Ajay K. Nooka, MD, MPH

A transplant is a method to deepen the response. So here we are using transplant as an additional maneuver to deepen the response, and every clinical trial that has ever been done so far has shown the benefit of a transplant in providing the depth of the responses measured by the MRD [minimal residual disease] negativity, as well as the PFS [progression-free survival] benefit.

…[In] the IFM 2009 trial, among these patients who received the 3 drugs of induction treatment with RVd [lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone], went for a transplant, and [had] the fixed duration of maintenance after consolidation with RVd versus patients who received RVd for 3 cycles followed by 5 cycles of consolidation followed by maintenance.

Among these 2 arms, which was questioning the timing of the transplant, you were able to see the achievement of MRD negativity among these patients, so to be favoring the transplant arm.

If you look at the benefit of the quality of MRD negativity among these patients, even though the patients who achieved [an] MRD negativity, who did not go for a transplant, had lesser PFS compared to those patients who achieved an MRD negativity that went for a transplant.

Suggesting that the quality of responses among those achieving MRD negativity matters, and this can only be amplified by using a transplant. We can have the most effective induction regimens, but transplant is there to deepen those responses, which has clearly shown to translate into [a] PFS benefit.

And right now, with the shorter follow-up, we may not be able to comment on the overall survival benefits, but what we are seeing is a surrogate to these overall survival benefits with the short endpoints, for the MRD negativity as far as the PFS benefits of favoring the transplant arms across all the studies.

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Before closing out his discussion on newly diagnosed multiple myeloma, Ajay K. Nooka, MD, MPH, FACP, emphasizes the continued role of transplantation in this setting.

Continued Role for Transplantation in NDMM

GRIFFIN [study] data has provided us a lot of information in terms of achieving those depths of responses, post-induction, post-transplant, post-consolidation. And with maintenance, you’re seeing the depth of responses.

What we don’t have in the long run is the safety of this combination, 6 or 7 years later, which we’ll be having down the line. But what we have in the United States is [the] advantage of the other studies that use the lenalidomide [Revlimid] maintenance as continuous therapy until progression.

We’ve seen that, as a single agent, these are very well tolerated, and these are able to sustain the responses. There are 2 ways of looking at it. Are you able to continue the maintenance with improving and sustaining that response? Or would we be losing that response in this same process?

All of what we are seeing was [that] continued maintenances led us to [the] improvement of these responses. And clearly, when you’ve achieved a mark of MRD [minimal residual disease] negativity, you’ve achieved a mark of a serological conventional response, like a deeper response, like a complete response. You are able to peel away 1 of those drugs, preferably daratumumab [Darzalex], because [of] your long-term safety data with lenalidomide in this maintenance setting, and we can continue this until progression.

And the side effects are much better in an aspect like this. Ideally, in a hypothetical world, every drug is paid [for] and the cost is never an issue. Continuing 2 drugs is absolutely the best way to go and the safety is much better as we had seen from all these trials.

But in the real world, that may not be applicable. In terms of resources, in terms of providing safety in the long run, it makes more sense for us to give the induction regimens using quadruplets, and then the maintenance using single-agent maintenance.

Daratumumab as a single agent is 1 of the most effective anti-myeloma agents with minimal side effects, yet even if there are minimal side effects every side effect needs to be addressed in the best possible way.

So what can you expect in the first cycles of daratumumab? Infusion-related reactions used to be a big deal, and management of infusion-related reactions to give the drug in the safest way used to be the practice with the IV version. With the transition to the subcutaneous version of daratumumab, which was approved 3 years ago, we have seen a significant mitigation of these adverse events.

And what was considered in the past to be a huge issue with the infusion-related reactions is no longer an issue. So, the first cycle, or the first dose and the second dose the patients need to be monitored very closely. In our practice, we typically keep the patients waiting for 4 hours or so after the first dose, which significantly declines as we go, starting the second dose [and] onwards.

