Editors:

(UPDATE) Carfilzomib (Kyprolis)

Updated: Friday, May 28, 2021

Posted: Wednesday, January 31, 2018

Selecting a therapeutic path for relapsed or refractory myeloma has become increasingly complex in recent years. Patients with relapsed or refractory disease often have limited treatment options and a poor prognosis. With increasing use of the second-generation immunomodulatory agent (IMiD) lenalidomide in the front-line setting as induction and maintenance/continuous therapy in both transplantation-eligible and -ineligible patient populations, there is a growing need for effective and tolerable lenalidomide-free regimens for patients who no longer respond to lenalidomide treatment.

Triplets Versus Doublets as Salvage Therapy

In general, triplets are preferred over doublets as salvage therapies. Although several triplets building upon the lenalidomide/dexamethasone backbone have been approved for patients with relapsed and/or refractory multiple myeloma, trials evaluating such combinations have largely excluded patients who were refractory to lenalidomide. The usefulness of these regimens, therefore, in the vast majority of patients whose disease is progressing on lenalidomide therapy is questionable. As expanding options have emerged, experts tend to prefer triplets incorporating drugs from two different “non-IMiD” classes, if available, as the first salvage regimen in lenalidomide-refractory patients.

Carfilzomib is an epoxyketone that selectively and irreversibly inhibits proteasomes. The ASPIRE trial,¹ which compared the efficacy of carfilzomib in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma, failed to show a significant progression-free survival advantage with the addition of carfilzomib. All patients enrolled in the ASPIRE trial had been previously exposed to lenalidomide.

Since the JNCCN 360 Spotlight on Carfilzomib was originally published (see Carfilzomib Spotlight for tips on the clinical use of carfilzomib, including administration and prevention/management of adverse effects), emerging research has indicated that triplet regimens of carfilzomib with dexamethasone and a CD38-directed antibody appear to be an effective treatment option for relapsed or refractory multiple myeloma, including lenalidomide-refractory disease.^2-4

EQUULEUS and CANDOR Trials

On August 20, 2020, the U.S. Food and Drug Administration (FDA) approved the use of carfilzomib, daratumumab, and dexamethasone for the treatment of relapsed or refractory multiple myeloma. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma also added daratumumab, carfilzomib, and dexamethasone with category 1 designation under preferred regimens.⁵ This addition is supported by the encouraging results of two clinical trials: EQUULEUS and CANDOR.⁶

The EQUULEUS (MMY001) trial is a nonrandomized, multiarm phase b study evaluating the anti-CD38 monoclonal antibody daratumumab in combination with a variety of backbone regimens. One arm of the EQUULEUS trial studied 85 patients with relapsed or refractory multiple myeloma who were not previously exposed to carfilzomib- and daratumumab.³ In this arm, patients received weekly carfilzomib (initial dose of 20 mg/m² on day 1 cycle 1, increased to 70 mg/m² on day 8 and 15, cycle 1 onward), dexamethasone, and daratumumab, with the option of first-dose infusion as single (n = 10) or split over 2 days (n = 75). Of note, 95% of the patients were lenalidomide-exposed, and 60% were lenalidomide-refractory. The overall response rate was 84%, and the 18-month progression-free survival rate was 66%.

A subgroup analysis of the EQUULEUS trial revealed comparable results in lenalidomide-refractory patients: the overall response rate was 79%, and the 18-month progression-free survival rate was 56%,^3,7 suggesting that the three-drug combination was effective in both the lenalidomide-exposed and lenalidomide-refractory populations.

The results of the phase III CANDOR trial further bolstered those of the EQUULEUS study, although the dose of carfilzomib used in the CANDOR trial was different (20 mg/m²; days 1 and 2 during cycle 1 followed by 56 mg/m² twice weekly, 3 of 4 weeks).² A total of 466 patients with relapsed or refractory multiple myeloma were randomly assigned to receive the carfilzomib, dexamethasone, and daratumumab triplet (n = 312) or carfilzomib and dexamethasone (n = 154). The triplet therapy significantly prolonged progression-free survival and reduced the risk of disease progression or death by 37% compared with carfilzomib and dexamethasone. The 18-month progression-free survival rates were 62% in the triplet group and 43% in the carfilzomib/dexamethasone group. Additionally, patients treated with triplet therapy achieved improved overall and deeper responses compared with doublet therapy, with a nearly 10-fold higher minimal residual disease–negative complete response rate at 12 months.

