Amrita Krishnan, MD is the executive medical director of Hematology at City of Hope Orange County. She is also director of the Judy and Bernard Briskin Multiple Myeloma Center and a professor in the Department of Hematology & Hematopoietic Cell Transplantation. 

Amrita Krishnan, MD, director, the Judy and Bernard Briskin Center for Multiple Myeloma, research professor, Department of Hematology and Hematopoietic Cell Transplantation, chief, Division of Multiple Myeloma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, discusses the effectiveness of teclistamab (JNJ-64007957) in relapsed/refractory multiple myeloma.

Data from the phase 1/2 MajestTEC-1 trial (NCT04557098) evaluated teclistamab vs patients in a real-world cohort.

Teclistamab elicited an improved progression-free survival, overall survival, and time to next therapy compared with to patients in the real-world database cohort, Krishnan explains, noting the limitations of a retrospective database study. Additional findings from the phase 1/2 MajestTEC-1 trial pointed to intriguing durability of responses in patients administered teclistamab, Krishnan says.

No new safety signals for teclistamab were reported on the trial, Krisnan adds. Infections continue to be an adverse effect to monitor with teclistamab, which is similar to other bispecific antibodies, Krishnan continues. It is important to bear in mind to optimize prophylaxis for those patients, Krishnan concludes.

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Amrita Krishnan, MD, discusses the effectiveness of teclistamab in relapsed/refractory multiple myeloma.


Dr. Krishnan of the Effectiveness of Teclistamab in Relapsed/Refractory Multiple Myeloma

 The other things of interest at ASH [American Society of Hematology Annual Meeting] cemented what we thought, now that we have more data from the GRIFFIN trial. There was a follow-up presented by Jacob Laubach about daratumumab-Revlimid-Velcade-dexamethasone vs RVd [lenalidomide, bortezomib, dexamethasone], stem cell transplant, consolidation, daratumumab–RVd [lenalidomide, bortezomib, dexamethasone] vs RVd [lenalidomide, bortezomib, dexamethasone], and then maintenance daratumumab-R [lenalidomide] vs R [lenalidomide]. With longer follow-up, we confirmed the greater depth of response in terms of MRD [minimal residual disease] negativity with the daratumumab arm. We didn’t see a significant statistically PFS [progression-free survival] benefit, but there was a trend to a better PFS benefit in the daratumumab arm. For me it cemented the use of quadruplet therapy for initial induction for the majority of patients.

I don’t want to overlook another class of drugs that have been presented before because we continue to have more follow-up data and await more data in terms of further combinations as well as use in earlier lines of therapy. Those are CELMoDs [cereblon E3 ligase modulators]. There were data presented at ASH about iberdomide in combination with dexamethasone in patients with relapsed/refractory myeloma and the dose expansion of CC-220 in the MM-001 trial. What they showed in this are patients who had greater than 3 prior lines of therapy, including lenalidomide, pomalidomide, a PI [proteasome inhibitor], and anti-CD38 antibody—patients who had a fair amount of prior therapy.

They reported on 107 patients with a median of 6 prior lines of therapy and showed an overall response rate of 26%, suggesting that in this heavily refractory group of patients, they could get responses with this new class of drugs. That includes patients who were refractory to other immunomodulatory agents. The adverse-effect profile is not unexpected in terms of hematologic toxicity in over 20% of patients, with 27% of patients having a grade 3/4 infection. But it suggested this oral regimen might be an option for patients, including patients who have advanced heavily pretreated myeloma.

One of my takeaways from ASH was the use of quadruplet therapy for up-front induction. We have the phase 3 German study of isatuximab–RVd [lenalidomide, bortezomib, dexamethasone] vs RVd [lenalidomide, bortezomib, dexamethasone]. We have the GRIFFIN study with daratumumab–RVd [lenalidomide, bortezomib, dexamethasone] vs RVd [lenalidomide, bortezomib, dexamethasone], both showing a greater depth of response with the use of the quadruplet induction. The next takeaway I have from ASH is the idea of using bispecific antibodies, and if you relapse on 1, it doesn’t preclude you from using another. Using 1 T-cell engaging therapy doesn’t preclude the use of another, suggesting that we’re going to be able to use this earlier in the course of disease and no longer thinking about reserving these therapies for our last therapy. That was very encouraging for the future of myeloma therapy: we have new classes of drugs that we can use early in the course of disease and probably in combination with our established therapies to improve care for our patients with myeloma.