So again, this is based on the median time [of] an infusion reaction based on the ... trials and the COLUMBA trial. Now, infusion reactions are not an issue. What are the specific issues that you can see with daratumumab?

Daratumumab is a good anti-myeloma agent, but it is used in a combination with lenalidomide or dexamethasone in the induction setting. So, the rates of neutropenia, anemia, [and] thrombocytopenia are slightly higher compared to what you see with the 3-drug regimen.

What else could you anticipate in the long run? There were infectious complications. This is an effective treatment. It not only affects the malignant plasma cells [but] the normal plasma cells are affected as well.

You can see hypogammaglobulinemia as an adverse event that you could see in the long run with [the] usage of daratumumab, and patients who have [a] higher risk of infection, who already have an infection as secondary prophylaxis would start IVIG [intravenous immune globulin] in these patients.

Daratumumab can also cause hepatitis reactivations. So anybody that has a positivity for the serologies, we certainly would like for them to be receiving antibody prophylaxis. These sufficient therapies really help to control the reactivations.

Ajay K. Nooka, MD, MPH, FACP, shares insight on strategies to optimally deliver maintenance therapy and manage toxicities in patients with multiple myeloma.

Newly Diagnosed MM: Optimizing Maintenance Therapy and Managing Toxicities

In the clinical practice, forced induction responses are extremely important for us to have, but we are not using a response direct to treatment. One has to realize that not every patient’s response is exactly the same.

What we have done historically is give 4 cycles of induction treatment because that is where you get the best bang for the buck. You get the best response [with] the minimal toxicities. Can you give a fifth cycle? Absolutely. Yes, you can give a fifth cycle. But do you get the same kind of benefit as the first 4 cycles? The answer is probably not.

We’re taking more risk in terms of the toxicities, which accumulated by the end of the fifth cycle. So holding off after the fourth cycle, if the patient is achieved rather than a partial response, moving on [to] a transplant for consolidation is probably the best way…to minimize the side effects and maximize the benefit that you can get from these regimens.

I would ideally like a complete response from every patient, but if I get more than a partial response, I’m happy.

There’s a lot of evolving data on this exact same question of continuing to progression or giving the treatment for a prespecified time point. I’ll start the example with the IFM study. The IFM 2009 study is a randomized trial evaluating the timing of a transplant. All patients would receive the first 3 cycles of induction therapy with lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone—the classic RVd regimen.

And then patients would receive the stem cell collection, and patients would receive a transplant in the transplant arm, and [they] would receive [a] further 2 cycles of consolidation and patients would receive a final period of maintenance for 1 year.

In the nontransplant arm, patients would receive 3 cycles of RVd, collect the stem cells, [a] further 5 cycles of consolidation with RVd, and again, these patients would receive a total of 1 year of fixed duration of maintenance. What we are seeing is [that] patients who received a transplant earlier had a PFS [progression-free survival] benefit of close to a year.

What you saw was a PFS of 48 months for the transplant arm versus 36 months for the nontransplant arm before they progressed. So taking that data is meant again for patients who have received a fixed duration of maintenance.

Now, there is another trial which is evaluating the same exact question among patients receiving RVd in both arms and evaluating the timing of a transplant, but patients who receive the continuous maintenance until progression in the United States version of the same study, and this is the DETERMINATION study, which would be presented at ASCO [American Society of Clinical Oncology] annual meeting] 2022.

And these studies’ results are eagerly awaited by all of us. So, until then, what is the data that we have? In the United States, again, all the studies that were done in the maintenance have led onto continue the treatment until disease progression.

And we are seeing the benefit of these PFS to be beyond the 6- or 7-year mark, more likely favoring the continued maintenance, than if exploration of maintenance in favor of the PFS for the continued maintenance studies.

Considerations for assessing treatment response and electing to continue therapy in patients with newly diagnosed multiple myeloma.

