Dingli Compares Trial Data and Recent ASH Updates in the Newly Diagnosed Multiple Myeloma Landscape

During a virtual Targeted Oncology Case-Based Roundtable event, David Dingli, MD, PhD, professor of Medicine at the Mayo Clinic, discussed date from clinical trial which support various therapies for newly-diagnosed multiple myeloma.

Targeted Oncology^TM: What are the recommended regimens for patients who received a new diagnosis of multiple myeloma who are eligible for transplant?

DINGLI: The National Comprehensive Cancer Network considers [multiple regimens] to be acceptable for transplant-eligible patients with a new diagnosis of multiple myeloma. [Most are combination therapies] that include RVd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone] or CyBorD [cyclophosphamide, bortezomib, dexametha-sone].¹ I also recommend KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone], D-RVd [daratumumab (Darzalex), lenalidomide, bortezomib, dexamethasone], and in some circumstances ixazomib [Ninlaro], lenalidomide, dexamethasone. Then there are other regimens that we may need to use very infrequently, at least in my practice.

What are the most important factors to consider when deciding whether to recommend a patient for transplant?

For me, it’s more than age; it’s the functional status of the patient. I’ve transplanted individuals up to the age of 75 if I am convinced that the patient is otherwise physically fit. A person who has multiple myeloma, remains quite active, with a performance status of 2 or better, and without significant comorbidities, is a transplant candidate. I will probably not consider tandem transplants in that patient, but 1 transplant we can do.

It’s true the data that support transplant in elderly individuals are not as solid as for younger patients, in part because most of the transplant data come from Europe. There, they typically do not include patients in studies if they’re older than 65 years. But we’ve shown that we can safely transplant these patients. I think many centers in the United States would transplant patients otherwise fit and healthy in their early 70s with similar outcomes compared with younger patients. So more than numerical age, it’s the functional status of the patient.

Can you give an overview of the most significant data in this setting?

There are data from 4 important studies, and 3 of these studies are relevant for our conversation today because these are regimens that we often use [TABLE on page 20].^2-5It’s hard to compare across studies because the end points are not exactly identical or the timing when these end points are reported is not exactly at the same phase of the disease.

The RVd regimen has been studied in the IFM [Intergroupe Francophone du Myélome]/DFCI2009 study [NCT01191060]. This was a large study between the IFM and Dana-Farber Cancer Institute in Boston, where patients were treated with RVd plus or minus stem cell transplant [SCT].² After postconsolidation therapy, the RVd regimen had a very good partial response [VGPR] or better of 78% if there was transplant included versus 69% if there was no transplant.

In the FORTE trial [NCT02203643], which was KRd with or without SCT, VGPR rates were 89% compared with KRd alone, which was 87%.³

The Cassiopeia trial [NCT02541383] was a randomized trial of daratumumab with VTd [bortezomib, thalidomide (Thalomid), dexamethasone (D-VTd)] versus VTd alone. It’s not a regimen that we will often use in the United States, but it was the first study looking at a quadruplet therapy versus a triplet.⁴ The VGPR rate was higher with the quadruplet.

More recent is the GRIFFIN trial [NCT02874742], which is a randomized phase 2 study of D-RVd [daratumumab, lenalidomide, bortezomib, dexamethasone]. The VGPR rate was almost 91% [with quadruplet therapy] compared with 73.2% [with triplet therapy].⁵

Why is minimal residual disease (MRD) negativity important in this setting?

The MRD negativity rates are quite high when you have triplets or quadruplets plus transplant. Something important to notice is that in the IFM/DFCI2009 study, the MRD negativity was 10^–4.² Whereas, in the GRIFFIN trial and the Cassiopeia trial, MRD was at 10^–5.^4,5

MRD negativity is not yet considered a valid end point by the FDA. But as we’re seeing more and more patients with multiple myeloma achieving deeper responses, MRD correlates quite well with an improvement in progression-free survival [PFS] for the multiple myeloma population. The better the quality of the responses, the better the outcomes are. There seems to be an important dichotomy among VGPR or better responses versus an inferior response. Complete response [CR] is better than VGPR, and stringent CR [sCR] is even better. MRD negativity is associated with a good outcome in most patients, not all patients, but certainly for the population [overall]. As more patients achieve MRD negativity, this population’s outcome is improved, at least with respect to PFS.

How did patients do on the IFM/DFCI2009 study?

