Landgren Details Pros and Cons of Multiple Myeloma Regimens in Treatment-Naive Setting

December 10, 2019

Article

 In a <em>Targeted Oncology </em>case-based peer perspectives live discussion with a group of physicians, C. Ola Landgren, MD, PhD, reviewed several combination regimens used in the treatment of multiple myeloma. Landgren, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, used the case of a 51-year-old man with standard-risk disease to highlight the benefits and drawbacks of each therapy strategy.

C. Ola Landgren, MD, PhD

In a Targeted Oncology^TMcase-based peer perspectives live discussion with a group of physicians, C. Ola Landgren, MD, PhD, reviewed several combination regimens used in the treatment of multiple myeloma. Landgren, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, used the case of a 51-year-old man with standard-risk disease to highlight the benefits and drawbacks of each therapy strategy.

CASE

A 51-year-old man presented with worsening fatigue on exertion and pallor.
Hemoglobin: 9.2 g/dL
Blood urea nitrogen/creatinine and calcium: within normal limits
Creatinine clearance: 95 mL/min
Lactate dehydrogenase: within normal limits
Serum b₂-microglobulin: 4.1 mg/L
Serum albumin: 3.2 mg/dL
Serum M-protein: 1.5 g/dL
l Free light chains: 110
Bone marrow biopsy: 66% plasma cells
Fluorescence in situ hybridization showed 13q deletion.
Urine protein electrophoresis: M-spike of 400 mg of l light chains in 24 hours
PET/CT: lytic lesions in ribs and L3, no increased standardized uptake values
Immunoglobulin G positive in urine and serum free light chains
Adequate liver and heart function
ECOG performance status: 1
Diagnosis: multiple myeloma, standard risk, stage II (International Staging System and Revised International Staging System)

TARGETED ONCOLOGY:What are the options for induction therapy?

LANDGREN: This is myeloma, standard risk. [You can use] daratumumab [Darzalex], lenalidomide [Revlimid], and dexamethasone [DRd]. It’s approved for nontransplant candidates [only]. If the patient says, “I’m not going to do transplant,” and you use DRd, and then he says he changed his mind, would you do that? It’s possible. There are a lot of patients who get daratumumab up front.

I was the lead principal investigator for [a study with daratumumab presented] at the American Society of Hematology [ASH] Annual Meeting in Orlando. We gave daratumumab with lenalidomide and dexamethasone together with Kyprolis [carfilzomib; KRd-D] for newly diagnosed disease, both standard risk and high risk. Eighty percent of patients [were minimal residual disease (MRD) negative with weekly KRd-D], no transplant. But when it comes to the collection, I said you can collect after [cycle] 4, 5, or 6. I actually said 4 [through] 8, and the FDA [told me I wouldn’t prove it if I didn’t] restrict it to 6 cycles. I said OK…and then they approved it, so then we opened the study.¹

We looked at the yield for collection. If you give daratumumab for 6 cycles or you give daratumumab for 4 cycles up front, the yield will go down a bit if you go to 6 cycles.

This patient has not been treated before. There were no major limiting factors. There’s no renal failure. There’s no cognitive failure. There’s no preexisting neuropathy. We could do whatever we want in these particular patients. Assuming that a 51-year-old patient who comes with melanoma wants to be treated successfully, you pick the best therapy you have.

Which regimens are recommended by the National Comprehensive Cancer Network (NCCN) guidelines?

In the most recent version [of the NCCN guidelines], we have bortezomib [Velcade], lenalidomide, and dexamethasone [VRd] and cyclophosphamide, bortezomib, and dexamethasone [CyBorD]. You might ask about it in someone with renal failure, so that’s why those are preferred here.

For other recommended regimens, KRd is supported by NCCN guidelines, and it also says in the NCCN guideline that you can use KRd once weekly if you do 56 mg of carfilzomib. Ixazomib [Ninlaro], lenalidomide, and dexamethasone is listed here but as a category 2B recommendation.

What do the categories of recommendations mean in the NCCN guidelines?