Importance of Depth of Response and Treatment Duration in NDMM

GMMG-HD7 study is a German study that evaluated the benefit of the addition of isatuximab [Sarclisa] to the standard regimen of VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone] backbone. So, the study, again randomized close to 660 patients to receive RVd, which is a standard of care arm, similar to the GRIFFIN study.

And here, the experiment lab is the addition of isatuximab to RVd backbone. The primary end point for this study is next-generation flow testing of MRD [minimal residual disease] negativity and the sensitivity of 10-5.

So again, the differences between [the] GRIFFIN study and this specific study, GMMG-HD7, [the] GRIFFIN study, the primary end point is [a] stringent complete response after 6 cycles, both as induction, as well as consolidation with a transplant sandwiched between. GMMG-HD7 study included the primary end point of MRD negativity by NGF [nerve growth factor] at 10-5 post-induction treatment.

When you compare both of these studies, I would not want people to be comparing apples to oranges, and that’s the reason why I’m explaining the differences between these studies. The primary end points are different. The number of cycles that the patients receive are different.

And here, the primary end point is MRD negative 10-5, which is seen in 50% of the patients that are receiving the isatuximab plus VRd, and the comparator arm had the MRD negativity at 10-5 seen in 35% of the patients.

If you look at the depths of responses, rather than VGPR [very good partial response], [they] were seen in 77% of the patients after 4 cycles of isatuximab plus VRd and the comparator arm had the depth of response of VGPR at 60.5%. So, this is a good study, again showing the benefit of the addition of a CD38 monoclonal antibody.

Again, both the studies showed exactly the same concept that we are discussing. [That] the addition of the fourth agent, which is a CD38 monoclonal antibody, is safe. Number 2, it is able to deliver those deeper responses at MRD negative rates to be significantly higher than what the standard of care is used in the United States.

Insight on the role of isatuximab and VRd in patients with newly diagnosed multiple myeloma following data from the GMMG-HD7 study.

Isa-VRd in NDMM: Results From the GMMG-HD7 Study

Dara [daratumumab (Darzalex)]-KRd [carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone] is used in the MASTER trial. It’s a single-arm trial. It did not have a comparative partner compassion arm to assess the benefit of daratumumab plus KRd versus KRd.

The MASTER trial evaluated 123 patients to receive daratumumab plus KRd as sequential boxes of treatments. So if you think about each box having 4 cycles of daratumumab plus KRd, all patients would receive the first induction treatment with 4 cycles of daratumumab plus KRd, and patients would receive an MRD [minimal residual disease] negativity soon after completing the induction treatment.

Patients would receive a transplant then, and patients would receive an MRD negative testing after transplant. And patients would receive the next box of treatment as 4 cycles of daratumumab plus KRd consolidation. And after every 4 cycles, which is after each box, an MRD test is being done.

The second part of the question that [the] MASTER trial has asked was, can we stop off the treatment among these patients who have achieved an MRD negativity? So, if you look [at] the entire context of the trial, the first question of daratumumab plus KRd, this efficacy was phenomenal.

You could see [that] 90% of patients after the completion of [the] induction treatment achieved close to a VGPR [very good partial response], and these responses only deepen after transplants. Seventy percent of the patients achieved a complete response.

Now, in the long run, again, the PFS [progression-free survival], as well as the overall survival in this study is very different than the previous studies that we discussed because there is a portion of patients that are coming off the treatment in this specific trial, which in my opinion, is not the right way to do [it]. And we are using a sharp demand point to make a treatment decision at this point in time.

Time will tell us in the long run who should not be stopping the treatment. We’re already seeing evidence of this hurting a group of patients, at least the high-risk patients, where patients tend to have the disease relapse during the period of maintenance. Of course, these patients are being treated again, but [it] may not be the right approach.

We’ve said it time and again, continuous treatment helps to keep the disease under control in multiple myeloma. And the point I would take home from this study is [that] Dara [daratumumab]-KRd is a great regimen, and the induction setting is able to deliver those responses that we are looking for.