Patients were randomized to receive RVd with or without SCT.² The patients received 3 cycles, followed by stem cell mobilization and collection, then followed by transplantation—or the patients had stem cell mobilization and collection and then continued with RVd for additional cycles—then patients in both groups were placed on lenalidomide maintenance.

In the transplant population, median PFS was superior at 50 months versus 36 months [without transplant]. This superiority was essentially true across the board, and for the standard-risk patients, transplant was superior. For patients who were high risk, although this number was not very high, the transplant was favored.

If we look at the depth of the response in these patients and the outcomes, patients who were MRD negative at the time of transplant did the best.⁶ Patients who were MRD negative who did not receive a transplant also did well, but not as well as patients who did. Patients who did the worst were those who did not have a transplant and who were not MRD negative. So clearly, there is something strong to be said about having a deeper response for the [MRD-negative] population.

What was the design and efficacy of the FORTE trial?

This was a rather complex, large clinical trial mainly conducted in Italy.⁷ Patients who received a new diagnosis of multiple myeloma were randomized into 3 groups. They were treated with either 4 cycles of KCd [carfilzomib, cyclophosphamide, dexamethasone] or 4 cycles of KRd. Then, these 2 groups had stem cell mobilization and collection.

A third group received KRd transfer cycles...then continued on KRd, and they received a total of 12 cycles of KRd. The patients who underwent transplant were then treated with consolidation for an additional 4 cycles with the same regimen as the induction therapy.

Then there was a second randomization to maintenance with lenalidomide alone versus maintenance with lenalidomide and carfilzomib. Note that the carfilzomib was given on days 1 to 15 and 16 at the time of maintenance and was only given for 2 years.

We don’t have the full results [from FORTE yet], but we do have some data on the first randomization result.

In this study, patients who received induction with KRd followed by transplant and then maintenance tended to do better than those who just received KRd and had stem cells collected and cryopreserved. The early relapse risk was lower for patients who had the transplant, 8% compared with 17% [P = .015]. The multivariate regression analysis was in favor of the transplant group compared with continuous therapy with KRd.

March 2021 | Case-Based Roundtable Meetings Spotlight 21So at least we have 2 studies [FORTE and IFM/DFCI2009], which suggest that even though we have all these modern agents, transplant still appears to benefit patients. This is the reason why we continue to advocate for early transplantation in patients who are deemed to be fit for it.

How were the FORTE results updated at the American Society of Hematology (ASH) Annual Meeting in 2020?

The PFS after the first randomization—patients who did the best were those who received KRd induction, followed by transplant, and the worst were the patients who received KCd and then transplant.³ We know that for a patient who had normal kidney function, an immunomodulatory imide drug [IMiD] is superior to cyclophosphamide for induction therapy. After the first randomization, the data suggest that KRd with transplant is superior to KRd for a total of 12 cycles.

The early data with respect to maintenance therapy after the second randomization were not surprising. Patients who received a doublet regimen for maintenance of carfilzomib and lenalidomide seemed to do better versus lenalidomide alone. This appeared to be across the board, independent of patients’ International Staging System stage, risk status based on fluorescence in situ hybridization, and the lactate dehydrogenase levels, whether it’s above the normal or within the normal range. A 3-year PFS rate at this time of the second randomization was 75% for the doublet versus 66% for lenalidomide alone [HR, 0.63; P = .026].

What did the Cassiopeia trial show in terms of quadruplet therapy versus triplet therapy for patients with multiple myeloma? How were these patients treated?

This was a study that ran in Europe, where VTd is often used as frontline therapy.4 In the United States, if we are going to use a triplet, we will use RVd almost certainly. But this was a study done in Europe and compared D-VTd versus VTd alone. These patients were transplant eligible and a fairly representative population; maybe one could argue that the fraction of patients with high-risk disease was slightly on the low side, with only 15%. It’s possible that for patients [who are high risk], the investigators would prefer to treat with something that does not include thalidomide.

This was a massive study with over 1000 patients. Patients were randomized to VTd or D-VTd for 4 cycles, stem cell mobilization, conditioning, and transplant, followed by 2 cycles of consolidation with VTd or D-VTd exactly the same as they received during induction.

The second randomization was to observation until progression or maintenance therapy with daratumumab every 8 weeks. There was a change at some point that the [observation] group did not get any maintenance with thalidomide, which has been used for many years in Europe as a maintenance regimen.

