How We Select Treatment in R/R Myeloma: A Conversation With 3 Experts

In this commentary, 3 multiple myeloma (MM) experts discuss the increasingly difficult task of selecting therapy for patients with relapsed/refractory disease. In recent years, there has been a rapid expansion of treatment options for MM; it seems that every few months a new drug is being approved. Although this advancement is continuing to improve patient outcomes, it also makes management of individual patients with MM, especially those with relapsed disease, even more challenging.

When to Start Therapy for Relapsed/Refractory MM

Shaji K. Kumar, MD:
Several factors need to be considered when starting or switching therapy for patients with relapsed/refractory MM, of most importance, which patients need to start their next line of therapy. Let’s discuss when we actually need to start or switch treatment.

Saad Z. Usmani, MD, MBA, FACP:
For patients who are symptomatic at the time of relapse (ie, full anemia or increasing fatigue, new bone pain or lesions, renal insufficiency, hypercalcemia, or even just a quick doubling time of free light chains or M spike), a change in treatment should be initiated as soon as possible. For patients who may be asymptomatic or who have slower-moving biochemical relapse, there is some luxury of time before changing the treatment strategy. That would be my general approach.

Suzanne Lentzsch, MD, PhD:
To be honest, I think this is a difficult question. Much more guidance exists for treating newly diagnosed MM or high‑risk smoldering MM. I agree with Dr. Usmani that deciding when to start or switch treatment for relapsed/refractory MM is an evolving goal that requires following the individual patient over time. How fast is the M-spike rising and what is the doubling time? Are there any new lytic lesions on PET/CT scans? Those findings might trigger the need to start treatment immediately. Some patients may have concerning symptoms like new anemia and need therapy immediately, whereas others may have only biochemical relapse and may not need immediate treatment. Ongoing follow-up is very important.

How to Determine if a Patient Is Refractory

Shaji K. Kumar, MD:
I think one of the key factors in terms of determining what to use as treatment for first relapse in MM is what agent the patient’s disease is refractory to. In particular, physicians need to understand how to determine if a patient is refractory to lenalidomide. In the context of clinical trials, “refractory” is typically defined as progression on therapy or within 60 days of discontinuing a particular therapy, and if it is a combination, the patient is considered refractory to each drug in the regimen. In real‑world practice, there are nuances. A patient might be on a very low dose of a single agent, as is the case with lenalidomide maintenance, which may not necessarily preclude using a higher dose of the same drug in a combination regimen. This choice also depends on whether patients can tolerate the drug or if they have residual toxicity from previous therapy. In general, I consider a patient who experiences disease relapse while on lenalidomide maintenance to be refractory to lenalidomide for the purpose of choosing next therapy.

How to Determine What Treatment to Recommend at First Relapse

Suzanne Lentzsch, MD, PhD:
Treatment of relapsed MM can be challenging. We are treating patients right now who were initially treated 4-5 years ago, usually with lenalidomide, bortezomib, and dexamethasone. Therefore these days, treatment of relapsed MM is typically a daratumumab-based therapy, combined with agents such as pomalidomide/dexamethasone (Pd) or carfilzomib/dexamethasone (Kd). Another option for patients who relapsed on lenalidomide would be pomalidomide/carfilzomib/dexamethasone. However, for patients who received upfront daratumumab, options are far more limited. Of note, daratumumab and isatuximab are the sole approved anti-CD38 antibodies, but other anti-CD38 antibodies are being evaluated at first relapse in clinical trials (eg, mezagitamab [TAK-079]).

Shaji K. Kumar, MD:
One question often asked is: Would an anti-CD38 antibody plus Pd be preferable to an anti-CD38 antibody plus Kd? Dr. Usmani, you participated in the CANDOR study; would you like to address this?

Saad Z. Usmani, MD, MBA, FACP:
Certainly. In results from the CANDOR phase III study presented at ASH 2020, the lenalidomide‑refractory subset of patients had a similar median progression-free survival (PFS) benefit with daratumumab plus Kd vs Kd as the overall study population (median: 28  vs 11 months, respectively). In the phase III APOLLO trial, patients with relapsed/refractory MM who were previously treated with ≥1 previous line of therapy, including both lenalidomide and a proteasome inhibitor (PI), were randomized to receive either daratumumab plus Pd or Pd alone and also showed a PFS benefit, even in patients who were refractory to lenalidomide (median PFS: 9.9 months with daratumumab plus Pd vs 6.5 months with Pd).

Based on these data, I tend to recommend daratumumab plus Kd for most patients, with the caveat that not every patient can tolerate the high doses of carfilzomib that was used in the CANDOR trial. For patients who may not be able to tolerate the carfilzomib dosing, daratumumab plus Pd is a very reasonable option.

