Triplet Regimen Options Reviewed for Multiple Myeloma

Ruben Niesvizky, MD

Two years after being diagnosed with stage II multiple myeloma, a patient continuing on daratumumab (Darzalex) plus lenalidomide (Revlimid) maintenance showed concerning symptoms during routine follow-up. Ruben Niesvizky, MD, the director of the Multiple Myeloma Center, and professor of Medicine at Weill Cornell Medicine New York Presbyterian Hospital, discussed next steps for treating the patient during a Targeted Oncology Case-Based Roundtable event.

Targeted Oncology^TM: What are the treatment options for this patient at this point?

NIESVIZKY: The NCCN [National Comprehensive Cancer Network] guidelines list [many] options for relapsed/ refractory myeloma,¹ but if we just focus on overall response rates, the winners for this remain the POLLUX, the CANDOR, the ASPIRE, and the CASTOR regimens; and understanding that these patients had daratumumab, probably KRd [carfilzomib (Kyprolis), lenalidomide (Revlimid), dexamethasone] or KPd [carfilzomib, pomalidomide (Pomalyst), dexamethasone] would have been a great option.

In the ESMO [European Society of Medical Oncology] guidelines,² the second-line options for relapsed/refractory multiple myeloma are divided into those patients we consider lenalidomide-refractory or lenalidomide-sensitive. In those patients who we consider lenalidomide-refractory, VPd [bortezomib (Velcade), pomalidomide dexamethasone], Kd [carfilzomib, dexamethasone], selinexor-Vd [selinexor (Xpovio), bortezomib, dexamethasone; SVd] or venetoclax [Venclexta; Vd] for those patients who are 11;14, and the lenalidomide-sensitive gives you several options including EloRd [elotuzumab, lenalidomide, dexamethasone], VPd, Kd, KRd [carfilzomib, lenalidomide, dexamethasone], IxaRd [ixazomib (Ninlaro), lenalidomide, dexamethasone], SVd, and, again, venetoclax.

In these particular patients, perhaps the VPd would have also been a great option, particularly if the patient had renal insufficiency, I like that combination. However, I tend not to use high-dose pomalidomide. At higher doses in elderly people, I found it difficult to tolerate in terms of somnolence, alterations in sensory with those patients. In a short course of pomalidomide, that could have also been a good option.

Anybody agree or disagree or have a comment?

MUNDIA: Just a question. If somebody progresses on a lower dose than full dose of lenalidomide, so anything less than 25 mg, would you consider them sensitive or would you consider them refractory (ie, should you up the dose to full dose before you label them as refractory or is progression on any dose of lenalidomide considered refractory)?

NIESVIZKY: That’s a very provocative question, I think. Anybody want to comment?

BONANNO: I think you’d have to consider why your patient is on the low-dose Revlimid to begin with.

NIESVIZKY: Sure, so let’s say that the patient is on low-dose Revlimid because of intolerance before, so definitely you won’t be able to increase the dose. But if the patient is on maintenance Revlimid, let’s say post-transplant Revlimid at 10 mg, 15 mg, is there room in your practice to increase the dose, or have you had any experience that increasing the dose would be helpful?

BONANNO: We would probably increase the dose first.

NIESVIZKY: That comes back, in my mind, to the idea where if they’re relapsed, it’s a high-risk relapse where the patient has a history of crisis with renal failure, hyperglycemia, things like that. I don’t think we have much time to reconsider a higher dose of Revlimid in that case. It used to be my practice to try to increase the dose, but again, similar to increase the dose or decrease the gap in between daratumumab, I don’t find that that effective.

NIESVIZKY: The FDA has approved selinexor in combination with Vd for the patients who have received at least 1 prior line of therapy.³ There is a lot of data in patients who have had at least had 4 prior therapies. They’re refractory to proteasome inhibitors, to immunomodulatory agents, and anti-CD38 antibodies. [This is] is typical in penta-refractory patients.

This approval is now based on the phase 3 BOSTON trial [NCT03110562]^4,5 where patients who had 1 to 3 prior lines of therapy were randomly assigned to receive selinexor/bortezomib/dexamethasone versus bortezomib/dexamethasone was given in the classic biweekly bortezomib schedule with dexamethasone 20 mg paired with bortezomib for a [1.3 mg/m²] dose weekly, followed by a maintenance typical of the initial approval of bortezomib; whereas, the seli/bortez/dex program was based already on phase 1/phase 2 data of weekly selinexor with bortezomib.⁶ Four hundred two patients were enrolled with a median age of 67, and 20% of those patients had revised ISS Type III at diagnosis and most of the patients (59.6%) were older than 65 years old. The primary end points were PFS [progression-free survival] and secondary end points included efficacy, overall survival, duration of response, time to next therapy, and safety.