The sCR rate was superior for the patients on the quadruplet versus the triplet [29% vs 20%; P = .001], and more patients achieved CR [or better; 39% vs 26%; P < .0001]. The MRD negativity at the 10^–5 level was 64% compared with 44%. This was highly statistically significant, and patients with negative MRD and CR or better were 34% [vs 20% with the triplet]. This is important because with the daratumumab, sometimes it’s difficult to [tell whether] a patient has a CR because the fixation [cannot] detect the therapeutic monoclonal antibody.

Do you think MRD is an appropriate end point for these trials?

It’s now possible to distinguish between the disease-related monoclonal protein and the therapeutic antibody with mass spectrometry. But in the absence of technology, sometimes it can be difficult to [tell whether a patient has a] CR because the therapeutic antibody will be detectable. Nonetheless, these were impressive MRD negative rates. MRD is becoming more important as a relevant end point and a good surrogate for PFS.

MRD is important, not only because of its prognostic value but also because it’s a faster end point to achieve. So, if we can show that the patient achieves MRD negativity early, most likely, that patient is going to do better. These studies can be done much faster if MRD negativity is the end point because it can be achieved in a time interval that is shorter compared with waiting for the observation so that there is a difference in PFS. Some studies are now starting to look at both MRD and PFS as coprimary end points.

Were there other efficacy data available for Cassiopeia?

This study met the primary end point; sCR was higher [with daratumumab]. MRD negativity was higher as well. Patients who received the quadruplet versus the triplet had a 53% reduction in the risk of progression after about 30 months of follow-up [HR, 0.47; 95% CI, 0.33-0.67; P < .0001]. Of the patients who were on the quadru-plet by next-generation flow cytometry, 64% were MRD negative [with daratumumab vs 44% without], and by next-generation sequencing, 57% versus 37% [were MRD negative]. The subgroup analysis for PFS favored the quadruplet therapy versus the triplet except in patients with high-risk disease.

Which other trials have studied the use of daratumumab in this population?

Now we come to the GRIFFIN trial.⁵ This is the randomized phase 2, open-label study in patients with transplant eligible, who, again, received a new diagnosis of multiple myeloma. Patients enrolled had to be between 18 and 70 years, have a good performance status, and have satisfactory kidney function. Patients were randomized to 4 cycles of D-RVd versus RVd alone. Daratumumab was given intravenously, on days 1, 8, and 15; lenalidomide by mouth for 14 days; and bortezomib subcutaneously on days 1, 4, 8, and 11, with dexamethasone on the day of and the day after the bortezomib and daratumumab.

Patients underwent stem cell mobilization and collec-tion, and most of them who were supposed to go to transplant did receive it. After transplant, patients were treated with consolidation for 2 cycles, either with RVd if received at induction or D-RVd. Then there was maintenance therapy with daratumumab and lenalidomide or with lenalidomide alone. Daratumumab was given every 4 weeks or every 8 weeks depending on the time after transplant.

The end point for the study was an improvement in sCR rates. In the GRIFFIN study, the fraction of patients with high-risk multiple myeloma was relatively low. I would expect that if I look at 100 patients who received a new diagnosis, I’ll find about 25, maybe 30, patients with high-risk disease, depending on how we define it. Now, in most studies, high-risk disease is defined as deletion 17p, t(4;14) and t(14;16). Granted, these are more common, and they’ve been established for a while, but I think we’re realizing more and more that patients with 1q amplification also have high-risk disease. Now we’re seeing more and more studies incorporating 1q amplification as a high-risk feature. This will increase the number of patients with high-risk disease to approximately 40%, perhaps more.

What were the updated results of the GRIFFIN study presented at ASH 2020?

Patients who received the quadruplet therapy had higher response rates and better-quality responses [after] 12 months of maintenance therapy. So patients have received induction, transplant, consolidation, and now 12 months of maintenance therapy. The sCR rate in the patients on the quadruplet therapy was 64% versus 47% [P = .0253], and CR rate was 18% versus 13% [P = .0014]. The overall response rate was in the range of 95%.