Notably, most patients (90%) in the CANDOR study were previously treated with bortezomib-containing regimens, and more than two-thirds of the cohort was exposed to an IMiD, mirroring the treatment landscape for typical patients with multiple myeloma. Consistent with outcomes in the overall population, the risk of disease progression or death was reduced with triplet therapy compared with doublet therapy across the prespecified subgroups with previous lenalidomide exposure and, perhaps more importantly, among those exhibiting refractoriness to lenalidomide (53% decrease in the risk of disease progression or death). Cardiotoxicity and severe infections were the most common adverse events for which carfilzomib and daratumumab were discontinued, respectively.

Triplet Therapy With Isatuximab-irfc

The IKEMA study evaluated the efficacy of another triplet regimen that included a different CD38-directed antibody, isatuximab-irfc, with carfilzomib (at doses used in the CANDOR study) and dexamethasone until disease progression or unacceptable toxicity in the treatment of relapsed or refractory multiple myeloma.⁴ The phase III study randomly assigned patients to receive carfilzomib, isatuximab-irfc, and dexamethasone (n = 179) or carfilzomib plus dexamethasone (n = 123). After a median follow-up of 20.7 months, the median progression-free survival was not reached with the triplet therapy versus 19.15 months with carfilzomib plus dexamethasone, with a hazard ratio of 0.531 (one-sided P = .0007).

These interim results indicate that the addition of isatuximab-irfc to carfilzomib and dexamethasone significantly improves progression-free survival and provides a clinically meaningful improvement in the depth of response. On March 31, 2021, based on data from the IKEMA study, the FDA approved carfilzomib, isatuximab-irfc, and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy.

Once-Weekly Versus Twice-Weekly Dosing

When carfilzomib was first added to the potential treatment paradigm for multiple myeloma, the inconvenience of the twice-weekly dosing schedule was considered a disadvantage. This changed in October 2018, when the FDA approved once-weekly dosing based on the results of the phase III A.R.R.O.W. trial.^8,9

This study directly compared two carfilzomib/dexamethasone doublets in patients with relapsed or refractory multiple myeloma: carfilzomib at 27 mg/m² intravenously twice weekly versus 70 mg/m² intravenously once-weekly—a higher cumulative dose despite less frequent administration. The investigators revealed significantly higher median progression-free survival in the once-weekly group compared with the twice-weekly group (11.2 vs 7.6 months, P = .0029).^8,9 These findings were confirmed in study subgroups, which looked at factors such as age, renal function, number of prior therapies, and bortezomib-refractory status.¹⁰

Dosing schedule was also evaluated in a cross-sectional comparison of the CANDOR and EQUULEUS trials.¹¹ After the first dose of carfilzomib at 20 mg/m² in both studies, patients in the CANDOR trial received a twice-weekly dose at 56 mg/m²; those in the EQUULEUS trial received a once-weekly dose at 70 mg/m².^2,3 In the comparison of dose strategies, once-weekly dosing of carfilzomib appeared to be as efficacious and safe as the twice-weekly dosing, but the once-weekly dosing offers a more convenient schedule that in turn may improve adherence, potentially leading to better outcomes in the real world setting. The FDA’s approval of carfilzomib, daratumumab, and dexamethasone has included both once-weekly and twice-weekly dosing regimens.

Ongoing Research in Newly Diagnosed Multiple Myeloma

A carfilzomib-containing regimen remains a treatment option (not listed under preferred regimens) for patients with newly diagnosed multiple myeloma.⁵ The ENDURANCE trial—a phase III trial published in 2020 that included patients with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate autologous stem cell transplantation—concluded that a regimen of carfilzomib, lenalidomide, and dexamethasone did not improve progression-free survival compared with a bortezomib, lenalidomide, and dexamethasone regimen.¹² The carfilzomib triplet regimen also was associated with increased toxicity compared with bortezomib. Therefore, the bortezomib triplet regimen remains the standard of care for induction therapy in patients with standard-risk and translocation (4;14) newly diagnosed multiple myeloma.

