Prof. Giannopoulos: Here and now needs in the treatment of myeloma

Katarzyna Pinkosz, Wprost: There has been a huge breakthrough in the treatment of multiple myeloma in recent years; most drugs appear to treat this disease. During the recent conference “Clinical and experimental hematology”, you pointed out that some treatment regimens are unavailable to patients in Poland; among others from the second line, a three-drug regimen with carflizomib is not available. Why is it so important and what does it change in patients’ prognosis? At what stage of the disease would such a regimen be needed?

Prof. Krzysztof Giannopoulos: Indeed, reimbursement needs appear from the second line. It must be said that recent decisions regarding the reimbursement of daratumumab – first in the treatment of patients eligible for transplantation, and from January 1 this year also in the treatment of the largest group of patients with multiple myeloma, i.e. those ineligible for transplantation – meet international standards.

In the second line of treatment, we have access to various therapies, but the first clinical challenge that appears is the issue of resistance to lenalidomide. Regardless of whether treatment discontinuation was due to treatment toxicity, resistance, or disease progression; regardless of the dose of lenalidomide, we cannot use it in the second line. The clinical challenge now is not only prior treatment with lenalidomide, but actually exposure to lenalidomide, regardless of the reason for discontinuing treatment. A big problem arises because all the regimens that are currently available in the second line are suboptimal for patients who have had prior exposure to lenalidomide.

What would be optimal for this group of patients?

We have two therapeutic groups available: one is three-drug regimens in which the core of the therapy is an immunomodulatory drug. It cannot be lenalidomide, so from our wide range of second-line options we remove all regimens containing this drug, but also regimens containing a newer generation immunomodulatory drug, i.e. pomalidomide. They appear to be relatively ineffective in patients who have had prior exposure to lenalidomide.

The second group of therapeutic options are regimens in which the core of the therapy is the carflizomib-dexamethasone regimen. This is where the urgent need for reimbursement arises, because we only have a two-drug regimen, which in two studies was compared with three-drug therapy, i.e. carflisonib-dexamethasone plus an anti-CD38 drug. Both studies showed a clear advantage of the three-drug regimen. At the reimbursement decision stage, we can basically only talk about one regimen: carflizomib-dexamethasone-daratumumab.

The results of the CANDOR study showed that the use of the KdD regimen compared to the Kd regimen prolonged progression-free survival by 13 months, and we had a 41% reduction in the risk of death or progression. It’s a lot; The median PFS (progression free survival) in therapy with the addition of daratumumab reaches almost 40 months. This is many times longer than in the case of three-drug regimens with pomalidomide and dexamtasone. It can be said that the KdD three-drug regimen has exceptional efficacy in patients who have had prior exposure to lenalidomide.

The introduction of the KdD scheme is a request for the “here and now”. When patients will receive daratumumab in the first line; the decision to administer daratumumab in subsequent relapses will be very individualized. In some cases we will not make this decision. Today, however, there is an urgent need for reimbursement of the triple drug regimen carflizomib-dexamethasone-daratumumab, due to its unprecedented effectiveness in patients after previous exposure to lenalidomide.

Can this regimen be considered the most important unmet need for patients with multiple myeloma at this time?

In the second line of treatment: definitely yes.

However, when thinking more broadly about myeloma patients and increasingly effective therapies in the first three lines, we must pay attention to the group of patients who have been exposed to all previous therapeutic groups. This is the place that immunotherapies occupy in international standards: the first one is CAR-T technology, the second one is bispecific antibodies.

With regard to CAR-T therapy, we cannot yet define our reimbursement needs to the Ministry of Health because none of the companies has submitted a reimbursement application; We hope that this year there may be a breakthrough and the refund process may be initiated. The second group are bispecific antibodies. It is worth mentioning that in the analysis of the reimbursement needs of PTHiT experts (Top 10 Hemato), as many as 5 out of 10 drugs are drugs from the bispecific antibody group; they are used not only in the treatment of myeloma, but also in indolent and aggressive lymphomas. Three bispecific antibody therapies for myeloma are already approved in the European Union; the most advanced in the reimbursement process is teklistamab. For patients above the third line of treatment, today it is the only therapeutic option consistent with the international standard. Returning to older polychemotherapies or even therapy with newer products is ineffective, and the ineffectiveness is greater the more effectively we treat in the first lines.

Is this the second, very important need for patients?

Yes, we also defined it in the letter which, as members of the Polish Myeloma Group and the Polish Myeloma Consortium, we addressed to the Minister of Health with a request for reimbursement.

So, firstly: patients resistant to lenalidomide in the second line of treatment, and secondly – patients after three lines of treatment. We also have further needs that we are slowly starting to define; I am thinking here about extended treatment with carflizomib for high-risk patients after transplantation, in accordance with the results of our Polish non-commercial study ATLAS. It would be good if Polish patients not only benefited from this regimen as part of a controlled clinical trial, but also had the opportunity to have wider access as part of the drug program.

Another request concerns the availability of ixazomib: the definition regarding high-risk patients has changed, hence our request that the availability in the drug program be adjusted to the current state of knowledge; all cytogenetic aberrations that are defined as high risk should be taken into account.