Relapsed/Refractory Patients:

Treatment Options - Kyprolis® (carfilzomib) for Injection



Kyprolis®


Overview

 

What is Kyprolis?

Kyprolis, also known as carfilzomib, is a next generation proteasome inhibitor in the same drug class as Velcade.

The MMRF and it's affiliate organization, the Multiple Myeloma Research Consortium (MMRC), played an integral role in the development of Kyprolis over the past 6 years. The MMRC provided clinical trial support and resources, including driving patient enrollment to the study which lead to the approval of Kyprolis. Download Kyprolis brochure.

How does Kyprolis work?

Proteasomes are enzymes found in cells that play an important role in regulating cell function and cell growth by controlling the breakdown of important enzymes. As a proteasome inhibitor, Kyprolis blocks the activity of proteasomes and in turn disrupts processes related to the growth and survival of cancer cells.

What types of patients can benefit from Kyprolis?

Kyprolis has been shown to be effective in patients with relapsed and refractory multiple myeloma following treatment with other available agents, including Velcade® and Revlimid®. In the trial supporting the FDA approval of Kyprolis, 20.6% of patients who did not respond to or could not tolerate Velcade and one or more IMiDs (such as Revlimid or Thalomid®) responded to Kyprolis alone.

In addition, Kyprolis has also been shown to be effective in patients with:

  • High-risk tumors with associated DNA abnormalities

  • History of previous neuropathy (nerve problems)

  • Advanced age (> 65 years old)

It can also be given safely given to patients with reduced kidney function.

Additionally, results from an early study in newly diagnosed patients suggest that the combination of Kyprolis and Revlimid-low-dose dexamethasone is effective, with 94% of patients responding to treatment.

How effective is Kyprolis in treating relapsed and refractory multiple myeloma?

Kyprolis was granted FDA approval for treatment of patients with relapsed or refractory disease based on the results of a large Phase II study (PX-171-003-A1) involving 266 patients who had received an average of five myeloma therapies prior to entering this trial.

  • 23% of patients achieved a partial response or better

  • On average responses lasted 7.8 months

  • Average survival was 15.4 months

In another Phase II trial (PX-171-004) involving 165 patients with relapsed or refractory multiple myeloma after 1 to 3 therapies, Kyprolis provided one of the highest single-agent response rates and longest response duration reported in this patient population. Results were assessed both for those who had never and who had previously received Velcade.

  • Of the 129 patients who had never received Velcade, the overall response was 42%. 14% had a very good partial response and 25% had a partial response

  • The overall response increased to 52% with a higher dose of Kyprolis

  • Responses were durable, lasting a median of 13.1 months

  • In the patients who had previously received Velcade but stopped responding to it, the overall response was 21%

    • Average duration of response was 11.5 months

    • Median time until the disease started to progress was 8.1 months

The Multiple Myeloma Research Consortium (MMRC), an affiliate organization of the MMRF that accelerates early-stage clinical trials, played a pivotal role in these clinical studies. For PX-171-003-A1, the MMRC enrolled nearly 60% of patients, yet represented just one-third of the total sites. Similarly, in study PX-171-004, MMRC member institutions enrolled approximately 44% of patients who participated.

How is Kyprolis given?

Each 28-day cycle includes a 2-10 minute IV administration over 2 consecutive days, for 3 consecutive weeks, followed by 12 days off. Treatment variations between the first and subsequent cycles may include:

  1. A dose increase after cycle 1
  2. Use of pre-dose and post-dose IV hydration
  3. Dexamethasone treatment

What are the possible side effects with Kyprolis?

It is important to remember that side effects of all treatments are based on the individual and vary from patient to patient. Kyprolis has been well tolerated in clinical trials and side effects were found to be manageable. The most common side effects in clinical trials were:

  • Fatigue
  • Anemia
  • Low blood cell and platelet counts
  • Nausea
  • Shortness of breath
  • Fever
  • Headache
  • Upper respiratory tract infection
  • Cough
  • Back pain
  • Swelling of extremities
  • Vomiting
  • Constipation

In particular, shortness of breath has been reported in 35% of patients in clinical trials. It was severe in 5% of patients. Other serious side effects include low blood cell and platelet counts.

Patients may experience reactions immediately following or up to 24 hours after receiving Kyprolis. These reactions can include fever, chills, achiness, flushing, facial swelling, vomiting, weakness, shortness of breath, low blood pressure, fainting, chest tightness and chest pain. However, dexamethasone given prior to Kyprolis reduces the incidence and severity of these reactions.

Importantly, there was a low incidence of peripheral neuropathy in clinical studies and it was generally mild when it occurred.

Please tell your doctor or nurse if you experience any side effects.

How is Kyprolis currently being studied?

Kyprolis is being studied in a variety of settings, including combination therapy for relapsed/refractory disease, maintenance therapy, and newly diagnosed patients.

A Phase III international study called ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma, PX-171-009) is comparing Kyprolis in combination with Revlimid- low-dose dexamethasone vs Revlimid-low-dose dexamethasone in patients with relapsed myeloma who have received 1-3 prior therapies. This study recently reached its target enrollment of 780 patients and is designed to support FDA approval of Kyprolis for relapsed disease in combination with Revlimid-low-dose dexamethasone.

In a second Phase III trial, called ENDEAVOR (RandomizEd, OpeNLabel, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma), Kyprolis in combination with dexamethasone is being compared to Velcade® (bortezomib) with dexamethasone in 888 patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens. The study will be conducted at approximately 200 sites worldwide.

Preliminary results from small early studies have shown promising results when Kyprolis was combined with other myeloma drugs.

  • Kyprolis-Revlimid-dex, followed by Revlimid maintenance in newly diagnosed patients: Nearly all patients responded in this study and the combination was well tolerated.

  • Kyprolis-Pomalyst-dex in relapsed/refractory patients: Promising anti-myeloma activity was seen in patients who were refractory to both Revlimid and Velcade, including patients who were high risk. The combination was well-tolerated.

Additional trials in which Kyprolis is currently being investigated in combination therapy are shown in the following table.

Kyprolis in combination with… Patient type Phase of development
Revlimid, low-dose dexamethasone Newly diagnosed Phase II
Clarithromycin (Biaxin®), Revlimid®, dexamethasone Newly diagnosed, elderly Phase II
Melphalan, prednisone Newly diagnosed, elderly Phase I/II
Cyclophosphamide, dexamethasone,Thalomid Newly diagnosed Phase I/II
Revlimid, low-dose dexamethasone Relapsed Phase I
Doxil® (liposomal doxorubicin) Relapsed/refractory Phase I/II
Panobinostat Relapsed/refractory Phase I/II
Revlimid, Zolinza® (vorinostat), dexamethasone Relapsed/refractory Phase I/II
ARRY-520 Relapsed/refractory Phase I/II
Pomalyst® Relapsed/refractory Phase I/II

Click here to go to the MMRF’s Clinical Trials Matching Service to view a list of ongoing Kyprolis clinical trials or call 1-800-866-603-MMCT (6628).



For more information on Kyprolis, visit www.Kyprolis.com.



Reviewed by Ravi Vij, MD,
Washington University,