Shaji K. Kumar, MD:
In addition to the data with daratumumab plus Pd or Kd, we now have data with isatuximab with both of these backbone combinations. In March 2020, the FDA approved the combination of isatuximab plus Pd for patients with RR MM who have received ≥2 previous therapies including lenalidomide and a PI based on data from the ICARIA-MM trial. Now, in March 2021, we have a new FDA approval for the combination of isatuximab plus Kd for patients with RR MM who have received 1-3 previous lines of therapy based on data from the IKEMA trial.

Selecting Therapy for a Patient Who Is Triple-Class Refractory

Saad Z. Usmani, MD, MBA, FACP:
Despite our best efforts, some patients with MM progress on lenalidomide maintenance after upfront therapy with lenalidomide, bortezomib, and dexamethasone, then progress on a PI plus an anti-CD38 antibody, and then relapse after a pomalidomide-based regimen. Treating these triple class–refractory patients is a real challenge, and we often suggest that they participate in clinical trials of novel agents (eg, bispecific antibodies, CAR T‑cell therapies).

Suzanne Lentzsch, MD, PhD:
I agree that discussing clinical trials with our patients is important, but there are also other FDA-approved therapies for this setting. Selinexor is approved in combination with bortezomib and dexamethasone for MM with ≥1 previous therapy (and with dexamethasone for patients with ≥4 previous therapies and whose disease is refractory to ≥2 PI, ≥2 IMiD, and an anti-CD38 antibody). Belantamab mafodotin,an antibody–drug conjugate, is the first FDA-approved B-cell maturation antigen (BCMA)–directed therapy which is also an option, as it is approved for patients with MM after ≥4 previous therapies, including an anti-CD38 antibody, a PI, and an IMiD. Most recently, the FDA approved idecabtagene vicleucel, a BCMA-directed CAR T-cell therapy, for adults with MM after ≥4 previous lines of therapy including an anti-CD38 antibody, a PI, and an IMiD so this agent is also now an option outside of a clinical trial. Selinexor can also be used off-label in combination with other MM backbone treatments, such as with a PI, for highly refractory patients. 

Shaji K. Kumar, MD:
I am grateful for these new classes of drugs. In addition, melphalan flufenamide (aka melflufen) was approved by the FDA in early 2021 in combination with dexamethasone for patients with MM who relapsed after ≥4 previous lines of therapy and whose disease is refractory to at least 1 PI, 1 IMiD, and 1 anti-CD38 antibody.

Dr. Lentzsch, how do you choose among these different treatment options in this setting?

Suzanne Lentzsch, MD, PhD:
I am enthusiastic about CAR T-cells in MM and favor either idecabtagene vicleucel or clinical trials for relapsed younger patients. That said, for older patients or those who are not going to enroll on a trial, I would have a discussion about the advantages and disadvantages of both belantamab mafodotin and selinexor-based therapy.

Belantamab is generally well tolerated and a very effective therapy. It is given as an IV infusion once every 3 weeks, but it is associated with a 50% risk for ocular toxicity that may affect a patient’s eyesight. Belantamab would not be a good choice for a patient who depends on good eyesight for driving or working. I might suggest selinexor plus bortezomib/dexamethasone instead.

Selinexor plus bortezomib/dexamethasone is also efficacious but comes with some potentially significant toxicities, including nausea/vomiting and cytopenias. The lower dose used in the combination has mitigated some of the toxicity initially seen with the twice-weekly dosing, but I would avoid this agent for patients who are frail or already malnourished. In contrast, for patients with high‑risk cytogenetics, such as del(17p) or loss of P53, selinexor might be more potent, particularly if combined with a PI.

Shaji K. Kumar, MD:
You bring up an important point regarding toxicity. Obviously, a clinical trial is the first choice, if one is available. But for patients who will be treated with approved agents, toxicity is important to discuss along with administration logistics and efficacy. Due to the eye toxicity with belantamab, there is a Risk Evaluation and Mitigation Strategy (REMS) program to guide its use that requires an eye examination before each dose. This is important but can create logistical challenges.

With selinexor, the main concern is thrombocytopenia and the gastrointestinal toxicity you mentioned, along with fatigue. During the past few years, most physicians have shifted using it from twice weekly to once weekly. Also, following positive results from the phase III BOSTON trial where it was used with bortezomib and dexamethasone, selinexor is increasingly used in combination regimens.

With CAR T-cell therapy, including idecabtagene vicleucel, the main concern is cytokine release syndrome. Currently, idecabtagene vicleucel must be administered at a certified healthcare facility under a REMS program and patients should be monitored at least daily for 7 days after CAR T-cell infusion at the certified healthcare facility to monitor for CRS and neurotoxicity.

Optimal use of melflufen is still being figured out. A better understanding of how this agent behaves outside of a clinical trial setting is needed. Dr. Usmani, what are your thoughts?

Saad Z. Usmani, MD, MBA, FACP:
Combining selinexor with a PI makes mechanistic sense and can be followed by belantamab mafodotin or idecabtagene vicleucel. I would likely reserve melflufen for a later line, as there is not much clarity yet on its activity in alkylator‑refractory patients. I would point out that even in patients who are responding well to any of these therapies, some may need a dose or schedule adjustment due to the toxicities mentioned.

