Multiple Myeloma Coverage From Every Angle

Ixazomib (Ninlaro®)

Posted: Friday, August 24, 2018

Current Treatment Options for Patients With Multiple Myeloma

Multiple myeloma remains an incurable but highly treatable disease. Results of intensive research have yielded numerous new treatment options for patients with multiple myeloma over the past 2 decades.1–3 Moreover, since the introduction and approval of novel classes of agents such as proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), histone deacetylase inhibitor (panobinostat), and monoclonal antibodies (daratumumab and elotuzumab), survival of patients with multiple myeloma has improved.1,2

Despite these major advances—along with the routine use of high-dose therapy followed by autologous stem cell transplantation (HDT-ASCT) in eligible patients and significant improvements in supportive care, which have all led to improved patient survival—management of multiple myeloma remains challenging, because relapse and disease progression seem inevitable.4 Furthermore, relapsed disease typically acquires additional genomic alterations that render it more resistant and refractory to each subsequent salvage therapy. This results in progressively shorter durations of remission and the development of relapsed and/or refractory disease.1–4

Benefits of Triplet Regimens and Long-Term Treatment

Selecting a regimen to treat relapsed and/refractory multiple myeloma from among multiple options can be challenging. Clinicians should consider patient characteristics (eg, age and frailty, performance status, comorbidities, bone marrow reserve), tumor features (eg, tumor burden, cytogenetic risk, bone lesions, lactate dehydrogenase level), type of therapy (eg, prior HDT-ASCT and exposure to proteasome inhibitors and immunomodulatory drugs, response and tolerability to and time from prior therapy, new treatment options, clinical trials), as well as patients’ preferences and expectations.2

In general, based on currently available prospective clinical trial data and retrospective analyses, triplet regimens, including both an immunomodulatory drug and a proteasome inhibitor,5 and extended-duration treatment, seem to be superior to doublet regimens and shorter, fixed-duration treatment, resulting in continuous disease suppression, deeper responses, and prolonged survival.6,7 However, long-term treatment with some current triplet regimens, such as those with bortezomib or carfilzomib, may be challenging due to treatment-related toxicities (eg, peripheral neuropathy, cardiovascular and renal toxicities, and the need for frequent clinic visits and repeat injections).8

Emergence of All-Oral Treatment Regimens: The Role of Ixazomib

When asked about the tolerability, convenience, patient quality of life, and impact of ixazomib, particularly the U.S. FDA–approved combination of ixazomib, lenalidomide, and dexamethasone (IRd),9,10 on the current treatment paradigm in patients with relapsed and/or refractory multiple myeloma, Shaji Kumar, MD, Professor of Medicine at Mayo Clinic in Rochester, Minnesota, said the proteasome inhibitors represent an important class of drugs for patients with multiple myeloma, both in newly diagnosed and relapsed and/or refractory settings. “One of the problems with some of the currently approved proteasome inhibitors is the inconvenience of having to come into the clinic,” explained Dr. Kumar. “Another disadvantage centers on the specific side effects seen with some of these drugs. For example, bortezomib requires patients to come into the clinic at least once a week to receive a subcutaneous injection. Bortezomib is also associated with significant peripheral neuropathy,11 which precludes its long-term use.”

Dr. Kumar then addressed the next-generation proteasome inhibitor carfilzomib, which “appears to be more potent than bortezomib, is associated with cardiorenal toxicity, and requires that a patient come into the clinic twice a week to receive an infusion.”12 Some data suggest that once-weekly administration is possible,13 but, that still means coming into the clinic at least once a week for 3 weeks of the 4-week treatment cycle.

Conversely, ixazomib offers the convenience of oral therapy. “A patient takes a pill once a week as part of the all-oral triplet IRd regimen, which requires coming into the clinic only once a month or so,” Dr. Kumar told JNCCN 360. “Moreover, ixazomib is associated with significantly less peripheral neuropathy than we have seen with bortezomib,9 which represents an additional advantage, as it allows patients to stay on therapy for a longer duration.8,9 So, these major advantages associated with ixazomib make it an important addition to the multiple myeloma treatment armamentarium,” according to Dr. Kumar.