The [median] PFS by intention to treat [when] you compare the 3 agents versus 2 agents [was 13.93 months versus 9.46 months, respectively, with] a hazard ratio [HR] of 0.7 with a confidence interval of 0.53 to 0.93 in favor of the selinexor-Vd.

[What’s so] interesting is those patients who have high-risk cytogenetics, particularly del(17p), show a remarkable HR of 0.38. These particular patients with del(17p) raise selinexor as a great option. Again, patients who have renal insufficiency similar to these patients and even patients with a lessor GFR [glomerular filtration rate] benefit from this combination against selinexor/bortezo/dexamethasone did show significant benefit in that particular group of patients.

[Also], patients who were elderly had benefit indicating that selinexor is not only a drug for aggressive fit patients but also frail and non-frail [patients] showed some benefit, [particularly] a HR of 0.5 in those patients who were elderly.

Before I open up for what your reactions are to this subgroup analysis on the trial, I wanted to mention that the advantage of selinexor as well as one of the disadvantages as a toxicity include the nausea and the vomiting, but that means that there is something affecting the CNS [central nervous system] and is an option for those patients who have CNS disease, so the fact that it can cross the blood-brain barrier has given me options in those patients with extramedullary disease.

GERSTEIN: I have a question on the first hazard analysis. The very top category was previous proteosome inhibitor therapy and the HR wasn’t good for those who had previous therapy. We’re using this in the second line with patients.

NIESVIZKY: [Patients] have to be exposed, but not refractory. Similar to the retreatment protocol there is 20% to 30% of patients who will respond again to a bortezomib regimen. It goes back to the history of already changing agents if they have tried to find other agents that they haven’t seen, or at least another class of agents.

GERSTEIN: Right, changing one agent. OK, I get it.

NIESVIZKY: In terms of response rates in the BOSTON trial, the overall response rate for the triplet was 76.4% with a complete response or more rate of 16.9%, more than a VGPR rate of 44.6% comparing favorably to the control arm [with an overall response rate of 62.3%, a complete response or better rate of 10.6%, and a VGPR or better rate of 32.4%]. The median time to response was 1.1 month [with the triplet] with a median duration of response of 20.3 months [versus 1.4 months and 12.9 months, respectively, with the doublet]. [Fewer] patients [had] progressive disease on the triplet [than on the triplet, 0.5% versus 4.8%].

The major emphasis in terms of toxicity in this relapsed/ refractory group is the myelotoxicity with thrombocytopenia, anemia, and neutropenia, and, of course, the malaise, fatigue, and nausea. If you compare the grade 3/grade 4 [events] between the triplet and the control arm, for fatigue it’s 13% versus 1%, but also remember that bortezomib and dexamethasone can cause significant fatigue as one of the most common adverse events that are reported in all the clinical trials. The management of thrombocytopenia and leukopenia is important in this particular case. The management of nausea and vomiting is important.

Olanzapine [Zyprexa], given that it crosses the bloodbrain barrier, can help [with some of] the adverse events as antinausea and vomiting.

In terms of dose reductions, it’s allowed from a 100 mg weekly to 80 mg weekly, and 60 mg and 40 mg and then permanently discontinue depending on the toxicity, including the nausea, vomiting, hyponatremia, etc.⁷

[There are] similar guidelines on the management of selinexor with thrombocytopenia and neutropenia where selinexor is reduced by one level depending on the numbers. If the patient has relapsed/refractory disease and it’s imperative to induce response, sometimes I support the patients with transfusions without dose reductions in the beginning, the first cycle, second cycle, and later on, I would start reducing the dose because it’s more important to recover that cytopenia once you achieve a response to myeloma, particularly in those patients who have bone marrow plasmacytosis of more than 50%.

_REFERENCES:

_{1. NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma, version 7.2021. Accessed June 19, 2021. https://bit.ly/3ha90QK}

_{2. Dimopoulos MA, Moreau P, Terpos E, et al; EHA Guidelines Committee; ESMO Guidelines Committee. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):309-322. doi:10.1016/j. annonc.2020.11.014}

_{3. FDA approves selinexor for refractory or relapsed multiple myeloma. FDA. December 18, 2020. Accessed June 19, 2021. https://bit.ly/3h8v6mI}

_{4. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3}

_{5. Dimopoulos MA, Delimpasi S, Simonova M, et al. Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: Initial results of the phase III BOSTON study. J Clin Oncol. 2020;38(suppl 15):8501. doi:10.1200/ JCO.2020.38.15_suppl.85}

_{6. Bahlis NJ, Sutherland H, White D, et al. Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. Blood. 2018;132(24):2546-2554. doi:10.1182/blood-2018-06-858852 7. Xpovio. Prescribing information. Karyopharm Therapeutics. 2020.}