Closing out her discussion on the management of newly diagnosed and relapsed/refractory multiple myeloma, Amrita Y. Krishnan, MD, shares key takeaways from the ASH 2021 Annual Meeting.

Key Takeaways From the ASH 2021 Meeting on Newly Diagnosed and Relapsed/Refractory Multiple Myeloma

 We’re very excited about the results of teclistamab and talquetamab, the bispecific-targeting antibodies. Right now, they’re being studied in patients with very advanced myeloma who failed anti-CD38 antibodies, IMiDs [immunomodulatory drugs], and PIs [proteasome inhibitors]. Naturally, given these responses, given the tolerability of these drugs, there’s an interest in moving them earlier.

I could see them in the 1-to-3-relapse space. The question is would they be given as a single agent or in combination? Because we also have an ongoing study of daratumumab plus teclistamab, and daratumumab plus talquetamab. In that first-relapse setting, perhaps we would use daratumumab plus 1 of these bispecific antibodies to see if we can get similarly high response rates, depth of response, and long progression-free survival.

Overall, bispecific antibodies are going to be moved earlier into the course of disease, including in the frontline setting, either in combination in the frontline setting with daratumumab or possibly after a standard IMiD-PI induction and using the bispecific, for example, as a consolidation, perhaps instead of autologous stem cell transplant in the future. Ultimately, the bispecifics are going to be moved very early in the course of disease. We still don’t know, for example, if you had a BCMA-targeting agent, will you respond to BCMA CAR [chimeric antigen receptor] T cells. That’s where the question becomes, which bispecific do you use first? If you have concerns about that, perhaps people would look more to talquetamab, the GPRC5D-targeting agent, earlier and save BCMA targeting for CAR T vs teclistamab. But as the data emerge, that will also become more clear to us in terms of sequencing these agents.

ASH [American Society of Hematology Annual Meeting] 2021 showed us other new targets for myeloma. Among them was FcRH5 and a bispecific antibody, cevostamab, which was also studied in the phase 1 setting and presented by Suzanne Trudel on behalf of the study team. Similar to the other bispecifics, it used step-up dosing to reduce the risk of cytokine release. Similar to the other bispecifics, patients who were treated had extensive prior therapy and a median of 6 prior lines of therapy. Also interestingly, 13 patients in that study had prior bispecific antibodies, and 28 had had prior CAR T cells. We’re seeing patients treated with other T-cell engaging therapies first coming on to the cevostamab trial.

Overall, the drug appeared well tolerated. The usual expected adverse events, including hematologic toxicity and cytokine release, were in about 80% of patients. We saw a response rate of 56% at the target dose, including a third of the patients getting a very good partial response or better with responses deepening over time. Data are a little short in terms of the durability of responses, but the median duration of response is 11.5 months, which is certainly encouraging. The news for patients with myeloma is that we now have multiple targeting bispecific antibodies. Also, we’ve shown that you can move from 1 bispecific antibody to another bispecific antibody and still get responses.

Amrita Y. Krishnan, MD, considers where bispecific antibodies will fit into the multiple myeloma treatment paradigms as single-agent or combination therapy. 

How Will Bispecific Antibodies Fit Into the Multiple Myeloma Treatment Paradigm?

 ASH [American Society of Hematology Annual Meeting] 2021 was exciting for the myeloma field because of data with bispecific antibodies. There were multiple different bispecific antibodies presented at ASH. One was the MonumenTAL-1 study that I presented, which used a bispecific antibody targeting GPRC5D, a receptor that’s highly expressed in myeloma cells. In this study with patients with relapsed/refractory myeloma who had a median of 5 to 6 prior lines of therapy, including 80% of them being penta-drug exposed, we saw response rates of 67% to 70%; that was very encouraging. Over 50% of the patients had a vgPR [very good partial response] or better.