But the point I’m not too enthused about is stopping those treatments when you achieve a short-demand goal, like an MRD-negative case.

Shifting his focus to the MASTER study in newly diagnosed multiple myeloma, Ajay K. Nooka, MD, MPH, FACP, highlights the role of daratumumab with KRd.

Dara-KRd in NDMM: Results From the MASTER Study

[the] GRIFFIN trial is the first randomized phase 2 trial reflecting the practice patterns in the United States where the standard of care arm is the lenalidomide [Revlimid], bortezomib [Velcade], dexamethasone, or the RVd arm.

So patients would be randomized to receive RVd, or addition of daratumumab [Darzalex] to this backbone, daratumumab plus RVd, and patients would receive 4 cycles first, followed by a transplant, followed by 2 further cycles of consolidation.

The daratumumab arm would get daratumumab plus RVd as consolidation. RVd arm would get RVd as consolidation for 2 further cycles. The primary end point for this trial is the stringent complete response after the consolidation. Patients would essentially receive a total of 6 cycles of induction plus consolidation therapies.

What we were seeing is the stringent complete response rates are close to 32% at the end of consolidation and the GRIFFIN trial. For the RVd arm, what the additional daratumumab [does], in this context, is the response rates, the stringent complete response rates, increased to 42% with the addition of daratumumab.

So those results again were published in 

. Pete Voorhees [Levine Cancer Institute, Charlotte, North Carolina] was the senior author. And these are very important results because when we are talking about the depth of response post-transplant to be a measure of long-term success, and clearly daratumumab plus RVd has provided us that depth of response.

Now, this brings us to the context of what Jacob Laubach [Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts] had presented at ASH [American Society of Hematology] meeting] of 2021. As the patients continue to receive the maintenance with daratumumab plus lenalidomide in the daratumumab arm versus lenalidomide in the RVd arm, what happened at the 24-month mark?

These responses tend to continue to deepen and deepen. And at 24 months, the stringent complete response rates in the daratumumab arm were 66%, which is 2 of the 3 patients achieved the stringent complete response. So, the same numbers, if you look for the RVd arm, these numbers were 48%.

Now taking this step further, if you look at the MRD [minimal residual disease] negative rates, these are significantly higher again, and both at 10−5 and 10−6, favoring the daratumumab combination.

Another step that was presented in Jacob [Laubach’s] presentation was can you sustain these MRD negative rates at the 6-month mark and the 12-month mark in both the daratumumab arm as well as the RVd arm?

And clearly, the daratumumab arm has shown the benefit. Again, in the sustaining of these MRD responses and 44% of the patients at the 12-month mark are 10−5, compared to a third, which is close to 15% in the RVd arm.

So not only the daratumumab arm has resulted in deeper responses, [but] it was [also] able to sustain those responses. And clearly, the PFS [progression-free survival] benefit at 89%. A 3-year PFS benefit was 89% in the daratumumab arm versus 81% in the RVd arm.

In other words, 19% of the patients have progressed on the RVd arm and 11% of the patients had progressed at the 3-year mark in the daratumumab arm. This is showing signs of initial success.

So overall survival benefits, you don’t find them at this point clearly for the same reasons that I discussed earlier, that the follow-up is too sharp. The longer that we follow, we tend to see these benefits over the long run.

Expert perspectives on the use of daratumumab with RVd in patients with newly diagnosed multiple myeloma in the context of updates from the GRIFFIN study.

Ajay K. Nooka, MD, MPH | Authors

Articles

Continued Role for Transplantation in NDMM

Newly Diagnosed MM: Optimizing Maintenance Therapy and Managing Toxicities

Importance of Depth of Response and Treatment Duration in NDMM

Isa-VRd in NDMM: Results From the GMMG-HD7 Study

Dara-KRd in NDMM: Results From the MASTER Study

Dara-RVd in NDMM: Updates from the GRIFFIN Study