REFERENCES

Stewart AK, Rajkumar V, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372:142–152.
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;396:186–197.
Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood 2019;134:421–431.
Moreau P, Dimopoulos MA, Mikhael J et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): Interim analysis of a phase 3, randomized, open-label study. 2020 ASH Annual Meeting & Exposition. Abstract 2316.
Kumar SK, Callander NS, Adekola K, et al. NCCN Clinical Practice Guidelines. Multiple Myeloma. Version 7.2021: Multiple Myeloma. April 26, 2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed April 28, 2021.
U.S. Food and Drug Administration. FDA approves carfilzomib and daratumumab with dexamethasone for multiple myeloma. August 20, 2020. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-carfilzomib-and-daratumumab-dexamethasone-multiple-myeloma. Accessed April 26, 2021.
Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab in combination with carfilzomib and dexamethasone in lenalidomide-refractory patients with relapsed multiple myeloma: subgroup analysis of MMY1001. 2018 ASCO Annual Meeting. Abstract 8002.
FDA Approves Once-Weekly Carfilzomib in Combination With Dexamethasone for Relapsed or Refractory Multiple Myeloma. The ASCO Post, October 1, 2018. Available at https://ascopost.com/News/59319. Accessed April 22, 2021.
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.
Dimopoulos MA, Niesvizky R, Weisel K, et al. Once- versus twice-weekly carfilzomib in relapsed and refractory multiple myeloma by select patient characteristics: phase 3 A.R.R.O.W. study subgroup analysis. Blood Cancer J 2020;10:1–13.
Leleu X, Beksac M, Chou T, et al. Efficacy and safety of weekly carfilzomib (70 mg/m²), dexamethasone, and daratumumab (KdD70) is comparable to twice-weekly KdD56 while being a more convenient dosing option: a cross-study comparison of the CAND and EQUULEUS studies. Leuk Lymph 2021;62:358–367.
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;21:1317–1330.

Spotlight

Fast Facts

Drug Class

Proteasome inhibitor

Indications

In combination with dexamethasone, lenalidomide plus dexamethasone, daratumumab and dexamethasone, or isatuximab-irfc and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. [Editor’s Note: The combination of isatuximab-irfc and dexamethasone is not FDA approved; also, the NCCN Guidelines include additional combinations.]
As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. [Editor’s Note: According to an NCCN 2A designation, a carfilzomib-containing regimen may be considered for front-line use in newly diagnosed multiple myeloma.]

Recommended Dosage

Calculate the dose using the patient’s actual body surface area at baseline. In patients with a body surface area greater than 2.2 m², calculate the dose based upon a body surface area of 2.2 m².
For the combination regimen with lenalidomide and dexamethasone, administer carfilzomib intravenously as a 10-minute infusion on 2 consecutive days, each week for 3 weeks, followed by a 12-day rest period. Each 28-day period is considered one treatment cycle; this dosing is for the first 12 cycles. The recommended starting dose of carfilzomib is 20 mg/m² in cycle 1 on days 1 and 2. If tolerated, escalate the dose to 27 mg/m² on day 8 of cycle 1. It is then given as 27 mg/m² on days 1–2 and 15–16 for cycles 13-18. Continue treatment until disease progression or unacceptable toxicity occurs. [Editor’s Note: All doses greater than 27 mg/m² should be administered over 30 minutes. Carfilzomib should be discontinued after cycle 18, with continuation of lenalidomide and dexamethasone thereafter (ASPIRE study¹).]
For the combination regimen with daratumumab and dexamethasone, administer carfilzomib as a 30-minute infusion on 2 consecutive days, each week for 3 weeks, followed by a 12-day rest period. The recommended starting dose of carfilzomib is 20 mg/m² on cycle 1, days 1 and 2. If tolerated, escalate the dose to 56 mg/m² on cycle 1, day 8 and thereafter. Administer dexamethasone 30 minutes to 4 hours before carfilzomib and 1 to 3 hours before intravenous daratumumab.
For the combination regimen with dexamethasone, administer carfilzomib intravenously as a 30-minute infusion, on 2 consecutive days, each week for 3 weeks, followed by a 12-day rest period. Administer dexamethasone at 20 mg, orally or intravenously, 30 minutes to 4 hours before carfilzomib. If 20 mg/m² of carfilzomib is tolerated on days 1 and 2, the dose may be escalated to 56 mg/m² on day 8 of cycle 1.
Alternatively, carfilzomib can be given as a once-weekly regimen.