If it says 1, that means that there’s a randomized study, which means it is FDA approved, so you don’t even have to look here. If the FDA approved it, you’re going to know it. But if it doesn’t say 1 and it doesn’t say 2B, it means that it is a category 2A, unless it says something else, which means that most of the people who are members of the NCCN guideline think that this should be reimbursed. For that reason, VRd, CyBorD, and KRd are equal.

What are some of the data supporting D-VRd in this patient population?

The GRIFFIN study is not yet published but was presented at ASH a year ago. This is a study that used VRd with and without daratumumab, and it’s randomized.²

Then patients get 4 cycles [of D-VRd]. Then they [get] transplant. Then they get additional [consolidation] cycles, 5 and 6, with D-VRd if they are randomized to that. Then they get daratumumab with lenalidomide in the maintenance phase. They presented that you have an overall response rate [ORR] after the 4 cycles of 94%. After transplant, it is 100%. After additional cycles of transplant and 2 more cycles, [the ORR is] 100%. After maintenance, the response stays. Also, the depth of response continues to deepen.

Phase II of the GRIFFIN study has the full randomization. You have the D-VRd versus VRd with transplant and additional cycles. Then here you have maintenance. This study [was scheduled to] be presented at ASH, so I cannot share all the details. The comparison for D-VRd [versus VRd] was presented last year, [showing] 25% MRD negativity with VRd, and it’s about 60% for D-VRd.

What is the significance of MRD in the treatment of multiple myeloma? How do you test for it?

We started using MRD about 5 years ago at Memorial Sloan Kettering [MSK]. We implemented flow cytometry, and about 2 years ago, we started doing parallel sequencing. It is quite complicated to do that. We spent a lot of money and a lot of time setting it up. We developed our own flow assay and whole workflow. We’ve had close to 10,000 visits from [patients with] myeloma to MSK, so with that high volume, we can’t do these assays. It’s too expensive. It’s too complicated. It would not justify the setting up.

When it comes to the sequencing, I think that probably will be a more viable vehicle going forward. I think when it becomes more commonly available, that would make a big difference. I think Adaptive Biotech’s [clonoSEQ] is now New York State approved, so you can send samples from your clinic to Adaptive [Biotech].³From what I understand, it was approved by CMS [Centers for Medicare & Medicaid Services]. If you do a biopsy of a patient who is on Medicare and you send it to Adaptive [Biotech], then it should be covered by CMS. For the individual insurance [carriers], I’m not 100% sure. You probably have to check…each insurance plan to see whether they pay for it or not.

What are other options for treatment-naïve patients?

[Patients with] newly diagnosed disease were examined in a study called CASSIOPEIA. Bortezomib, thalidomide, and dexamethasone [VTd] was examined with or without daratumumab. VTd [is used more in] European countries; it is less expensive, basically. They gave it for 4 cycles. They did transplant, then another 2 cycles, and then they crossed again. They randomized patients to either [no maintenance] or daratumumab every other month. There was no lenalidomide.⁴

This study enrolled patients with a median age of <60 years. Fifteen percent of patients were high risk based on the cytogenetics. Twenty-nine percent have stringent complete response [sCR] with daratumumab plus VTd [D-VTd] versus 20% with VTd. It was significant because they have a large number of patients. The primary end point in this study was sCR.

Is sCR an established primary end point in myeloma? How do these response rates compare with those observed in GRIFFIN?

It is not, but you can do whatever you want as long as the FDA approves the patient protocol. They were able to statistically prove that there were more sCRs.

If you look at the complete response [CR] or better rate, it is 39%. Looking at the previous study of D-VRd, this is not as good. If you look at the paper in theLancet,you also see there are patients who cannot tolerate VTd because of the neuropathy. I think there are a lot of patients dropping out because of toxicity. That probably brings these results down lower.

With D-VTd versus VTd, after induction and transplant, you continue to see improvement. A very good partial response (VGPR) or better is seen in almost 90% of the patients. Thirty percent of them have VGPR, so it’s around 50% of patients who have CR or better. How does that compare with VRd? It’s comparable, I think, so D-VTd looks to me not that different from VRd alone. If you look at KRd, it’s even better.

