ASH 2018: Four-Drug Combo with Carfilzomib vs. Triplets Before Transplant

Graham Jackson, MD, PhD of the Northern Institute for Cancer Research in the United Kingdom (and colleagues) shared study results at the recent ASH 2018 comparing a four drug combination vs. a sequence of three drug combinations as induction therapy before stem cell transplant. The UK has an incredible amount of data about myeloma patients as thousands are included in large studies. These results were based on the Myeloma XI study.

The goal was to combine myeloma therapies to maximize the depth of first response to improve overall outcomes. The study reviewed the use of carfilzomib as induction therapy because, according to Dr. Jackson:

"Carfilzomib is a novel irreversible inhibitor of the proteasome that has been suggested to have greater activity than bortezomib, with deeper responses and improved outcomes."

In the study, one group (526 patients) received 4 cycles of a four-drug combination including:

• Carfilzomib
• Cyclophosphamide (commonly used in Europe)
• Lenalidomide
• Dexamethasone

Another group (265 patients) received 4 cycles of a three drug (CTD) combination including:

• Cyclophosphamide
• Thalidomide
• Dexamethasone

Another group (265 patients) received 4 cycles of a three drug (CRD) combination including:

• Cyclophosphamide
• Revlimid
• Dexamethasone

If patients had a less-than optimal response with the CTD/CRD, they switched to Cyclophosphamide/Velcade/Dex (CVD) or no additional treatment prior to their transplant.

Patients with refractory disease (which means their disease kept progressing even when getting the medications) also received Cyclophosphamide/Velcade/Dex.

After transplant, patients were randomized to receive Revlimid as maintenance or no maintenance. The myeloma genetics were noted for each patient. High risk patients were those who had t(4;14), t(14;16), t(14;20), del(17p) or gain(1q). Ultra-high risk patients were those who had more than one of these features.

At follow up, the data showed:

KCRD gave patients longer progression free survival (PFS) than either of the triplet combos

• PFS for KCRD hadn't been reached yet vs. 36.2 for CTD or CRD
• KCRD also gave deeper responses vs. CTD or CRD

• KCRD allowed more patients to undergo the transplant
• Patients who also got KCRD had longer progression free survival than patients who did the CTD or CRD and then the CVD following a lack of response

The authors concluded that KCRD is a four drug combo that is well tolerated and provides deep responses both before and after transplant and has significant progression free survival compared to the triplet therapies.

Note: In the United States, the induction therapies typically include a triplet that include an immunomodulator (like Revlimid), a proteasome inhibitor (like carfilzomib, ixazomib or Velcade) and dexamethasone.