Rationale Taken From Trial Data for Using Daratumumab in Multiple Myeloma

Alex Mejia-Garcia, MD

During a Targeted Oncology Case-Based Peer Perspectives Roundtable event, Alex Mejia-Garcia, MD, medical oncologist, Cleveland Clinic, discussed the use of daratumumab as treatment of multiple myeloma. Mejia-Garcia's discussion was based on the case scenario of a 51-year-old patient.

Targeted Oncology™: What factors influence your choice of therapy in a patient with newly diagnosed multiple myeloma?

MEJIA-GARCIA: The presence of comorbidities and patient preferences [play a role]. I think comorbidities is a big one. If a patient comes in and has a history of cardiac problems, I may stay away from the carfilzomib [Kyprolis]–based regimens. Peripheral neuropathy is an adverse effect [AE] of bortezomib [Velcade], and that’s something to keep in mind in patients with diabetes. Perhaps these patients are not going to do very well with a proteasome inhibitor [PI], bortezomib. Then there is the cost to consider, as well, and the infusions. I have patients who have mentioned the challenges with frequent visits, especially when they are treated with CD38 monoclonal antibodies. So, those are different factors that can influence the therapy that we choose for patients with newly diagnosed myeloma.

Do the National Comprehensive Cancer Network (NCCN) guidelines currently recommend daratumumab (Darzalex) as a subcutaneous injection?

There’s a new version of daratumumab, which is noted as a footnote in the guidelines.1 Daratumumab and hyaluronidase-fihj Darzalex Faspro] are now available as a subcutaneous injection.

The guidelines identify bortezomib [plus] lenalidomide [Revlimid] as the preferred regimen. That also includes the bortezomib/cyclophosphamide–based regimen. Other regimens include carfilzomib/lenalidomide/dexamethasone. The guidelines also discuss the ixazomib [Ninlaro]/lenalidomide/dexamethasone regimen, although a press release [stated that] this trial did not meet the primary end point. However, I think that numerical values were different in this regimen. They also touch on other useful circumstances in other regimens, including a chemotherapy approach with patients who have more of a plasma-cell leukemia.

When was the subcutaneous dose approved?

The FDA approved the subcutaneous form in May 2020 and listed the indications that the intravenous [IV] version was approved for.²

These indications included in combination with bortezomib, melphalan, and prednisone in patients with new diagnoses who are ineligible for autologous stem cell transplant [ASCT]; in combination with lenalidomide and dexamethasone in patients with new diagnoses who are ineligible for ASCT and in patients with relapsed/refractory multiple myeloma who have received at least 1 prior therapy; in combination with bortezomib and dexamethasone in patients who have received at least 1 prior therapy; and as monotherapy in patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent.

Where would you use the quadruplet therapy for multiple myeloma?

The quadruplet therapy features the combination of daratumumab, bortezomib, thalidomide, and dexamethasone [VTd]. There is no survival advantage when the monoclonal antibody is added, although the response and depth of response are higher than with the standard of care [VTd]. I have not necessarily adopted a quadruplet approach in the front line. Perhaps it’s something we can delay considering until we get more information on survival benefit. I will stick, probably, with the triplet therapy.

I will point out that if we’re thinking that the patient is a candidate for an ASCT, we need to consider that in a quadruplet combination; we see a lot of cytopenias. We have to be careful about how long we use this regimen prior to collection or following with stem cell transplantation. So, I think that’s something to take care of, as well, and I will likely not use this regimen in more than 3 or 4 cycles before either collecting and continuing the approach or moving to an ASCT.

A number of studies have explored the addition of daratumumab to current standard-of-care treatment. Could you explain the main findings?

I can start with the oldest trial, the IFM trial [NCT01191060].³ The trial evaluated a group of patients who were randomized to receive bortezomib, lenalidomide, and dexamethasone and then moved on to transplantation or not. Those in the transplant group had better response rates and depth of response than those patients who did not undergo transplant. The investigators reported a complete response rate of 48% in the nontransplant group versus 59% in transplant group. The transplant group also had a higher depth of response. That was a rate of very good partial response [VGPR] or more of 88% versus 77%.

When progression-free survival [PFS] by minimal residual disease [MRD] was examined, those patients who received maintenance therapy had a higher PFS rate compared with the nonmaintenance group. These findings were reported at the beginning of the treatment and after maintenance lenalidomide.

I think one of the most important findings that this trial established is the benefit of stem cell transplantation and obtaining depth of responses. So, I think the transplant still has a role.