These major advantages associated with ixazomib make it an important addition to the multiple myeloma treatment armamentarium.

Discussing the same issues of tolerability, convenience, patient quality of life, and ixazomib’s impact on the current treatment paradigm in patients with relapsed and/or refractory multiple myeloma, Kathleen Colson, RN, BSN, BS, a clinical research nurse with the Multiple Myeloma Program at the Dana-Farber Cancer Institute, Boston, said, “The approval of ixazomib in combination with lenalidomide and dexamethasone in November 201510 represented another significant expansion of our treatment armamentarium for patients with multiple myeloma. Its significance stems mainly from the fact that it is the first oral proteasome inhibitor approved for patients with multiple myeloma. This, in addition to its being well tolerated, translates into significantly improved patient convenience and quality of life compared with other proteasome inhibitors. Patients who are on the IRd regimen can go about their normal daily activities without worrying that they have to come to the clinic once or twice a week to receive their treatment for their multiple myeloma.”

Treatment Selection: Previous Therapy and Convenience

When it comes to deciding which patient with relapsed and/or refractory multiple myeloma to treat with IRd, several factors come into play. Dr. Kumar told JNCCN 360 that, “this decision-making process can be quite a challenge for U.S. physicians, because most patients with relapsing disease are refractory to lenalidomide, which is typically given as maintenance therapy in the front-line setting.” For patients who are not lenalidomide-refractory, there are four options: IRd, carfilzomib-Rd (KRd), daratumumab-Rd (DRd), and elotuzumab-Rd (ERd). “If a patient has had quite a bit of exposure to proteasome inhibitors, then I tend to go with a monoclonal antibody–based combination such as DRd or ERd. If they didn’t have a lot exposure to proteasome inhibitors or they responded well to bortezomib-Rd (VRd) in the front-line setting, then I tend to go with either KRd or IRd,” he suggested.

The next factor that enters into the decision-making process is convenience. “For a younger patient who does not mind coming into the clinic once or twice a week, I consider KRd,” said Dr. Kumar. He continued: “In contrast, if an older or frail patient cannot come into the clinic that often, I would consider IRd. For most patients [in the United States] with lenalidomide-refractory disease at the time of relapse, we tend to use some of the drugs I mentioned previously, in combination with pomalidomide.3 Ixazomib, in combination with pomalidomide, has been shown in a phase II trial to be safe and effective.14 So, that is one of the options for these patients.”

Ixazomib, in combination with pomalidomide, has been shown in a phase II trial to be safe and effective.

Once-Weekly Dosing and Adherence

In terms of ixazomib administration, Dr. Kumar explained that, generally, it is recommended that ixazomib be taken on an empty stomach or a couple of hours after a meal. “Considering that it is taken only once a week, timing does not present much of a problem. However, the fact that ixazomib is taken orally once a week could present an adherence problem. Missing one weekly dose represents one-third of the monthly dose. This potential issue is addressed typically by patient education, nurse follow-ups with patients, and reminders sent through various electronic channels,” he said.

Ms. Colson concurred with Dr. Kumar on adherence. “Frequently, we encourage our patients to take the medication before bedtime, and they can take it along with lenalidomide. That way, they can sleep through whatever side effects they may have. Even steroids such as dexamethasone can be taken at bedtime. This may seem counterintuitive, but some of the associated side effects, such agitation and anxiety, may start kicking in around the time when a patient is about to wake up. So, as the day progresses, these side effects abate, and the patient has less trouble in the evening falling asleep.”

Duration of Therapy

With regard to the duration of therapy, Dr. Kumar said, “Typically, I try to keep patients on IRd for a minimum of 1 year or up to 1.5 years—depending on how well they are tolerating it—until they achieve an excellent response. Thereafter, I typically think about maintenance with either lenalidomide or ixazomib.” Type of toxicities and drug exposure guide Dr. Kumar in choosing one agent over another. “All things being equal, if a patient has high-risk disease with 17p deletion or one of the high-risk translocations, I use ixazomib,” he said.