By subgroup analysis, virtually all groups except those high-risk patients [in whom] it doesn’t statistically change anything benefited from the addition of daratumumab.

Was there an improvement in progression-free survival (PFS) with the CASSIOPEIA combination?

In the intention-to-treat population for PFS, the HR is 0.47 for D-VTd versus VTd; it’s highly significant. In refractory studies, if you are MRD negative or if you are in sCR, it doesn’t matter how you are treated. It’s the deep response that predicts your PFS. It’s not how you are treated. It is all about how deep a response you have that seems to predict PFS.

Again, you have subgroup analysis for PFS. There’s no subgroup that stands out, and daratumumab seems to be working across the board.

What are the adverse events seen with the D-VTd combination?

I think it’s important, obviously, to recognize that the peripheral neuropathy of any grade occurred in 59% and 63% [in the D-VTd and VTd arms, respectively], which is a high rate for peripheral neuropathy. That’s why we don’t use that in the United States.

Who is transplant eligible?

• Age <70 years; upper limit if fit

• Good performance status

• Adequate organ function

Ejection fraction (EF) >50%

Forced expiratory volume in 1 second, forced vital capacity, diffusing capacity for carbon dioxide >50% predicted

• Absence of concomitant multiorgan amyloid

• Adequate stem cell harvest ≥4 × 10⁶CD34-positive cells/kg

• No active infections

What criteria do you use to define transplant eligibility? How do you define transplant eligible?

This says to me every patient is a transplant candidate, so I don’t know whether I agree with that. We have done transplants in 75- to 80-year-old patients who really wanted it or they needed it or both. Good performance status, organ function, EF, and the lung status [are all important]. No other organ failure. You obviously need to have stem cells; otherwise, it’s going to be hard to give it. No active infection.

If this patient achieved a deep MRD-negative response to primary therapy, would you proceed to transplant or wait until disease progression?

We say we don’t think that there’s any impact on overall survival because you can’t always rescue, and we say that there may be slightly shorter PFS without transplant. It could be the same for MRD-negative [response]. Then we let every patient see a transplant doctor as well as a myeloma doctor. They probably won’t say the same thing. Transplant doctors will say that it’s better to do the transplant, but we let every patient do that. Then let the patient decide.

Have you implemented the use of KRd in your practice?

The data with KRd-D are getting close to an 80% [response rate].¹

We use it as our default in our program now; we switched from VRd to KRd, and we switched about 5 years ago. We used to give it twice a week for every patient at 20 mg/m²…up to 6 cycles of that. We target around 50% to 60% MRD negativity.

In 2020, [we will most likely] switch from 20 to 56 mg/m². I caution you if you use KRd to not use 70 mg/m². It’s not safe. Very, very bad things can happen. You can have [serious adverse effects]. We have, unfortunately, tried.

I think VRd or KRd is equally safe. I think the only difference is that you have the high rate of neuropathy with bortezomib that you don’t have with carfilzomib. I do not give KRd in my practice to a patient who is fragile or older or [who has] multiple comorbidities. I would always give VRd or VRd-lite, but it depends. I would always do an echo[cardiogram] and an [electrocardiogram], and then I would do KRd. That’s my default.

References

Landgren O, Hultcrantz M, Lesokhin AM, et al. Weekly carfilzomib, lenalidomide, dexamethasone and daratumumab (wKRd-D) combination therapy provides unprecedented MRD negativity rates in newly diagnosed multiple myeloma: a clinical and correlative phase 2 study. Presented at: 61st Annual American Society for Hematology Annual Meeting; December 6-9, 2019; Orlando, FL. ash.confex.com/ash/2019/webprogram/Paper126378.html.
Voorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab (Dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; dara‐VRd) vs. VRd in patients (Pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT). Blood. 132(suppl 1; abstr 151). doi: 10.1182/blood-2018-151.