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Saturday, April 13, 2024

We are waiting for the optimal second line

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Interview with prof. Dominik Dietfeld from the Department and Clinic of Hematology and Bone Marrow Transplantation at the Medical University of Warsaw. Karol Marcinkowski in Poznań, President of the Polish Myeloma Consortium.

More and more new drugs and regimens are becoming available in the treatment of myeloma, and each year brings information about new breakthroughs that open up opportunities for patients. Treatment options for myeloma in Poland have also changed significantly. Since the January reimbursement decision, first-line treatment options have expanded significantly. Are second-line treatment options also optimal for patients who are resistant to previously treated lenalidomide and bortezomib?

It is great that we can now use lenalidomide as first line in almost all patients. First-line treatment options for myeloma are currently very good: we have good four-drug therapy for patients who need a transplant, and we can later use lenalidomide as maintenance treatment.

In transplant-ineligible patients, we can use lenalidomide in a very good three-drug combination. Today this is a very good first line solution. However, the vast majority of patients at the time of myeloma progression will be resistant to lenalidomide or unable to use it due to intolerance. In these patients, we will not be able to use lenalidomide-containing regimens in the second or subsequent lines. This is a clinically important issue because there may be many such patients; Therefore, choosing the optimal therapy for them is not easy.

Currently, we can only offer them suboptimal regimens: carfilzomib plus dexamethasone (CD) or pomalidomide, bortezomib and dexamethasone (PVD). These are the second choice schemes. The number 1 choice for this group of patients is triple therapy: carfilzomib, dexamethasone and an anti-CD38 antibody, that is, daratumumab or isatuximab.

Why would choosing a three-drug regimen be significantly better than a Kd regimen for this group of patients?

Three-drug regimens are more effective – we have evidence of this from randomized clinical trials. The KdD regimen, i.e., carfilzomib, daratumumab, and dexamethasone, was registered based on the CANDOR trial. At the center where I work, we participated in this clinical trial; it showed that median progression-free survival increased from 15 months (for patients treated with the Kd regimen) to 28 months in the three-drug group.

So it was almost doubling the time with no progress. In Poland we can use the Kd regimen for this group of patients; we cannot use two very good drugs together: carfilzomib and daratumumab. Therefore, we cannot optimally exploit the potential of both of these drugs.

In the case of myeloma, the second line is often almost the beginning of treatment. Are these patients in good general condition?

Many patients are in good physical condition. In the second line, the increase in progression time with a three-drug regimen was very large, so we would like to be able to use this treatment.

When it comes to best meeting the needs of myeloma patients, will a three-drug KdD regimen be the most anticipated today?

As our knowledge of myeloma advances, medicine advances, and reimbursement for our patients improves, the needs increase. The fact that lenalidomide came into the first line and very good treatments moved from the second and third lines to the first line created a vacuum in the second and third lines.

Therefore, the first priority today is to address the needs of patients resistant to lenalidomide. This is the number one need, although in myeloma the needs are greater because third- and fourth-line patients also do not have access to the latest treatments. There is also a huge need to improve their treatment.

Should treatment be optimal from the earliest possible lines?

We must offer patients the best therapy at every stage of the disease. If at some stage we do not provide optimal therapy, the patient will ultimately lose. We have been saying for years that three-drug therapy is more effective than two-drug therapy. Different effects will occur as a result of the combined use of therapy with three drugs, as well as different effects as a result of sequential use of the three drugs. Myeloma requires optimal treatment if we are to achieve the best results.

Do you have patients who should receive a three-drug regimen of carfilzomib and deratumumab, but this is not possible today?

Certainly; Thanks to the fact that our center participated in clinical trials, I have very good experience with this regimen. Carfilzomib is a second-generation proteasome inhibitor that is more effective than bortezomib but has no neurological toxicity (bortezomib often causes neuropathy). Carfilzomib does not cause this: it is a stronger and safer proteasome inhibitor. Adding daratumumab to it practically does not change the safety profile and increases the potential of treatment. It’s like a new generation of therapy.

With these subsequent treatments becoming more and more optimal, is myeloma increasingly becoming a chronic disease?

We are moving in this direction, at least for some patients. However, this is only possible by optimizing treatment. If you use optimal treatment regimens at each stage, the effect will be best. This means that we cannot give up at any stage.

What modern advances in the treatment of myeloma are worth implementing?

First of all, this is immunotherapy. Over time, myeloma becomes resistant to the treatment used – even very good immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (i.e. bortezomib, ixazomib, carfilzomib), monoclonal antibodies (daratumumab, elotuzumab, isatuximab). At some point, resistance to these three groups of drugs will arise – the mechanisms we use in treatment will no longer be effective.

That’s why we want to use the immune system to fight myeloma. Here we have two types of treatment: bispecific antibodies and CAR-T therapy. Secondly, this is an optimal combination of drugs that, as we know, are effective – for example, daratumumab is effective, carfilzomib is also effective, but their combination with the addition of dexamethasone is even more effective. This is why it is so important to combine therapy within three-drug regimens. Another trend is four-drug therapy, which we already know is the future. Today we can use four-drug therapy as first line; I think there will be more such schemes in the future. This may further improve the effectiveness of treatment.

Do patients hope that these new, more effective treatment regimens will also appear in Poland?

We often say that in Poland there are problems with modern treatment, but I must say that I am very pleased with the possibilities that we have today in the first line of treatment for myeloma. The schemes we have access to are truly at European level. This means we need to improve second-line treatments for patients who have become refractory to first-line therapy.

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Source: Wprost

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