In the FORTE trial, a newer PI, carfilzomib, was evaluated [NCT02203643].⁴ Carfilzomib was [compared] with a combination containing cyclophosphamide followed by single stem cell transplantation—4 induction cycles followed by 4 consolidation cycles after stem cell transplantation using cyclophosphamide or lenalidomide. The trial also evaluated…whether or not patients will benefit from 12 cycles of carfilzomib, lenalidomide, and dexamethasone without transplantation. Patients were subsequently randomized to maintenance with either lenalidomide or a combination of lenalidomide and carfilzomib.

Based on this trial, we can see that the combination of a PI with an immunomodulator is probably better than the combination of a PI with chemotherapy and cyclophosphamide. Those patients who went to transplant or who received just 12 cycles of carfilzomib, lenalidomide, and dexamethasone had more than a VGPR...across the board.

The area of relapse was lower for those patients who proceeded to stem cell transplantation versus no transplantation. So, the PFS or the rate of relapses was lower, 8% versus 17%, and this was driven mostly by the patients with higher-stage disease.

The next question is “Which is the better PI when used in combination with an immunomodulator and dexamethasone?” And that was explored in the phase 3 ENDURANCE trial [NCT01863550].5 When the findings were presented, the trial did not meet the primary specified end point for PFS. There were a lot of safety signals in this trial. But some of the criticism of ENDURANCE is based on the actual design of this study. It’s confusing at first. You are randomizing these patients to different PIs, and then there is the second randomization of patients receiving or not receiving maintenance therapy with lenalidomide. I think it was somewhat expected, but if you look into the details of the presentation there was a lot of toxicity. That includes cardiopulmonary and renal toxicity.

But for those of us who have used carfilzomib/lenalidomide/dexamethasone with some frequency in the setting of clinical trials, as well as in the standard practice, monitoring the fluids around the infusion can affect cardiopulmonary toxicity. Once you can do that, cardiopulmonary toxicity is not that prevalent.

One of the criticisms I have for the trial is that I don’t think they describe how much fluid was given around this. The investigators did not explain the management process. But then again, this was a trial that did not meet the PFS end point, and I think we’ll hear more from that, as well.

Another criticism of the trial is that it excluded those patients who had high-risk features. I think that’s potentially important information that is missing.

How do you see 4-drug regimens fitting into the treatment landscape for a patient in our case?

I think it will have a role in the treatment landscape of patients with newly diagnosed multiple myeloma, but I think until there is longer follow-up in terms of survival data, it’s something that we have not adopted as a standard approach in the frontline setting. I think the depth of response is what we see with these combinations, and since we’re not measuring MRD on a standard basis, I’m not sure if we are adopting that at the beginning.

What were the key findings from CASSIOPEIA (NCT02541383)?

The CASSIOPEIA trial evaluated the monoclonal CD38 targeted agent daratumumab in combination with bortezomib, thalidomide, and dexamethasone.⁶ This was in patients who were newly diagnosed and transplant eligible. The trial was mostly conducted in European countries. These patients were randomized in 2 arms. They are containing VTd versus not VTd, followed by the second randomization in terms of maintenance therapy.

The primary end point for this trial was complete response [CR] rates, which are the stringent CR rates. The primary end point was met with a stringent CR rate of about 29% compared with 20% in those patients who did not [receive] daratumumab. Patients who had high risk did not benefit. Most of the benefit of this trial was seen in patients who were a standard risk. However, the conclusions were that daratumumab/thalidomide before and after ASCT was favored. That combination increased the depth of response and the PFS in this population of patients who are transplant eligible with newly diagnosed multiple myeloma.

If you were to have survival data, I would probably think this would be a better end point. However, the investigators did show a subgroup analysis that showed PFS. Since it was delayed, that’s probably another reason they showed obtainment of the depth of response rather than survival benefit. We’ll have to see with longer follow-up if this continues to be the case. I think these were our registration trials, and I think that was an accepted end point, but there are no overall survival [OS] benefit as of yet.

What were the AEs in the trial?

In this trial, a higher number of cytopenias, thrombocytopenia, and lymphopenia were observed in the treatment arm. And because they were using IV daratumumab, we are going to see a higher degree of drug-related reactions.

However, the proportion of those AEs that were grade 3 or higher was less in general but still higher in the group of patients who received daratumumab. They also had a higher degree of infections, as seen in this trial. Another consideration is that some of these patients went into transplant and they used chemotherapy to mobilize these cells. They used a cyclophosphamide- based regimen, which is also something that we are not using too much in this part of the world.

