Optimizing Multiple Myeloma Treatment with Advanced Drug Combinations

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• Treatment Evolution in Myeloma
• MRD Negativity as the New Goal
• Advanced Detection Technologies
• Three-Drug vs. Two-Drug Regimens
• Four-Drug Combination Therapy
• Future Treatment Directions
• Full Transcript

Treatment Evolution in Myeloma

Dr. Nikhil Munshi, MD, highlights a significant shift in multiple myeloma treatment. At least six new medicines received approval in the last five years. Two-drug regimens are now largely replaced by three or four-drug combinations. This evolution has dramatically improved patient outcomes. Dr. Anton Titov, MD, discusses these advances with Dr. Nikhil Munshi, MD. Response rates now approach 100% in many cases.

MRD Negativity as the New Goal

The treatment objective has moved beyond complete remission. The new benchmark is minimal residual disease (MRD) negativity. Dr. Nikhil Munshi, MD, explains that complete remission was historically defined by bone marrow examination. This method could detect roughly one myeloma cell in 100 cells. Achieving MRD negativity signifies a much deeper response. It is a critical predictor of long-term treatment success.

Advanced Detection Technologies

Advanced technologies are crucial for defining MRD negativity. Dr. Nikhil Munshi, MD, describes two primary methods. Next-generation sequencing offers extremely high sensitivity. Multicolor flow cytometry, using 10 to 12 colors, is another powerful tool. These technologies can identify one myeloma cell in a million normal cells. This represents a 10,000-fold increase in detection sensitivity over older methods.

Three-Drug vs. Two-Drug Regimens

Clinical studies clearly demonstrate the superiority of three-drug regimens. Dr. Nikhil Munshi, MD, notes these typically combine a steroid with two key drug classes. A proteasome inhibitor and an immunomodulatory drug form the backbone. This combination has proven significantly better than two-drug therapies. The improved efficacy is measured in both response rates and progression-free survival.

Four-Drug Combination Therapy

The next frontier involves adding a fourth drug to the regimen. Dr. Nikhil Munshi, MD, identifies CD38-targeting monoclonal antibodies as this fourth agent. These antibodies attach to a specific protein on myeloma cells. Studies show four-drug combinations provide better responses than three-drug regimens. They achieve MRD negativity in approximately 50% of patients. This represents the current gold standard in induction therapy.

Future Treatment Directions

Ongoing research continues to refine multiple myeloma treatment. Dr. Nikhil Munshi, MD, mentions numerous studies across different countries. These trials compare various permutations of the available drug classes. The optimal combination likely includes a proteasome inhibitor, an immunomodulatory drug, a steroid, and a CD38 antibody. Dr. Anton Titov, MD, explores these future directions with Dr. Nikhil Munshi, MD. The goal remains achieving the deepest possible response for every patient.

Full Transcript

Dr. Nikhil Munshi, MD: At least six new medicines for multiple myeloma were approved in the last five years. Two-drug regimens have now been replaced by three- or four-drug combinations, and response rates, as you mentioned, are close to 100%, with complete remission happening in over 50% of multiple myeloma patients.

So how do we identify the most efficient combination of new drugs for multiple myeloma in treatment induction and also in maintenance treatment regimens? It's a good problem—a problem of success—that a lot of treatments are giving us 100% response rates.

Because we get 100% response rates, we are beginning to move on to determining what is called minimal residual disease negativity. To simply describe MRD: when we currently—or until the recent past—determined response and called it complete response, we did a bone marrow test to see if there were no myeloma cells in the bone marrow. That was one of the requirements to call someone in complete remission.

That determination of bone marrow negativity was based on regular pathological examination under a microscope, and our ability to find myeloma cells in that setting was around one cell in 100. So if there was one myeloma cell in the bone marrow among 100 cells, we might be able to find it by doing the staining we use. That was our standard until recently.

Now, newer technologies—sequencing-based technology and also doing multicolor, 10- and 12-color flow cytometry—have allowed us to identify one myeloma cell in a million. That’s 10,000 times deeper estimation of myeloma cell presence.

Utilizing such a very sensitive method, we are redefining response. Our aim now is not just to get complete remission alone, but to get MRD negativity, which doesn't happen in 100% of patients yet—it happens in around 50%.

Using such methodologies, we are beginning to compare multiple drug combinations. We have clearly shown in many studies that three drugs are better than two drugs. The three drugs usually involve one steroid, but the main two drugs end up being a proteasome inhibitor and an immunomodulating drug. That’s very clear.

Now, we are all greedy—we want to get more and more. We want 100% of patients to have the best response. So what we began to do is combine a fourth drug, which is an antibody that targets a cell surface molecule called CD38.

These CD38 antibodies have become an important component of four-drug regimens: three that are described, plus the fourth antibody. Now there are multiple studies showing that four drugs provide better responses and progression-free survival compared to three drugs.

So four drugs are becoming better. But because there are multiple permutations and combinations available, there are many studies ongoing simultaneously in different countries and regions, asking which one may be better.

Most likely, general analysis would be that a proteasome inhibitor, a CD38 antibody, and one immunomodulatory drug with steroid—those four drugs provide currently the best induction response, usually around 50% MRD negativity and overall 100% response rates.