Combination Regimens Show Different Levels of Efficacy for Patients With Myeloma Ineligible for Transplant

Ajai Chari, MD

During a virtual Targeted Oncology Case-Based Roundtable, Ajai Chari, MD. a professor of Medicine, Hematology, and Medical Oncology at the Icahn School of Medicine at Mount Sinai in New York, NY, discussed the case of a 72-year-old patient with multiple myeloma.

Targeted Oncology^TM: What criteria do you use to define transplant eligibility?

CHARI: I think if you’re below 75, fit, with good performance status, it’s reasonable to consider.

Can you walk us through these regimen options?

These are your preferred regimens: RVd [lenalidomide (Revlimid), bortezomib (Velcade), dexamethasone] versus Rd [lenalidomide, dexamethasone], DRd [daratumumab, lenalidomide, dexamethasone], Rd [lenalidomide, dexamethasone], CyBorD [cyclophosphamide, bortezomib, dexamethasone], and [KRd (carfilzomib [Kyprolis], lenalidomide, dexamethasone)]. We have 3 category 1 [National Comprehensive Cancer Network (NCCN) recommendations] based on phase 3 studies.¹

I think with all of oncology, but to consider particularly as patients get older, we have 3 major buckets of variables—patient disease and treatment factors. Within treatment factors, we now know there’s myeloma frailty indices that predict mortality independent of our ISS [International Staging System]. So you can have frailty predicting how a patient is going to do. All those other features—performance status, renal insufficiency—often I think in older patients we don’t appreciate how the lack of muscle mass contributes to renal impairment. It’s important to dose patients by calculating that creatinine clearance and not just using that creatinine.

Our main bucket, if you will, [of treatment regimens] for the transplant-ineligible [patients come from the] SWOG 777 [NCT00644228], RVD Lite [NCT01782963], ALCYONE [NCT02195479], and MAIA [NCT02252172] trials.

All of these are phase 3, except RVD Lite, which is a single-arm phase 2 with 50 patients. A huge difference in these studies is median age. Everybody uses SWOG RVd versus Rd as evidence of transplant-ineligible studies. But the median age was only 63, and in some ways that’s particularly important, because SWOG showed not only response benefit but also PFS [progression-free survival] benefit and OS [overall survival] benefit.²

If we look at this study with a median 55-month follow-up, as I alluded to, 82% is better than 72% response; PFS 43 versus 30 months with a hazard ratio of 0.71; OS 75 versus 64 months, 0.71 is the hazard ratio. So if we were going to [consider] significant until proven guilty, is this the arm to beat? But I would ask you to consider 2 things, 1 that this is a median age of 63; and 2, the bortezomib dosing, which is twice weekly, or 21 days for 8 cycles for 6 months. How many of truly older patients can tolerate twice-weekly bortezomib for 6 months? I think it’s important to remember that between the median age and that twice weekly, you can’t generalize this study for the “truly transplant ineligible” population. This study was just without the intent for transplant.

So RVd Lite, you could say, is more reasonable. It’s a smaller study, 50 patients, older; a very good response rate, 86%. PFS is encouraging, 35 months; obviously there’s no control arm.³ But here bortezomib was given only weekly. I think many [oncologists] are even giving weekly bortezomib to our transplant ineligible, so I’m guessing [that this is for their] older patients.

The ALCYONE study—daratumumab [Darzalex]/VMP [bortezomib/melphalan/prednisone] versus VMP—we don’t use VMP in the United States. But the reason this [is mentioned is because], yes, we see response and PFS benefit, but there is actually an OS benefit [HR, 0.60].4 And it goes back to using your drugs early, particularly for these older patients. Because if you don’t get them in remission, you may not be able to salvage them, and they have comorbidities and other things that come into play. So sometimes with the older patients you have 1 shot, and you have to get it right because they may not make it to your next shot.

In MAIA, phase 3, older patients; so, all of these other 3 studies are older patients. Superior response [for DRd versus Rd], 93% versus 81%; hazard ratio of 0.56 [for PFS], which was specifically significant and there’s an encouraging hazard ratio of PFS2 [HR, 0.69], because the median follow-up here is only 36 months. We don’t have OS, but already PFS2 not reached versus 47 months. And actually, I would call your attention to PFS, [which was] not reached for the daratumumab [arm] but 34 months [with Rd], and 34 months is really good for a control arm. For the Rd patients here, 34 months is almost as good as with RVd Lite. And in spite of that, the addition of daratumumab [resulted in] almost 50% reduction in the risk of progression.⁵

So there are thoughts that DRd is going to give us a PFS somewhere in the order of 50-plus months for the transplant-ineligible population, which actually, believe it or not, is coming pretty close to the IFM 2009 study [NCT01191060], which is RVd with transplant and lenalidomide maintenance; so, really encouraging data.

