Reacting to Relapsed/Refractory Myeloma in the Clinic

Peter Voorhees, MD: When we refer to relapsed multiple myeloma, we’re talking about multiple myeloma that has previously responded to therapy and has subsequently progressed. Typically, we want to see at least a minimal response for a 25% reduction in M [monoclonal] protein followed by subsequent progression. That would constitute relapse. Refractory is different. Refractory essentially means that a patient’s disease is resistant to a particular therapy. That typically means the disease has progressed in the face of that therapy or has progressed within 60 days of stopping that therapy. There are also patients who have primary refractory disease, which has not responded to any initial treatment. Then there’s the relapsed and refractory, which means the patient has responded to therapy in the past, they’ve relapsed, and now the disease has become refractory to treatment.

Suzanne Lentzsch, MD, PhD: The number of patients refractory to treatment varies according to the stage of the disease. Almost all patients usually respond when they start the initial treatment. We have tested RVd [lenalidomide, bortezomib, dexamethasone], for instance, for newly diagnosed patients, or KRd [carfilzomib, lenalidomide, dexamethasone], and saw response rates over 90%. That rate of response decreases the number of relapses. We know that patients who have the third, fourth, or fifth relapse have a response rate of 30%. We recently saw that on trials using Blenrep [belantamab mafodotin], melflufen, and selinexor. In principle, you can say that the rate of responses decreases with the number of relapses, from initially over 90% of the overall response to fourth or fifth relapse to less than 30% of the response. That brings a huge challenge to the treatment of our patients. We know that the response rate decreases, but at the same time, patients do not tolerate the treatment very well. In addition to the decreased response rate, we see that the response duration decreases from initially 5 years after the first treatment with transplant to up to 6 months, or 4 months, for instance, which we saw in the melflufen trial.

It’s very important to point out that the initial response really matters. The goal of the treatment in multiple myeloma is to induce a long and deep response. We know that when patients receive MRD [minimal residual disease] negativity with the first treatment, the response can last much longer in comparison with patients who receive only a VGPR [very good partial response]. My goal with treatment is it to induce a deep response and MRD negativity initially.

I also want to point out that the goal of the treatment and response changes according to the age of the patient. In younger patients, the goal is to have a response over many years and to postpone the relapse by many years so that we first have an initial progression-free survival of 5, 6, or 7 years. That changes completely with the age of the patient. The goal of treatment in a 50-year-old patient is completely different from the goal of treatment in a patient who is 90 years old. In general, I’m more aggressive in transplant-eligible patients. In patients who are over 80 or 90 years old, the goal of the treatment is to maintain the quality of life, but control the disease at the same time. It’s important to point out that the quadruplet we are using in a 50-year-old patient may only be a doublet in a 90-year-old patient.

Peter Voorhees, MD: The biggest challenge is keeping the disease under control once you’ve achieved a response to a particular therapy. The general paradigm has been that with each relapse, the likelihood of responding to therapy begins to drop. Even for those patients who do respond to therapy, the durability of the remission tends to decrease over time, to the point where the disease becomes relapsed and refractory to essentially all available therapy. That’s the biggest challenge. The other challenge, which is probably more relevant to patients who have had multiple prior lines of therapy, is management of adverse effects of treatment. These patients are often suffering from significant adverse effects of their disease, but also significant adverse effects of prior therapy, some of which may not have fully resolved. They may be more sensitive to low count issues related to treatment. Those are the biggest challenges as far as managing a patient who has relapsed/refractory myeloma.

Transcript Edited for Clarity