Frontline car-BIRD Regimen Shows Potential for Patients With Multiple Myeloma

Ruben Niesvizky, MD

For the upfront treatment of patients with multiple myeloma, the standard of care consists of combination therapy with a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and a corticosteroid. But new research shows that there may be another safe and effective option.

In a phase 2 study of 74 patients with multiple myeloma (NCT01559935), carfilzomib (Kyrpolis) in combination with clarithromycin (Biaxin), lenalidomide (Revlimid), and dexamethasone (car-BIRD) was administered as sequential therapy. Efficacy in the study was primarily determined by response to the car-BIRD regimen, which was defined by the achievement of a stringent complete response (sCR), complete remission (CR), very good partial remission (VGPR), partial remission (PR), stable disease (SD), or by the development of progressive disease (PD). Secondary end points of the study included event-free survival, minima residual disease (MRD) negativity following treatment with car-BIRD, progression-free survival, and stem cell collection.

Response to the novel regimen surpassed that observed with the standard of care, and the median PFS was 37.3 months (95% CI, 27.9-52.7).

In an interview with Targeted Oncology™, Ruben Niesvizky, MD, director of the Multiple Myeloma Center at New York Presbyterian Hospital-Cornell Medical Center, discussed current outcomes in multiple myeloma and how the introduction of the car-BIRD regimen may improve upon them.

TARGETED ONCOLOGY™: What are outcomes like for patients with multiple myeloma who receive standard of care therapy?

Niesvizky: Well, the standard of care has shifted significantly since the advent of the monoclonal antibodies. The manuscript that we're discussing is before the era of the monoclonal antibodies, or at least when those monoclonal antibodies were going to be used only in the relapsed/refractory setting. So, during that time, the standard of care was able to achieve a complete response of about 30% and then overall response rates were about 90% in using triplets of PIs, immunomodulatory drugs, or corticosteroids. Then there was the VRd [bortezomib [Velcade], lenalidomide, and dexamethasone] construct and more recently the KRd [carfilzomib, lenalidomide, and dexamethasone] construct. But there had been no discovery that KRd had an increased number of complete responses and better minimal residual disease. And, it had been thought through all the trials that carfilzomib was superior to bortezomib even in certain parameters, therefore, we decided to move into this trial in which we combined carfilzomib and dexamethasone induction until maximum response followed by lenalidomide, clarithromycin, and dexamethasone.

Can you explain the potential need for sequential therapy followed standard of care in patients with multiple myeloma?

The kinetics of the responses have traditionally followed a very rapid response. Most individuals tend to achieve a plateau and the biology of that is poorly understood. In other words, most of the tumor bulk is reduced rapidly in 3 or 4 cycles, but then there is left over disease that presumably is a more resistant subset of subclones that are refractory to the induction. Therefore, the second line of therapy for consolidation therapies was designed to try to eliminate those receivable clones, and traditionally, those were high-dose chemotherapy. It remains one of the most common strategies that we use particularly for both fit or unfit patients.

Those of the drugs can change the duration of inductions and this is still not clear. Study investigators say the induction should last 4 to 6 cycles, but that's based basically on traditional treatment programs. We believe that induction should continue. While there is evidence of response if particularly consolidation with high-dose therapy is not going to be introduced early. Because of this, in our program, we're using 2 agents as induction at the highest dose possible than the consolidation therapy, but in a more response adaptive fashion.

What did you hope to demonstrate in this study?

The key goal of this study was to see if sequential therapy in response adaptive fashion can achieve similar results to traditional induction consolidation programs, which are the current standard of care. So, therefore, we designed a phase 2 study of induction with carfilzomib and dexamethasone with carfilzomib at the highest dose possible, then switching to the BIRD regimen following maximum response. In order to achieve the maximum response possible, the Carfilzomib was those 20 milligrams per meter squared on days 1 and 2. Then, in the first part of the protocol, we escalate to 45 million square meters per meter squared. For the following 26 patients at the end of the trial, we were able to escalate the carfilzomib to 56 meetings to permit a meter squared. The schedule of carfilzomib is 20 days 1 and 2 of cycle 1 with the rest being 56 biweekly scheduled 3 weeks in a row and 1 week. Then we continue with these regimens in a monthly basis following the IWG criteria for maximum response and then upon plateau or maximum response we switched to the BIRD regimen, which consists of lenalidomide 25 milligrams daily for 21 days, with 7-day breaks. Clarithromycin 500 milligrams IV for the whole month, and dexamethasone 40 milligrams on a weekly basis administered orally.

Can you explain the findings of this study?

We were very happy with the results. Again, this is before we are going to monoclonal antibodies, the overall response rate for the full regimen was 94%, whereas 83% of the patients can achieve more than a VGPR. So that was quite gratifying, which compared favorably to the current regimens available. Looking at that complete response, more than 35% had a stringent CR by adding the BIRD regimen followed lenalidomide maintenance, and we could extend their response rate to 90%, reaching our target CR rate of more than 55%.

The median overall survival has not been reached with a median follow-up of 60 months. The toxicities were low-grade and manageable. They were hematological, as we expected for this trial. So, the conclusions were that the regimen is indeed effective and safe and it could be used as an alternative when consolidation programs want to avoid transplant.

Based on your understanding of sequencing in multiple myeloma so far, what do you recommend after Car-BiRD?

Well, these regimens allow us to use post-consolidation regimens, particularly based on second-line agents. With monoclonal antibodies, so many of our patients who had failed these regimens that gone onto CD38 antibody-based therapy in combination with alkylating agents or with an immunomodulatory agent, the majority of these patients have the stem cells harvested, so this could also serve as a preamble before transplant. So, if there is evidence of progression, patients should be moved on to stem cell transplant as a second portion of the consolidation. That will allow achieving profound CRs with MRD negativity.

Do you have any further advice for oncologists who may use this treatment strategy?

Recently, a randomized trial from a Spanish group showed that indeed, the addition of clarithromycin to this regimen induces better and higher response rates. However, the toxicity for frail patients was prohibitive. And therefore, using this type of combination in frail patients is not recommended, but it's an excellent combination that could be used in patients who fit or unfit for chemotherapy.

_Reference:

_{Forsberg PA, Ross AC, Boyer A, et al. Carfilzomib and dexamethasone induction with lenalidomide, clarithromycin and dexamethasone consolidation and lenalidomide maintenance for newly diagnosed multiple myeloma. Am J Hematol. 2021;96(12):1554-1562. doi: 10.1002/ajh.26329.}