What other aspects are notable from the SWOG and RVD Lite trials?

Even though this study was without the intent to transplant, 68% actually had an intent for transplant. The PFS hazard ratio was 0.742—for twice-weekly bortezomib, that hazard ratio is worse than the other ones that we saw with the addition of CD38 [antibodies in the] front line.²

Adverse effects [AEs] with RVd were as you might expect: neuropathy and GI [gastrointestinal] issues. Again, this was a twice-weekly bortezomib IV [intravenous infusion] back in the day. We talked about RVd Lite, but the rates of neuropathy are much better here, 11.6%; limited dose reduction, as is common for this age.³

Was anything else notable from the MAIA trial?

So medium PFS not reached yet versus 31.9 months; again, hazard ratio of 0.56; MRD [minimal residual disease] negativity, 24% versus 7%—kind of what you would expect to see with those responses. So whether [the patient is] MRD negative or positive, the [patients on] daratumumab did better than their counterparts [on the control arm].

Safety, which is particularly important in the older population— we do see again that neutropenia, [grade 3/4] 50% versus 35%. And the other nonhematologic toxicities—slight trend for pneumonia, 14% versus 8% [grade 3/4], but otherwise not a major difference in infusion reactions, relatively low grade; this was with IV daratumumab.

What are your thoughts on how to choose between the relevant regimens in this setting?

Personally, I tend to go with DVd [daratumumab, bortezomib, dexamethasone] in patients with renal failure or severe cytopenias because if you’re already starting off with a heavy marrow replacement and your neutrophil count is very low, borderline, you’re going to basically end up with grade 3/4 neutropenia. So I refer to sometimes do DVd for a cycle, but DRd has the obvious long-term advantage of maintenance with the oral drug.

The other important point I would make is to take time to calculate that lenalidomide dose. I almost never start 25 mg on people over 70. I don’t see the point. I think it’s better to start at 15 mg or even lower based on the creatinine clearance. Then you can always go up from there because, for the older patients, above all, do no harm. And I think that would just be my one word on that.

What are the data for the KRd regimen in patients with multiple myeloma?

So, the ENDURANCE study [NCT01863550], I wanted to go over because we’ve been alluding to this a little bit with the frontline K [carfilzomib (Kyprolis)] versus D [backbone] question.

The ENDURANCE study [looked at patients who had] newly diagnosed [cases with] no intent for transplant immediately. And it was basically bortezomib twice weekly at 1.3 mg/m2 or carfilzomib at 20 mg/m², 36 mg/m² twice weekly, and then there’s a second randomization [for maintenance with lenalidomide].⁶

High risk was excluded here; [patients] couldn’t have t(14;20), t(14;16), deletion 17p, LDH elevation, or plasma cell leukemia.

[PFS was] surprising to some, not surprising to others. Personally, I wasn’t surprised: PFS of 31.7 months versus 32.8 months, and that was [with] censoring. When you censor for transplant, there was no difference. But including everybody as an ITT [intention to treat], you can see their curves are superimposable.⁷

One of the subgroups of interest is the over 70. That actually favors RVd. And so I think the use of carfilzomib in older patients is associated with more [adverse] effects, and so that is something to consider for a transplant-ineligible population or over 70.

For responses, there was a slight benefit in VGPR [very good partial response] that favored the addition of carfilzomib, but that did not translate into a PFS benefit. Then the OS is still superimposable [HR, 0.98; P = .923].

There are some toxicity issues, [though]. There were more issues with cardiopulmonary and renal toxicities with KRd, [whereas there are] more issues with neuropathy with bortezomib, as you might guess. In some ways, though, it’s not a fair comparison because cardiopulmonary, renal—[it’s a] composite end point. So, we’re kind of comparing apples to oranges, but within that, if you [look at the toxicity differences], there are clearly differences in the drug.

How does the ENDURANCE trial affect your use of frontline carfilzomib? Are you waiting to see if it’s going to show a benefit in high-risk patients?