What were the differences between GRIFFIN and Cassiopeia?

The GRIFFIN trial [NCT02874742] was conducted in the United States, and the regimens evaluated more closely mirror what we use here, which is a combination of lenalidomide, bortezomib, and dexamethasone with or without daratumumab.⁷

The induction cycle was probably shorter than in patients who were enrolled in Cassiopeia. The doses for dexamethasone were also lower; in Cassiopeia, it was 40 mg in phase 1 and phase 2. And so far, these were all 20 mg the day before and after, even.

Patients were randomized to daratumumab-RVd versus RVd. Some patients had stem cells collected, and then there was a consolidation for an additional 4 cycles followed by the maintenance phase, which was daratumumab/lenalidomide versus lenalidomide alone. Again, the primary end point for this trial is still stringent CR, similar to the Cassiopeia trial, and secondary end points are depth of response and survival outcomes.

In the trial, the alpha was 0.1 for a stringent CR. So, this is why the P value is a bit more than .05. However, that may define barriers. So, this was significant, 42% versus 32% stringent CR rate with the addition of CD38 daratumumab versus no daratumumab. Also, the postconsolidation depth of response was a similar number and increased in those patients who had the monoclonal antibody. We see that these responses deepened over time—at the end of induction, at the end of ASCT, and at the end of the 4 cycles of consolidation. Then, in the clinical cutoff, some data included the maintenance phase. So, we can see that this is a common approach that had additional benefits with transplant maintenance and the use of the monoclonal antibody in induction.

The investigators reported a higher degree of MRD negativity in those patients who had the daratumumab-based combination.

Safety profiles were somewhat similar to the Cassiopeia trial, especially regarding cytopenias and possible infusion-related reactions. Any-grade infections were higher in daratumumab/RVd versus RVd, 82% versus 55%.

Regarding the mobilization of the stem cells—even though, numerically, there was less with the use of daratumumab, lenalidomide, and dexamethasone compared with no daratumumab— these patients were successfully collected using the nonchemotherapy–based approach. These patients used a growth factor mobilization as needed. Those patients have collected successfully.

Regarding safety concerns with the quadruplet therapy, my only concern will be that if we are using this quadruplet therapy prior to transplant, you have to make sure not to use it too much. I’m somewhat concerned that the collection of stem cells might be an issue if we use, let’s say, 5 cycles or more. I would probably send this patient to transplant early on.

Are you using MRD assessment routinely in your practice?

I think, as a group, we are not using MRD outside of a clinical trial, in general. For some patients we are, but typically, it depends on the high-risk characteristics—also, whether the patient wants to defer stem cell transplantation. I think in the very knowledgeable patient, that’s come up a couple of times. I will still suggest collecting stem cells and perhaps, if they want to defer, I would be more at ease if I know they are MRD negative. But that is something we are not using across the board; a few cases here and there, but not standard of care yet.

Do you think it’s reasonable to consider it in a patient who’s been on maintenance for a period of time and wants to get off it?

I would consider it. I would consider it in standard-risk myeloma. In a patient who is high risk and MRD positive, I would not take him off maintenance. So, [standard risk] is the only setting I will use it in. But I guess we are kind of learning about this as we go. And as I said, everybody is different in terms of their approach. But I’m not sure if there’s a right or wrong answer here.

What do you think about these poll results?

It appears that the frequency of therapy administration has changed, opting for oral therapy over IV therapy. And the oncologists also chose “none of the above,” at 28%.

Which study led to the approval of the subcutaneous form of daratumumab?

The COLUMBA phase 3 noninferiority study that was conducted in patients who had relapsed/refractory multiple myeloma led to this approval [NCT03277105].⁸

Patients were randomized to receive daratumumab subcutaneous, which is given at this dose of 1800 mg in comparison with the standard dose of daratumumab IV, which is 60 mg. The coprimary end points were overall response rate [ORR] and the maximum drug concentration.

The reason this trial was carried out is that the daratumumab IV infusion involves multiple visits, with a 10-hour infusion that is a barrier for some patients who work. They view this as cumbersome, to come in weekly and spend so much time in the infusion room, along with the infusion-related reactions.

This was a noninferiority trial, and the investigators needed to meet about 60% of the lower limit of the confidence interval. If they were within 60% or more of that lower confidence interval, they considered this form of treatment as noninferior for patients who receive the subcutaneous form in those settings.

