Recap: Dana-Farber Experts Review Treatment Options for Newly Diagnosed Multiple Myeloma

In this special edition of Around the Practice^®: Institutional Insights, physicians from the Dana-Farber Cancer Institute and Massachusetts General Hospital in Boston, Massachusetts, reviewed current treatment options for patients with newly diagnosed multiple myeloma. They discussed how treatment differs based on transplant eligibility and baseline patient presentation.

The discussion was moderated by Noopur Raje, MD, director of the Center for Multiple Myeloma at Massachusetts General Hospital and professor of medicine at Harvard Medical School. She was joined by colleagues Jacob Laubach, MD, MPP, chief of the Multiple Myeloma Division, clinical director of multiple myeloma, and senior physician at Dana-Farber Cancer Institute as well as assistant professor of medicine at Harvard Medical School; Omar Nadeem, MD, clinical director of both the Myeloma Immune Effector Cell Therapy Program and the Center for Prevention of Progression, associate director of the Multiple Myeloma Clinical Research Program, and senior physician at Dana-Farber Cancer Institute as well as an instructor in medicine at Harvard Medical School; and Andrew J. Yee, MD, clinical director of the Center for Multiple Myeloma at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School.

Therapy for Transplant-Eligible Newly Diagnosed Multiple Myeloma

CASE 1

• A 72-year-old man went for a routine physical in 2015.
• Laboratory values:
  • Elevated total protein of 10.4 g/dL
  • Serum protein electrophoresis showed immunoglobulin (Ig) G κ monoclonal protein of 2.94 g/dL and reciprocal depressions of quantitative Igs.
  • Total serum IgG level of 4363 mg/dL
  • κ free light chains of 398 mg/dL and a ratio of 55
  • Creatine of 0.98 with no evidence of hypercalcemia
  • Hemoglobin of 11.1 g/dL and declining
  • β2 microglobulin of 2.9 µg/mL
  • Albumin within normal limits
• Medical history showed diabetes, hypertension, and coronary disease.
• The patient was taking metformin, glipizide, metoprolol, lisinopril, aspirin, levothyroxine, and gabapentin.
• Bone marrow biopsy showed 70% involvement and κ-restricted plasma cells.
• Fluorescence in situ hybridization (FISH) showed a translocation (11;14).
• Skeletal survey did not show any lytic bone disease.
• PET and CT scans were negative.
• The patient was diagnosed with International Staging System (ISS) stage I and revised ISS stage I standard-risk multiple myeloma and was considered transplant ineligible.
• Patient treatment:
  • Use of RVd-lite vs daratumumab, lenalidomide, and dexamethasone (DRd) was discussed with the patient.
  • He was enrolled onto the MAIA trial and randomized to DRd in early 2016.
• Patient follow-up:
  • Treatment was tolerated and he achieved a complete response (CR) after 6 cycles.
  • He is still on therapy after receiving cycle 74.
    • He experienced lenalidomide-associated diarrhea, neutropenia, and intermittent upper respiratory infections.
  • He received 5 mg of lenalidomide and subcutaneous daratumumab every month.
  • He continues intravenous Ig for infectious prophylaxis and colestipol for diarrhea.

Raje: How would you treat patients with a 3-drug regimen vs a 4-drug regimen?

Laubach: This is an important and pressing question for our field because this evolution from 2 drugs to 3 drugs, and now 3 to 4 drugs, has happened fast. We don’t want to get ahead of ourselves and where the data are. Further data from phase 3 trials will be critical in terms of our thinking about how and when to implement a 4-drug induction therapy for patients who are transplant eligible. Should it be given across the board, or should we reserve it for patients with higher risk as we wait for more data? On the one hand, we haven’t seen major safety concerns with the 4-drug regimens. The depth of response is outstanding, and the initial data we have on PFS [progression-free survival] are impressive. You could make an argument to utilize 4-drug regimens for any patient with newly diagnosed myeloma who’s transplant eligible. On the other hand, the data for RVd [lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone] followed by transplant are impressive. The other school of thought is to continue use of RVd as a standard induction approach, with transplant followed by lenalidomide maintenance, and to wait for additional data on the quadruplets, recognizing that for high-risk patients, the addition of daratumumab [Darzalex] makes sense.

Raje: How do you determine when to use bortezomib or carfilzomib [Kyprolis]?

Nadeem: There have been head-to-head studies with bortezomib- and carfilzomib-containing induction regimens, and the take-home message for me is that they have different toxicities. They’re both active proteasome inhibitors, and they both work well in these combinations. There are some deeper responses seen with the carfilzomib-containing regimens, but then there are some toxicity concerns, particularly related to cardiovascular risk, that come into play when you’re choosing the optimal induction regimen. I don’t think I am choosing one over the other because of the risk of disease. It’s mostly determined by patient-related factors.