With dexamethasone: Administer carfilzomib intravenously as a 30-minute infusion on days 1, 8, and 15 of each 28-day cycle. The recommended starting dose of carfilzomib is 20 mg/m² on day 1 of cycle 1; if tolerated, the dose can be escalated to 70 mg/m² on day 8 of cycle 1.
With daratumumab and dexamethasone: Administer carfilzomib intravenously as a 30-minute infusion on days 1, 8, and 15 of each 28-day cycle in combination with intravenous daratumumab and dexamethasone. The recommended starting dose of carfilzomib is 20 mg/m² on day 1 of cycle 1. If tolerated, escalate the dose to 70 mg/m² on day 8 of cycle 1 and thereafter. Administer dexamethasone 30 minutes to 4 hours before carfilzomib and 1 to 3 hours before intravenous daratumumab.

Administration

Infuse over 10 or 30 minutes depending on the carfilzomib dose regimen. Do not administer as a bolus.
Hydrate prior to each dose in cycle 1; hydrate after carfilzomib infusion as necessary.
Premedicate with dexamethasone, either orally or intravenously, before cycle 1 and if infusion reactions develop or reappear. Dosing varies based on clinical practice and the regimen used.

Common Adverse Events (≥ 20% of Patients in Monotherapy Trials)

Anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, and peripheral edema

Common adverse events (≥ 20% of Patients in Combination Therapy Trials)

Anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia

Warnings and Precautions

Cardiac toxicities: Monitor for signs and symptoms of cardiac failure or ischemia and manage promptly. Withhold carfilzomib for grade 3 or 4 events until recovery and consider risk/benefits.
Acute renal failure: Monitor serum creatinine regularly.
Tumor-lysis syndrome (TLS): Administer pretreatment hydration. Monitor for TLS, including uric acid levels, and treat promptly. Withhold carfilzomib until TLS is resolved.
Pulmonary toxicity, including acute respiratory distress syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease: Withhold carfilzomib and evaluate promptly.
Pulmonary hypertension: Withhold carfilzomib and evaluate.
Dyspnea: For severe or life-threatening dyspnea, withhold carfilzomib and evaluate.
Hypertension including hypertensive crisis: Monitor blood pressure regularly. If hypertension cannot be controlled, interrupt treatment with carfilzomib.
Venous thrombosis: Thromboprophylaxis is recommended.
Infusion reactions: Premedicate with dexamethasone.
Hemorrhage: Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose, as appropriate.
Thrombocytopenia: Monitor platelet counts; interrupt or reduce carfilzomib dosing as clinically indicated.
Hepatic toxicity and hepatic failure: Monitor liver enzymes regularly. Withhold carfilzomib if appropriate.
Thrombotic microangiopathy: Monitor for signs and symptoms. Discontinue carfilzomib if suspected.
Posterior reversible encephalopathy syndrome: Consider neuroradiologic imaging (MRI) for onset of visual or neurologic symptoms; discontinue carfilzomib if suspected.
Progressive multifocal leukoencephalopathy (PML): Consider PML if new or worsening neurologic manifestations. Discontinue carfilzomib in patients who develop PML.
Increased fatal and serious toxicities in combination with melphalan and prednisone in newly diagnosed transplant-ineligible patients.
Embryofetal toxicity: Carfilzomib can cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated with carfilzomib.

Adapted from carfilzomib (Kyprolis^®) prescribing information.

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