The adverse-effect profile showed that the majority of patients, 77%, had cytokine release but mostly mild. Some of the unique adverse effects with talquetamab were in terms of its target on keratinized tissue, so we did see nail toxicity and some skin rashes in up to 70% of patients. We also saw dysgeusia in about 60% of patients. The encouraging thing about the drug was that patients seemed to get durable and deep responses, and many patients are still on treatment in both the weekly and biweekly dosing cohorts.

The other bispecific that was also very exciting was the teclistamab, a bispecific targeting BCMA. Teclistamab is in a more crowded space because there are multiple BCMA-targeting bispecific antibodies and, as many people know, also BCMA-targeting CAR [chimeric antigen receptor] T cells. Nonetheless, teclistamab in the MajesTEC-1 study showed very promising results in patients with advanced myeloma. We had about 70% of patients penta-drug exposed, and 30% were penta-drug refractory. They saw an overall response rate of 62%, with 58% of the patients getting a vgPR or better. Overall, the drug did seem to be well tolerated. There was a signal of infections in about a third of patients, so that certainly bears watching.

Teclistamab seemed to show durable and deep responses, and 1 question with bispecifics has always been the durability of response. Teclistamab did present some early progression-free survival [PFS] data. The 6-month PFS was 64%, the 9-month PFS was 58.5%, and the median overall survival has not been reached. It seems quite encouraging in terms of the durability of these responses.

Insight on results from the MonumenTAL-1 and MajesTEC-1 studies, which evaluated bispecific antibodies in patients with relapsed/refractory multiple myeloma.

A Role for Bispecific Antibodies in R/R MM: Data From MonumenTAL-1 and MajesTEC-1 Studies

 For patients with first relapse in myeloma, there are multiple treatment options. A lot of it depends on the prior therapies for that patient and the toxicities and comorbidities. Many of us use daratumumab-pomalidomide, and dexamethasone based on the APOLLO study. It showed a benefit to daratumumab-pomalidomide plus dexamethasone compared with pomalidomide-dexamethasone alone in terms of progression-free survival. The other thing is that the advent of subcutaneous daratumumab has been also a tremendous step forward. Although the APOLLO study used intravenous daratumumab, in clinical practice, most of our patients are on subcutaneous daratumumab.

The APOLLO study was a very important study because it represents what we’re doing in clinical practice for patients with early relapse. In this trial, patients had to have at least 1 prior line of therapy, which included lenalidomide and a proteasome inhibitor. If they’ve had only 1 line of therapy, they had to be lenalidomide refractory. They were randomized to either daratumumab-pomalidomide and dexamethasone or pomalidomide and dexamethasone. The important part of this trial was that daratumumab was subcutaneous or IV [intravenous] on a traditional schedule.

What we found in the study was that the progression-free survival was significantly better for patients who received the daratumumab plus the pomalidomide-dexamethasone at 12.4 months vs only 6.3 months in patients who received pomalidomide-dexamethasone alone. The hazard ratio was 0.63. This trial was important because it cemented what we often do in clinical practice. Many of the patients we see are lenalidomide refractory because they’re progressing after lenalidomide maintenance. And the therapy that we choose at first relapse is often daratumumab plus pomalidomide and dexamethasone, especially with the advent of subcutaneous daratumumab.

One question that always comes up for us in that first-relapse setting—certainly, we use daratumumab quite a bit—is what’s the best partner for daratumumab? Would it be daratumumab, pomalidomide, and dexamethasone or daratumumab, bortezomib, and dexamethasone? Many of the patients that we’re seeing in that first relapse setting are lenalidomide refractory.