The quadruplet is associated with the deeper responses, which is not something shown in this study, but I can tell you that, in general, quadruplet therapy is associated with faster responses. There are, at least theoretically, advantages or a faster response: (1) The patient will do better with less bulky disease, (2) the risk of end-organ damage from bulky disease is less, and (3) they will be able to tolerate subsequent therapy much better because the disease burden of the bone marrow will be lower. From a functional perspective, patients feel better. In principle, the additional advantage of a rapid reduction in disease burden is that it decreases the potential for tumor evolution. Because tumor evolution depends on the bulk size of the tumor, the more tumor cells there are, the higher the probability is that we find mutant subclones that are going to emerge as resistant.

March 2021 | Case-Based Roundtable Meetings Spotlight 23At the 12-month cutoff after maintenance, the MRD negativity rate was 62.5% versus 27% [with daratumumab vs without], so more than double. MRD negativity with a CR or better, meaning sCR, was almost 60% versus 24%. For the patients who had a response better than CR, MRD negativity was 76.5% versus 42%. So clearly, the quadruplet was associated with much better, deeper responses.

How did specific subgroups of patients do in the GRIFFIN trial?

The subgroup analysis...of the patients with sCR [showed] these patients did better if they were on the quadruplet therapy, [and it was the same for] patients who were MRD negative. In any way we cut the data, the quadruplet regimen was superior. Now, one can argue that maybe that’s not the case in patients with high-risk disease. This is something that has been observed more than once. I would say that a patient with high-risk disease is not any worse after given quadruplet therapy. And because the number of patients enrolled with high-risk disease was small, it is harder to prove there was a benefit. The confidence interval was somewhat wider compared with some other subgroups that had many more patients.

What are the PFS data available so far?

It’s too early to see a difference in PFS, but at 24 months, 95% of the patients on the quadruplet have not progressed. This attests to the efficacy of combination therapy with transplant followed by consolidation and maintenance. Time will tell whether there’ll be a separation of these curves and whether the quadruplet regimen ended up superior in the long term with respect to PFS and depth of response. There’s no question that it is superior [otherwise].

Please describe the toxicity profile for the GRIFFIN regimens.

The most common adverse effects [AEs] associated with the quadruplet were hematologic: neutropenia, thrombocytopenia, and leukopenia. There were some grade 3/4 events of cytopenia. In part, this is related to the fact that CD38 is expressed not just on plasma cells but also on some common myeloid cells. I’m sure anyone who has used daratumumab has observed this.

In general, at least from my experience, the cytopenias occur early with the initiation of daratumumab, especially in combination with an IMiD because the disease burden would be high. We are giving daratumumab with quite a bit of intensity weekly. Most times, we’re able to tie the patients over sometimes with growth factors, sometimes by modifying the IMiD. As dose intensity of the CD38 antibody decreases, the blood counts improve. They also improve because the disease burden, the bone marrow, goes down.

Other common AEs included fatigue, which was similar in both arms. Most of the time, it is more related to the steroids and the IMiDs than to the monoclonal antibody. The 1 other thing I would like to mention is infections. Upper respiratory tract infections and pneumonia appear to be somewhat more common with the quadruplet combination compared with the triplet.

With the approval of subcutaneous daratumumab (Darzalex Faspro), has your practice switched over? Are there any issues with subcutaneous treatment?

Infusion reactions can occur. Typically, in my experience, these occur with the first 2 infusions. After this second infusion, no patient experienced any reactions at all. Importantly, now we have subcutaneous daratumumab. In my practice, I’ve been switching pretty much all my patients to the subcutaneous route because the drug is very well tolerated. It’s much more convenient. Infusion is over in 5 to 10 minutes. The risk of delayed reactions is essentially nil. It’s a quick in-and-out visit for the patient, minimizing exposure to other patients and to staff.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 4. 2021. Accessed February 17, 2021. https://bit.ly/36w3EKZ}

_{2. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexa-methasone with transplantation for myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750}

_{3. Gay F, Musto P, Scalabrini DR, et al. Survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the randomized Forte trial. Blood. 2020;136(suppl 1):35-37. doi:10.1182/blood-2020-136907}

_{4. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexametha-sone with or without daratumumab before and after autologous stem-cell trans-plantation 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}

_{5. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bort-ezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288}

_{6. Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132(23):2456-2464. doi:10.1182/blood-2018-06-858613}

_{7. Gay F, Cerrato C, Petrucci MT, et al. Efficacy of carfilzomib lenalidomide dexa-methasone (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):8002. doi:10.1200/JCO.2019.37.15_suppl.8002}