Raje: Based on results of the phase 2 GRIFFIN trial [NCT02874742],¹ how long would you continue to use daratumumab in this case?

Yee: That’s a question we all struggle with because clinical practice and clinical trial data are moving together quickly. The data from GRIFFIN are fantastic and are quickly becoming adopted across various practices. If you wanted to be true to the GRIFFIN data, daratumumab was [given] until cycle 32, and then [treatment shifted to] lenalidomide maintenance. At the same time, in the [phase 3] MAIA study [NCT02252172], which was in transplant-ineligible patients, daratumumab was continued [over the] long term.² There wasn’t a fixed duration of daratumumab. There was also the [phase 3] CASSIOPEIA study [NCT02541383], but that’s a separate [therapy backbone].³ Daratumumab is well tolerated; I don’t have any patients complaining about being on daratumumab aside from coming in for the infusion visits, which I understand is a burden. From an adverse effect [AE] profile standpoint, patients tolerate it well. I appreciate that long term, we don’t know what it means to be on daratumumab. Something that’s becoming appreciated in this era of COVID-19 is the risk of infection. I don’t think we talk about it as much, but with daratumumab, yes, there is a higher risk of infection and more hypogammaglobulinemia. That’s something to pay attention to.

Treatment for Transplant-Ineligible Newly Diagnosed Multiple Myeloma

CASE 2

• A 57-year-old woman presented with relapsed/refractory IgA κ multiple myeloma.
• She had right pathologic hip fracture and a t(14;20) by FISH.
• She received initial therapy of RVd followed by lenalidomide maintenance.
• She was refractory to multiple lines of therapy:
  • Daratumumab, bortezomib, and dexamethasone
  • Daratumumab-RVd
  • Carfilzomib, lenalidomide, and dexamethasone (KRd)
  • Carfilzomib, pomalidomide (Pomalyst), and dexamethasone
• Patient treatment:
  • Three years after diagnosis, the patient was enrolled on a clinical trial with an anti–B-cell maturation agent (BCMA) bispecific antibody for triple-class refractory disease.
  • She started step-up dosing of anti-BCMA bispecific antibody.
  • A week later, the full dose was received.
  • Two days after the full dose, the patient experienced febrile neutropenia, 101°F temperature, and confusion.
  • Tocilizumab and dexamethasone were given for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).
• Patient follow-up:
  • No further CRS or ICANS
  • A CR occurred while on the trial.
  • Treatment is being continued more than a year later.

Raje: Would you use a triplet in this patient or would you even consider a quadruplet? How would you define frailty in such a patient?

Laubach: Regarding factors that determine choice of therapy, we think about the disease characteristics, which include traditional prognostic factors, [such as] β2-microglobulin, albumin, and [lactate dehydrogenase], as well as cytogenetic abnormalities. We think about frailty as a patient characteristic, their physical function, kidney function, and the amount of morbidity related to bone events in patients with multiple myeloma. We think about their social circumstances as well. Certain situations, like just getting back and forth to the clinic, [may be] difficult, and we consider the patient’s preferences about the mode of delivery of their care as well. Fortunately, in this space, we have excellent treatment options with 2 regimens, RVd as well as DRd, that have been associated with a survival benefit in phase 3 clinical trials. With the highest level of evidence for both, it can be challenging to choose one vs the other. A patient who has preexisting peripheral neuropathy, for example, would be a great candidate for DRd.

Having been in the field for a while and remembering some of the early data on how well proteasome inhibitors work in [patients with] bone involvement, I’m typically inclined to include a proteasome inhibitor, and bortezomib is a great choice in that context. Those are some of the factors that I consider. In some frail patients we still would utilize a 2-drug regimen, either lenalidomide and dexamethasone, or perhaps bortezomib and dexamethasone. The question about quadruplet regimens in older patients is being evaluated in ongoing clinical trials.

Raje: Let’s talk about the updates seen in survival for the MAIA trial.

Yee: Now that the trial has had longer follow-up, a recent update looked at the overall survival [OS] differences between DRd and Rd. At the 5-year mark, it was about 60% vs 50% and the hazard ratio was [0.68; 95% CI, 0.53-0.86; P = .0013]. The takeaway message is that the addition of daratumumab to lenalidomide and dexamethasone improved OS. When we think of clinical trials and what we do for our patients, we want to help them live better and longer. It was great to see in the update the improvement in OS. There weren’t any major changes even though they were on this treatment for [such an] extended time. Regarding new safety [issues] or AEs, there weren’t any new signals.