I personally would say, as I alluded to earlier, that it’s hard to believe that a drug is going to do really well for high-risk patients but not have that much benefit for standard risk. If it’s a really potent drug, we should be seeing those potencies translate into deeper responses and PFS, which we’re not seeing. But I think the devil is in the details, because remember: 36 mg/m² twice weekly with Rd. People confuse the ENDEAVOR study [NCT01568866], which is carfilzomib 56 mg/m² twice weekly [versus] bortezomib 1.3 mg/m² twice weekly, no IMiD [immunomodulatory drug]. That was clear. In a relapsed setting, carfilzomib at 56 mg/m² is better than bortezomib at 1.3 mg/m².⁸ But the reality is, you can’t give 56 mg/m² twice weekly with a concurrent IMiD for the cardiopulmonary issues, and it’s in the frontline setting.

So I think with carfilzomib, the messaging is that it depends on the disease stage; it depends on the partner drug, and it depends on the dosing and schedule. So it’s not a one-size-fits all for everyone, just to keep in mind.

What is your approach to maintenance therapy in this population?

I always say, maintenance, to my mind, should be mindless. If a patient is struggling [with] AEs, what’s the point of torturing them?

The STaMINA study [NCT02322320] looked at those patients that discontinued lenalidomide at 38 months versus those who did not.9 Those that continued actually did better than those who discontinued. And that was after having been on lenalidomide for 3 years. And conversely, there was no impact on secondary malignancies with continued lenalidomide. So it’s not a cumulative issue.

The FIRST study [NCT00689936] shows that this was a fixed duration [18 cycles] of lenalidomide versus continuous lenalidomide, [and survival favored] continuous lenalidomide.10 Even patients who had CR [complete response] and VGPR benefited from continuous lenalidomide from a PFS perspective elective [compared] with the fixed duration.

So I think the message here is, if a patient is tolerating lenalidomide, we have no data that continuing lenalidomide results in worse outcomes. Now, I don’t want to extrapolate that that means quadruplets should be continued forever; I think this is speaking to the importance of PFS using dose-attenuated therapy.

How has coronavirus disease 2019 (COVID-19) affected how you treat your patients with multiple myeloma?

I’ll direct your attention to a manuscript in Blood.11 Unfortunately, we’ve had now over 100 patients with myeloma and COVID-19, and we contributed to a global series of 650 patients with myeloma. The message there was—the Spanish group has shown—patients with myeloma do have a higher mortality rate than health match control, about 30% compared with 20%. But the risk factors for worse outcome in patients with myeloma were age, renal failure, high-risk disease, and “uncontrolled” myeloma. And I think that’s what goes back to this: We can’t compromise myeloma disease control completely. Maybe for the frail, elderly, where you’re worried about them coming out of the house, you can use oral therapies. But for the younger, fit patients, compromising on their chemotherapy might actually lead to more harm than skipping it—so, just some things to consider.

What is your experience with the subcutaneous formulation of daratumumab (Darzalex Faspro)?

I would just say from our experience that we’ve done tons of daratumumab subcutaneously. It’s the rare time where you are better in safety—less than 10% infusion-related reaction; comparable efficacy; markedly more convenient, 3 to 5 minutes. Patients love it, nurses love it, pharmacists love it. It’s going to be a slam dunk, and in the era of COVID-19 particularly, people can act faster. I think it will save everybody a lot of time and hassle.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 4.2021. Accessed February 5, 2021. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf}

_{2. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stemcell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X}

_{3. O’Donnell EK, Laubach JP, Yee AJ, et al. A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma. Br J Haematol. 2018;182(2):222-230. doi:10.1111/bjh.15261}

_{4. Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141. doi:10.1016/S0140-6736(19)32956-3}

_{5. Facon T, Kumar S, Plesner T, et al; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. doi:10.1056/NEJMoa1817249}

_{6. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(10):1317-1330. doi:10.1016/S1470-2045(20)30452-6}

_{7. 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):LBA3. doi:10.1200/JCO.2020.38.18_suppl.LBA3}

_{8. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(10):1327-1337. doi:10.1016/S1470-2045(17)30578-8}

_{9. Hari P, Pasquini MC, Stadtmauer EA, et al. Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM). J Clin Oncol. 2020;38(suppl 15):8506. doi:10.1200/JCO.2020.38.15_suppl.8506}

_{10. Facon T, Dimopoulos MA, Dispenzieri A, et al. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018;131(3):301-310. doi:10.1182/blood-2017-07-795047}

_{11. Chari A, Samur MK, Martinez-Lopez J, et al. Clinical features associated with COVID-19 outcome in multiple myeloma: first results from the International Myeloma Society data set. Blood. 2020;136(26):3033-3040. doi:10.1182/ blood.2020008150}