All things being equal, if a patient has high-risk disease with 17p deletion or one of the high-risk translocations, I use ixazomib.

Ixazomib Toxicity Profile and Management of Adverse Events

Gastrointestinal Adverse Effects

Describing ixazomib-related adverse events and how to manage them,15 Dr. Kumar said, “Although adverse events depend somewhat on the specific partner that ixazomib is given with, gastrointestinal side effects such as nausea are common. If that happens, we provide an antiemetic, such as granisetron, at the start of therapy and discontinue it once the patient becomes accustomed to the drug. Also, dexamethasone seems to make some gastrointestinal adverse events less prominent, which can be helpful. If a patient reports diarrhea, an antidiarrheal or—once the timing of diarrheal episodes becomes clear—prophylactic medication is usually sufficient without any dose modification of ixazomib.”

Ms. Colson and her team advise patients to have some antidiarrheal medication at home to use as needed. For patients who experience constipation with ixazomib, “We suggest starting stool softeners and increasing fluid and fiber intake along with physical activity,” she told JNCCN 360. Similarly, patients who experience nausea and vomiting are instructed to take their antinausea medication before their ixazomib dose.

Dermatologic Toxicity and Peripheral Neuropathy

Another adverse event that is not uncommon with ixazomib, according to Dr. Kumar, especially in combination with lenalidomide, is skin rash. A limited rash can be managed with topical medications. However, if rash is more severe, “sometimes you need to reduce the dose or stop ixazomib altogether,” Dr. Kumar pointed out. Ms. Colson added, “Typically, we treat rash with over-the-counter antihistamine medications such as diphenhydramine or loratadine, although sometimes steroids may be needed.

With respect to peripheral neuropathy, Dr. Kumar noted that he has seen it much less often with ixazomib than with bortezomib. “We educate patients to report any peripheral neuropathy symptoms, such as tingling, numbness, burning, coldness, or pain in their feet or hands, to their physician for appropriate intervention, including potential dose modification.”

Myelosuppression and Fatigue

Thrombocytopenia is typically transient with ixazomib. However, Dr. Kumar noted, “if the count drops too low, we need to dose modify. In case of neutropenia with IRd, I would dose reduce lenalidomide first and then, if that does not help, I would dose reduce ixazomib; whereas in the case of thrombocytopenia, I would do the opposite—first reduce the ixazomib dose and then reduce the dose of lenalidomide, if necessary.”

Fatigue is also typically managed with supportive care. If necessary, it can be handled with dose modifications or breaks between cycles, Dr. Kumar said.

Ms. Colson told JNCCN 360 that “appropriate supportive care is key to keeping patients safe and on track with their therapy. The IRd combination may cause myelosuppression, which can include neutropenia and thrombocytopenia. With regard to neutropenia, we monitor patients’ complete blood cell counts and blood differential; depending on the neutrophil cell count, we decide whether to modify the ixazomib dose or use growth factor support such as a filgrastim injection.” Both ixazomib and lenalidomide can cause thrombocytopenia, which reaches its nadir between days 14 and 21, Ms. Colson explained. Then it usually returns to baseline at the start of the next cycle of therapy. Managing myelosuppression can prevent or reduce serious complications.  

“When it comes to specific dose modifications of ixazomib,” Dr. Kumar explained, “the first one is down to 3 mg/week and then to 2.3 mg/week, 3 weeks out of a 4-week cycle. Sometimes,” he remarked, “we give it every other week instead, as in the maintenance phase, if we want to keep the patient on it. In the end, it all depends on the adverse events. Again, in case of thrombocytopenia, we try to dose modify each drug in the combination to see where we can get the maximal benefit.”

Take-Home Points

“The key step is to proactively manage toxicities,” concluded Dr. Kumar. For example, he gives patients granisetron prophylactically before the first dose of ixazomib. “If patients start off with significant nausea,” he emphasized, “it becomes much harder to continue with therapy. You want to give patients the best chance of maintaining the dose in the beginning, because many of the gastrointestinal toxicities improve with time. So, for the first few doses, we give antiemetics and antidiarrheals as needed. Thereafter, once we see the patient is handling the new regimen well, we can back off some or all of the supportive care medications.”