At the recent ASH [American Society of Hematology Annual Meeting], there was an abstract doing an indirect comparison of daratumumab-pomalidomide-dexamethasone with daratumumab-bortezomib-dexamethasone or bortezomib and dexamethasone in patients with relapsed/refractory myeloma. Of course, this is challenged by some of the issues with these indirect comparisons through patient databases. But they used the data for the daratumumab-pomalidomide-dexamethasone cohort from the APOLLO study and then data from the EQUULEUS study, which was a phase 1 study of daratumumab-pomalidomide-dexamethasone. For the daratumumab-bortezomib-dexamethasone arm, they used the data from the CASTOR trial, another open-label phase 3 study that compared daratumumab-bortezomib-dexamethasone with bortezomib-dexamethasone alone.

There were limitations when they were using some of these data sets. One of the biggest limitations was that they weren’t able to get ISS [International Staging System] data for a large number of patients and were also missing some data in terms of the myeloma type. You have to take that as a caveat because those may be important issues in terms of some of the responses, as we know in patients, especially ISS stage. But with these indirect treatment comparisons, what they did find was that there was a progression-free survival benefit for daratumumab, pomalidomide, and dexamethasone compared with daratumumab, bortezomib, and dexamethasone and bortezomib-dexamethasone alone. This isn’t particularly practice changing. It just reflects another reason to use our standard practice of daratumumab-pomalidomide-dexamethasone in that early relapse space.

With the advent and approval of subcutaneous daratumumab, there’s been a lot of question about its use vs IV daratumumab. For the majority of our patients, we use subcutaneous daratumumab, and that includes patients who’ve previously been treated with intravenous daratumumab; we’ve switched them over. Most have been quite happy with the switch, especially in terms of convenience, time in the chemotherapy room, and the lower degree of infusion reactions with that first dose. The use of subcutaneous has been a big step forward.

I’ve had a handful of patients I can count on 1 hand who requested to switch back to the IV formulation from the subcutaneous and not for any particular 1 adverse effect. One thought was that they had more neuropathy. Another was that they had some atypical joint pains with the subcutaneous formulation. As I said, a handful of patients requested the switch back to IV, but the majority of my patients are on subcutaneous daratumumab. Certainly, when we’re starting newly diagnosed patients or patients who are new to daratumumab, we always start with a subcutaneous route.

Expert perspective on the management of multiple myeloma at first relapse in the context of recent clinical data from the ASH 2021 Annual Meeting.

Treatment Options for Patients With MM at First Relapse 

Amrita Krishnan, MD, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research and a professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, discusses key aspects of the phase III ELOQUENT-2 and -3 trials in relapsed/refractory multiple myeloma.

ELOQUENT-2, published in 2015, evaluated the addition of elotuzumab (Empliciti) to the combination of lenalidomide (Revlimid) and dexamethasone in patients with relapsed/refractory myeloma. Lenalidomide and dexamethasone served as the control arm. Results showed a significant progression-free survival (PFS) advantage with elotuzumab, as well as a well-tolerated toxicity profile, says Krishnan.

In the randomized phase II ELOQUENT-3 trial, elotuzumab was combined with pomalidomide (Pomalyst) and dexamethasone and compared with pomalidomide and dexamethasone alone. These results also conferred a PFS advantage with the addition of elotuzumab. Specifically, researchers reported a PFS of approximately 10.3 months in the elotuzumab arm versus 4.7 months in the doublet arm. This came as a welcome surprise to the community, says Krishnan, especially in a setting of patients who had received a median of 3 prior regimens.

Amrita Krishnan, MD, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research and a professor in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, discusses key aspects of the phase III ELOQUENT-2 and -3 trials in relapsed/refractory multiple myeloma.

Amrita Krishnan, MD

Articles

Dr. Krishnan of the Effectiveness of Teclistamab in Relapsed/Refractory Multiple Myeloma

Key Takeaways From the ASH 2021 Meeting on Newly Diagnosed and Relapsed/Refractory Multiple Myeloma

How Will Bispecific Antibodies Fit Into the Multiple Myeloma Treatment Paradigm?

A Role for Bispecific Antibodies in R/R MM: Data From MonumenTAL-1 and MajesTEC-1 Studies

Treatment Options for Patients With MM at First Relapse

Dr. Krishnan on Key Aspects of the ELOQUENT Trials in Relapsed/Refractory Multiple Myeloma