Raje: Is there ever a struggle with choosing between DRd vs RVd? How do you select patients in whom you’d use one vs the other?

Nadeem: That’s a pertinent clinical question that most oncologists face when they see patients like this. There are great data for both and there is a survival advantage for both. Based on the [phase 3] SWOG [S0777; NCT00644228] study, RVd was shown to be superior to Rd.⁴ Now with the MAIA trial, you have DRd. There hasn’t been any head-to-head comparison, so we have the caveat in place that we don’t know which one is better. Some of the important differences are toxicities. Bortezomib has an issue with peripheral neuropathy, although that’s mitigated now with subcutaneous and weekly use, particularly in the RVd-lite platform [administered over 35 days with 15 mg of oral lenalidomide on days 1 to 21; 1.3 mg/m² of bortezomib subcutaneously on days 1, 8, and 15; and 20 mg of oral dexamethasone day of or after bortezomib for 9 cycles then 6 cycles of consolidation].5 It can still be a problem for the older patients when they develop it. It’s also important to know that in the SWOG study, there was a fixed duration of bortezomib, whereas in the MAIA trial, we’re continuing daratumumab until progression. Despite fixed duration, you saw a survival advantage with RVd. These are some of the nuances we must keep in mind when we’re choosing therapy. I usually present both options to patients, and I go over the data and look at their comorbidities and give them an option as to which one they may prefer.

There is some bone involvement benefit with bortezomib, but overall, we’re seeing benefits across the board with the addition of daratumumab in the frontline setting. Most people, as you see with this case, do tolerate daratumumab monthly quite easily. The other thing I see often in practice is that when you have a second agent going like that until progression, you have a lot more flexibility. This patient had diarrhea, so I was able to dose-reduce the lenalidomide and not worry about losing response as much because they’re on another drug. This gives us a lot more flexibility to continue a regimen like that. The practice patterns are shifting more toward DRd as the superior frontline option.

Raje: How do cytogenetics play a role in choosing therapy for older or younger populations?

Nadeem: When you see a younger high-risk patient in front of you and you know that you’re not necessarily going to be able to get them through a quadruplet induction transplant and perhaps multiagent maintenance—that’s what we think about. I try to mirror that as much as I can with substantial dose modifications because the transplant-ineligible bucket is quite large. A patient who is in their early 70s with comorbidities but has a reasonable performance status and somebody who’s 85 and frail [represent] very different patient populations. In the first cohort, if that patient has high-risk disease, I would still try to get the best response as quickly and as early as I can. In that case, I think daratumumab plus RVd-lite quadruplet is certainly something that I would prefer, particularly in the high-risk patient, to try to get that deep response and [minimal residual disease] negativity; it gives them the best chance of having a longer-term first remission. That’s the goal of that patient. I don’t think that’s an option in an older, frail patient. At that time, you have to tailor therapy based on the patient’s performance status and overall condition as opposed to the disease characteristics, and then try to get them on at least a triplet that you could continue until progression.

Raje: What combinations would work for a patient who has lenalidomide-refractory disease and is in a first relapse?

Yee: In this current scenario, nearly all patients have had lenalidomide up front and they are on lenalidomide maintenance. When I think about patients who have developed refractory disease, I do think about the factors that influence treatment decisions. Was this an early relapse, within a year or 2 years of their initial diagnosis, or was this later on, like 5 or more years later? Is it an asymptomatic biochemical relapse or is it a relapse that has some clinical feel to it, such as when a patient notices the relapse upon having painful lytic bone disease or more fatigue and is becoming increasingly anemic or develops renal dysfunction? Those are things I think about in terms of the ideal therapy. Typically, when I think of a patient who has not had a CD30 antibody, I usually think that should be next if they have not had it in the beginning. Now there is an opportunity to receive it at this point, because an ongoing theme here is that you want to give your best treatments upfront and not save them for later because there is this continued attrition over time. When they relapse, that indicates that the disease is acting up and it’s time to think about intensifying their therapy.

At first relapse, I typically think of using anti-CD38 antibodies, either daratumumab or isatuximab [Sarclisa], and there are growing clinical data using triplet-based combinations with either daratumumab or isatuximab. Criticisms [of] data from the [phase 3] CANDOR [NCT03158688] and [phase 3] IKEMA trials [NCT03275285] are that half of patients [received] lenalidomide. But if you look at the lenalidomide-refractory cohort of CANDOR or IKEMA, those patients did quite well with the triplet-based combination.^6,7 I also realize that you have to think about the patient in front of you, and for some patients, carfilzomib can be tougher to manage. Over time, we have been able to better manage and reduce the risk of some of the cardiac AEs.

