for standard risk myeloma. For example, if a trial includes 70% of patients who are high risk and the drug doesn't work well for these patients, but works well for the 30% of standard risk patients, the drug is at risk of not getting approved at all.

For clinicians and companies, finding patients across all these disease spectrums is challenging and recruitment can be very slow. The slower the clinical trial, the more likely the study results are unimportant because new science is available, even just a few years down the road. 

One idea is for companies to do confirmatory trials in higher risk populations, such as extramedullary patients or renal failure patients. Today, these patients lack access to T cell therapies (CAR T and bispecifics) and it is increasing disparities. 

A significant challenge was debated. Sagar Lonial, MD of Emory University noted along with Natalie Callander, MD of University of Wisconsin and many others that there are patients with an unmet need. He suggested that you could use them as a patient group (or cohort in a study) if they relapsed within two years of their first therapy. This includes extremedullary patients, oligosecretory patients, plasma cell leukemia patients and other high risk genetic feature patients. 

FDA noted the need to have adequate data about these patients before the trials get designed. But investigators wanted to know how to design an appropriate comparator arm for these trials. with appropriate end points. The comparator arm question went unanswered, but FDA said that normal progression free survival and overall survival end points would still matter. 

Johnson & Johnson noted that certain response rates take a while to show. For example, in CAR T patients, it can take months or over a year to have the m-protein disappear, even though the disease is gone in the bone marrow.  This shows up as a longer "response" in clinical trial data. 

Using Biomarkers and MRD Results

A session was hosted about the use of additional biomarkers in clinical trials. Maria-Victoria Mateos, MD, PhD from University of Salamanca noted that myeloma is already a small subpopulation, so it may be better to use retrospective experience. She noted that many trial sites have to get involved to find small patient populations.

With the recent challenges faced by the FDA approval process in venetoclax for t(11;14) patients, Jesus Berdeja, MD of Sarah Cannon suggested that if a biomarker is being used it may be best to use a standard therapy backbone for both arms and then add the other drug for a more realistic comparison. Ajai Chari, MD of UCSF noted that patients with specific biomarkers like t(11;14) can also have del17p or other confounding genetics, which can complicate results. Sagar Lonial, MD of Emory University echoed his comment that for t(11;14) specifically, combination therapy is important because he has one patient on venetoclax that has done well for 5 years and other with t(11;14) and del17p who is relapsing early. This makes clinical trial design tricky for a single genetic subtype of myeloma.

With patients living so much longer, researchers are not wanting to wait for overall survival (OS) data, because trials could take 10+ years for the data to read out. FDA stated that they need more data to support MRD testing as a new end point. Dr. Munshi asked if they had the data, would it change the need for randomized trials? FDA mentioned that data is helpful but they still need the randomized trials. Dr. Munshi said, "I tried."

Newly Diagnosed Patient Trials

Earlier in the meeting, Dr. Munshi asked if we should still be dividing patients into transplant eligible vs. ineligible groups as they consider how the clinical trials are constructed. With quadruplet therapies being used more in the newly diagnosed myeloma setting and patients experiencing longer remissions, stem cell transplant is not being used as often. The groupings of transplant eligible vs. ineligible might not matter much any more. He suggested as examples that we may instead want to run global trials for standard risk patients vs. high risk patients instead. 

Additionally, should stem cell transplant really be a comparator arm if we know that transplant can be reserved for later lines of therapy or if patients might not want it? All clinicians include Noopur Raje, MD of Massachusetts General and Dr. Rajkumar noted that we shouldn't wed ourselves to stem cell transplant to get new drugs approved. The question was asked if transplant eligibity isn't used as a key criteria, what criteria should we use? 

Many of the doctors said that the current "fit" or "frail" status means very little in today's clinics. How does that affect eligibility for CAR T or bispecific trials? It is complicated. Hearn Cho, MD of Mount Sinai and Chief Medical Officer of the MMRF said that if you use lab values to restrict participants, this restricts diversity in clinical trials and a balance needs to be found. 

FDA Efforts to Accelerate Approvals

Andrea Baines, MD from FDA talked about FDA efforts to pursue more traditional and accelerated approvals. FDA has new initiatives called OCE Project Frontrunner and OCE Project Optimus that aim to resolve issues they are seeing in approvals. 

Project OCE FrontRunner is an Oncology Center of Excellence (OCE) initiative to encourage drug sponsors to consider when it may be appropriate to first develop and seek approval of new cancer drugs for advanced or metastatic disease, in an earlier clinical setting rather than the usual approach to develop and seek approval of a new drug for treatment of patients who have received numerous prior lines of therapies or have exhausted available treatment options. 

Project OCE Project Optimus is an effort to reform how early dose testing is performed becuase poor dosing and dose scheduling can lead to higher side effects without additional benefit, severe toxicities that require many dose reductions and intolerable toxicities that lead to premature discontinuation of the drug. 

Summary

In summary, the FDA/IMS Joint Workshop was a robust discussion about many topics of serious concern to myeloma patients. It is a balance between what is ideal vs. realistic and what makes sense in today's myeloma environment. There is not complete alignment between the doctors and companies who are trying to get drug approved for patients, and a regulatory body whose concern is safety, but the discussion was critical to identify the top issues and work through them together. As patients, we hope this conversation continues.