One of the benefits of the subcutaneous dosage is that infusion duration was decreased significantly, from 10 hours or so to just 5 minutes. So, that was one of the benefits of using daratumumab subcutaneously, which was administered in the abdominal area.

The investigators reported the ORR was 37% in the daratumumab IV group compared with 41% in the daratumumab subcutaneous group. The relative risk was 1.11, but the lower limit of normal of the confidence interval was higher than 0.6. Therefore, it was within the expected boundaries of the confidence interval.

As a result, we find the subcutaneous dose was deemed not inferior to the IV dose with very comparable rates of VGPR, as well as CR rates. Also, the coprimary end point of the concentration plot in cycle 3 in day number 1 met the same coprimary end point.

The response was maintained across the subgroup analysis. One of the questions we always have is if the patient is overweight or obese. Will they have different outcomes? According to the subgroup analysis, they did not. The secondary efficacy end points, PFS and OS, were similar to those seen in patients who had the daratumumab IV.

In the study, common treatment-associated AEs include anemia, neutropenia, and thrombocytopenia, which is similar to the daratumumab IV dose. The infusion-related reactions were significantly reduced from 34.5% to 12.7%. So, this is also important because we can probably avoid immune-related reactions if we start from the beginning of treatment with the subcutaneous dose.

Investigators reported that grade 3–related events in the subcutaneous arm were similar to those patients with IV. The safety profile was deemed to be comparable to the IV form There are also patient-reported outcomes in terms of satisfaction. Of course, patients who received the subcutaneous dose were spending less time in the infusion room, so they score higher in terms of satisfaction and in terms of the treatment compared with daratumumab IV.

What is the rationale for using the subcutaneous dose of daratumumab in the front line?

Daratumumab subcutaneous was evaluated in the phase 3 PLEIADES trial [NCT03412565] in patients with newly diagnosed multiple myeloma. This multicenter open-label trial is combined with standard regimens in the transplant-eligible and -ineligible settings and in the relapsed setting. Patients are using the subcutaneous form in combination with VRd, VMP [bortezomib, melphalan, and prednisone], or rituximab and dexamethasone.

Patients showed sustained primary end points that were met for all the different cohorts with similar ORR, rates of VGPR in those patients with VRd and those patients with VMP and those patients with lenalidomide/dexamethasone.⁹

Do you still need to observe the patient for AEs?

Correct. We still keep the patient here about 1 to 2 hours before sending them out. If you look at the details on the trial, I think that AEs occur rather early compared with delayed reactions.… So, this is extremely likely.

Is there evidence that patients might benefit from the retreatment with daratumumab subcutaneous?

Another trial looked at this, [NCT03871829].¹⁰ This is an ongoing trial that evaluated patients who had progressed or used daratumumab IV previously. They were randomized to use carfilzomib/daratumumab subcutaneous versus carfilzomib/dexamethasone. The primary end points are a VGPR rate and a VGPR rate with other response rates as a secondary end point. We’ll wait to hear about this trial later.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2021. Accessed August 27, 2020. http:// bit.ly/2EwGqd4}

_{2. FDA approves daratumumab and hyaluronidase-fihj for multiple myeloma. FDA. Updated May 1, 2020. Accessed August 27, 2020. http:// bit.ly/2F6kchL}

_{3. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma; IFM 2009 Study. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750}

_{4. Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. J Clin Oncol. 2019;37(suppl 15). doi:10.1200/ JCO.2019.37.15_suppl.8002}

_{5. Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial. J Clin Oncol. 2020;38(suppl 18). doi:10.1200/JCO.2020.38.18_suppl.LBA3}

_{6. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1}

_{7. Voorhees PM, Kaufman JL, Laubach J, et al; GRIFFIN Trial Investigators. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288}

_{8. Mateos MV, Nahi H, Legeic W. et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Published online March 23, 2020. Lancet Hematol. doi:10.1016/S2352-3026(20)30070-3.}

_{9. Chari A, San-Miguel J, McCarthy H, et al. Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy: Pleiades study update. Blood. 2019;134(suppl 1):3152. doi:10.1182/blood-2019-123560}

_{10. Bahlis NJ, Zonder JA, Wroblewski S, et al. Subcutaneous daratumumab in patients with multiple myeloma who have been previously treated with intravenous daratumumab: a multicenter, randomized, phase II study (LYNX). J Clin Oncol. 2020;38 (suppl 15):TPS8553. doi:10.1200/JCO.2020.38.15_suppl.TPS8553}