How Do CAR T-Cell Therapies and Bispecific Antibodies Compare in the Treatment of MM?

Saad Z. Usmani, MD, MBA, FACP:
A bispecific antibody is engineered to recognize both an antigen expressed on cancer cells and a surface marker on the T-cell, generally CD3. This brings the cytotoxic T-cells in close proximity to the malignant cell to jump start the immune response and results in cell killing of the tumor cells. CAR T‑cells accomplish a similar goal but by a different mechanism. T-cells are taken from the patient and engineered to target a specific antigen on a cancer cell, expanded in vitro, then reinfused into the patient following lymphodepleting chemotherapy. The most basic CAR is a synthetic, hybrid molecule comprising an antigen-binding domain derived from an antibody fused to a CD3ζ T-cell activation domain.

An important difference is time to treatment: Bispecific antibodies can be given quickly as they are an “off-the-shelf” option, whereas CAR T-cells are patient specific and take time to be manufactured and reinfused. Another difference is that bispecific antibodies can be given repeatedly vs CAR T-cells that are given once with no maintenance treatment. On the one hand, this makes the bispecific antibodies safer, since treatment can be discontinued if adverse events occur. But on the other hand, patients who receive CAR T-cells may have long-term benefit without a need for continual therapy afterwards. At the recent ASH 2020 meeting, multiple presentations demonstrated that both strategies, particularly the BCMA-targeted agents, are quite effective in MM.

Suzanne Lentzsch, MD, PhD:
It is relatively early for bispecific antibodies in MM. Most of the trials are still in phase I or phase II, but the results from ASH were very promising (eg, overall response rate >60% for talquetamab and >80% for pavurutamab). These agents seem to have less incidence of cytokine-release syndrome compared with CAR T-cell therapies.

The data from ASH 2020 showing subcutaneous administration of bispecific antibodies as an option were very encouraging. Replacing IV therapy by subcutaneous injection will be very desirable, especially for older patients. I expect that bispecific antibodies in combination with other MM agents such as an anti-CD38 antibody might be the future of MM.

Shaji K. Kumar, MD:
I agree that ongoing trials will provide clarity on whether bispecific antibodies work better in combinations. I am also excited about moving these agents that engage a patient’s own T-cells earlier in the treatment paradigm, possibly even as upfront therapy at the time of initial diagnosis, to use these agents when patients are more likely to have better T-cell health.

When Sequencing Therapies for Heavily Pretreated Patients, Can Agents From the Same Class Be Used? (For example, isatuximab in a patient who is relapsing or is refractory to daratumumab or one BCMA-targeted agent after another)

Suzanne Lentzsch, MD, PhD:
I would try to switch to different classes of agents first. For example, high-risk or older patients who are failing daratumumab can benefit from elotuzumab, which is very well tolerated in combination with pomalidomide and can help achieve stable disease. We now have selinexor-based combinations and even melflufen. In the case of anti-CD38 mAbs, I typically exhaust the option of switching to different classes before returning to another anti-CD38 antibody like isatuximab.

Shaji K. Kumar, MD:
Considering that MM is a chronic disease, there is always going to be a role for reusing classes of drugs, especially if the patients have not been exposed recently and in combination with different agents.

Saad Z. Usmani, MD, MBA, FACP:
I agree. BCMA has also become an important target in MM treatment, and multiple bispecific antibodies, CAR T-cells, and antibody–drug conjugates are in development that target BCMA.

The short answer for whether we can use an anti-BCMA bispecific antibody after an anti-BCMA specific CAR T-cell is that we do not know yet. Ongoing clinical trials of BCMA-targeted agents have begun enrolling patients who have already received other BCMA‑targeted agents, so I think we will eventually (in 1-2 years) gain a good sense of what benefit is possible through sequencing. Dr. Lentzsch, what is your perspective on this question?

Suzanne Lentzsch, MD, PhD:
It is true that we do not know the answer yet. In the past, patients with previous BCMA-targeted treatment have been excluded from clinical trials using a BCMA-targeted antibody or CAR T-cell therapy. My concern is that once a patient develops resistance to a BCMA-targeted therapy, the target might be exhausted, resulting in less response to subsequent BCMA-targeted agents. It will be important to use the most potent and safe BCMA-targeted drug as early as possible in treatment.

Shaji K. Kumar, MD:
I agree that this is a concern, but there is some hope that since the mechanisms of these different classes of BCMA-target agents differ, there may be efficacy if you go from a CAR T-cell therapy to an antibody–drug conjugate or a bispecific antibody or vice versa. As we increasingly use these classes of drugs, it will become more clear how much resistance is dependent on antigen expression compared with depletion of the immune system.

There are certainly going to be new and emerging treatment options for our patients with MM, and it is exciting to see how the treatment paradigm continues to evolve and improve outcomes for our patients with this disease.

Your Thoughts
How is your treatment of relapsed/refractory MM changing as new agents are approved? Share your challenges in the comment box below.