Ms. Colson noted that patients who are just starting with IRd are typically asked to come into the clinic more often during the first cycle of therapy to monitor their blood cell counts and for toxicity assessment. “We do that,” she told JNCCN 360, “to make sure their platelets and white blood cell counts are not getting too low and to do dose modifications, if necessary. Typically, the platelet count reaches its nadir between weeks 2 and 3 and recovers to normal before the next round of therapy—that is one of the reasons that week 4 is therapy-free. Also, because IRd is an all-oral regimen and some patients may become overwhelmed by relatively complicated schedules, we can use those visits to address potential adherence issues through comprehensive patient education, emphasizing the importance of staying on therapy.” To reinforce information, Ms. Colson’s team provides tools such as handouts, calendars, and diary cards.

“Keeping patients on their myeloma therapy is critical to their response and control of their disease,” Ms. Colson concluded. “Supportive care is a key factor in keeping myeloma patients healthy and safe.”

 

Disclosures

Shaji Kumar, MD, has disclosed that he received institutional research grants for clinical trials from Celgene, Takeda, Janssen, BMS, Sanofi, Kite Pharma, Merck, AbbVie, MedImmune, Novartis, Roche-Genentech, and Amgen; served as an unpaid consultant for Celgene, Takeda, Janssen, Kite Pharma, Merck, AbbVie, MedImmune, Genentech, Oncopeptides, and Amgen; served on an independent review committee for Oncopeptides; and received honoraria from Dr. Reddy’s Laboratories and Ono Pharmaceuticals.

Kathleen Colson, RN, BSN, BS, has disclosed she has served as a consultant for Celgene.

 

References

  1. Chim CS, Kumar SK, Orlowski RZ, et al. Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. Leukemia 2018;32:252–262.
  2. Nijhof IS, van de Donk NWCJ, Zweegman S, Lokhorst HM. Current and new therapeutic strategies for relapsed and refractory multiple myeloma: an update. Drugs 2018;78:19–37.
  3. Kumar SK, Callander NS, Biermann JS, et al. NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 1.2019. Accessed August 14, 2018. To view the most recent version of these guidelines, visit NCCN.org.
  4. Kumar SK, Dimopoulos MA, Kastritis E, et al. Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. Leukemia 2017;31:2443–2448.
  5. Offidani M, Corvatta L, Gentili S. Triplet vs. doublet drug regimens for managing multiple myeloma. Expert Opin Pharmacother 2018;19:137–149.
  6. Guglielmelli T, Palumbo A. Multiple myeloma: is a shift toward continuous therapy needed to move forward? Expert Rev Hematol 2015;8:253–256.
  7. Hari P, Romanus D, Palumbo A, et al. Prolonged duration of therapy is associated with improved survival in patients treated for relapsed/refractory multiple myeloma in routine clinical care in the United States. Clin Lymphoma Myeloma Leuk 2018;18:152–160.
  8. Richardson PG, Kumar S, Laubach JP, et al. New developments in the management of relapsed/refractory multiple myeloma: the role of ixazomib. J Blood Med 2017;8:107–121.
  9. Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016;374:1621–1634.
  10. Ninlaro (ixazomib). FDA prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208462s001lbl.pdf. Accessed August 14, 2018.
  11. Richardson PG, Delforge M, Beksac M, et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia 2012;26:595–608.
  12. Rosenthal A, Luthi J, Belohlavek M, et al. Carfilzomib and the cardiorenal system in myeloma: an endothelial effect? Blood Cancer J 2016;6:e384.
  13. Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol 2018;19:953–964.
  14. Krishnan A, Kapoor P, Palmer JM, et al. Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma [published December 18, 2017]. Leukemia, doi: 10.1038/leu.2017.352
  15. Kumar S, Moreau P, Hari P, et al. Management of adverse events associated with ixazomib plus lenalidomide/dexamethasone in relapsed/refractory multiple myeloma. Br J Haematol 2017;178:571–582.



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