Raje: How does CAR [chimeric antigen receptor] T-cell therapy play a role in
this setting?

Nadeem: We now have 2 CAR T-cell therapies approved. Ide-cel [Idecabtagene vicleucel; Abecma] was approved in March 2021 and now this year we have cilta-cel [ciltacabtagene autoleucel; Carvykti], approved in February [2022].^8,9 Ide-cel was approved based on the [phase 2] KarMMA trial [NCT03361748], which [enrolled] patients who were heavily pretreated; it had impressive results, including a response rate of more than 70% and a CR rate of more than 30%. These patients had a median PFS of about 9 months.¹⁰ If you look at the higher-dose cohorts, those results are closer to a year. If you look at patients who have had a CR, it’s close to [18 months] to 2 years. You clearly see some impressive results based on that study leading to the approval.

Cilta-cel’s approval is based on the [phase 1b/2] CARTITUDE trials [NCT03548207] with about 100 patients. It had impressive results, with a close to 100% response rate and a CR rate of more than 80%.¹¹ Responses are a lot deeper, and that’s translating into median PFS that is approaching close to 2 years. In practice, we have had a lot of interest in these therapies and a lot of referrals for them. The availability of these therapies has been quite limited ever since their approval, mainly because of some shortages with how these cells are made using the viral vector. Hopefully as that improves, we will have more options to treat patients. But so far, these have been some of the highest responses and some of the longest PFS numbers that we have seen in this heavily pretreated patient population.

Raje: Can you discuss CRS and neurotoxicity, specifically with bispecific
T-cell engagers?

Nadeem: When this all first came about with CAR T-cell therapy, we started to see this syndrome that’s now termed CRS; we have become very familiar with its management. The majority of, if not most, patients with CAR T-cell therapy end up getting CRS. The timing can be different depending on the product. It can happen early with ide-cel and it happens about a week later with cilta-cel, but it’s more predictable and we now know what to look for. The rates are pretty high, although early intervention may limit the incidence of higher-grade CRS, which is something we have learned over the years as we have taken care of more of these patients. If you look across the board, the incidence of CRS is lower for bispecific antibodies, falling more in that 60%-to-70% range; it’s close to 90%-plus with most of the CAR T-cell therapy products. The other good news is that its low grade.

In terms of neurological toxicity, it’s the same story. We haven’t seen much neurological toxicity with BCMA-targeted products in myeloma, compared with some of our counterparts [who treat diseases] such as lymphoma. In terms of management, we now have teams equipped to handle this in the hospital, to give tocilizumab [Actemra], steroids, and other agents to break the cycle. Most patients are able to get through that window and then usually it’s just limited to the first step-up dosing. It may be on cycle 1, day 1, but [that’s what happens with] bispecific antibodies. It’s more predictable, it’s finite, and then once you get the patient through, most of the time they are in the clear.

References

1. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of Griffin after 24 months of maintenance. Blood. 2021;138(suppl 1):79. doi:10.1182/blood-2021-149024
2. Facon T, Kumar SK, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596. doi:10.1016/S1470-2045(21)00466-6
3. Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390. doi:10.1016/S1470-2045(21)00428-9
4. Durie BGM, Hoering A, Sexton R, et al. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020;10(5):53. doi:10.1038/s41408-020-0311-8
5. O’Donnell EK, Laubach JP, Yee AJ, et al. Updated results of a phase 2 study of modified lenalidomide, bortezomib, and dexamethasone (RVd-lite) in transplant-ineligible multiple myeloma. Blood. 2019;134(suppl 1):3178. doi: 10.1182/blood-2019-128000
6. Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197. doi:10.1016/S0140-6736(20)30734-0
7. Moreau P, Dimopoulos M-A, Mikhael J, et al; IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361-2371. doi:10.1016/S0140-6736(21)00592-4
8. FDA approves idecabtagene vicleucel for multiple myeloma. FDA. March 26, 2021. Updated March 29, 2021. Accessed July 13, 2022. https://bit.ly/3aD6K5k
9. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Updated March 7, 2022. Accessed July 13, 2022. https://bit.ly/3z4EoKN
10. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850
11. Martin T, Usmani SZ, Berdeja JG, et al. Updated results from CARTITUDE-1: phase 1b/2 study of ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T cell therapy, in patients with relapsed/refractory multiple myeloma. Blood. 2021;138(suppl 1):549. doi:10.1182/blood-2021-146060