Guidelines for determination of the number of prior lines of therapy in multiple myeloma

A line of therapy consists of ≥1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens (eg, 3-6 cycles of initial therapy with bortezomib-dexamethasone [VD] followed by stem cell transplantation [SCT], consolidation, and lenalidomide maintenance is considered 1 line).

A treatment is considered a new line of therapy if any 1 of the following 3 conditions are met (Table 1):

1. Start of a new line of treatment after discontinuation of a previous line: If a treatment regimen is discontinued for any reason and a different regimen is started, it should be considered a new line of therapy. A regimen is considered to have been discontinued if all the drugs in that given regimen have been stopped. A regimen is not considered to have been discontinued if some of the drugs of the regimen, but not all, have been discontinued.

2. The unplanned addition or substitution of 1 or more drugs in an existing regimen: Unplanned addition of a new drug or switching to a different drug (or combination of drugs) due to any reason is considered a new line of therapy.

3. SCT: In patients undergoing >1 SCT, except in the case of a planned tandem SCT with a predefined interval (such as 3 months), each SCT (autologous or allogeneic) should be considered a new line of therapy regardless of whether the conditioning regimen used is the same or different. We recommend that data on type of SCT also be captured.

Illustrative examples are given here.

• Lenalidomide plus low-dose dexamethasone (RD) as initial therapy, and due to inadequate response, bortezomib is added (RVD): counted as 2 lines.

• Toxicity with RD as pretransplant induction, and therefore treatment is switched to bortezomib, cyclophosphamide, and dexamethasone (VCD): RD is counted as 1 line; VCD (and subsequent planned SCT) is line 2.

• Posttransplant observation without maintenance, and then, due to paraprotein rise 6 months later, lenalidomide is started, which is not planned maintenance; hence, lenalidomide will be considered as a new line.

If a regimen is interrupted or discontinued for any reason and the same drug or combination is restarted without any other intervening regimen, then it should be counted as a single line. However, if a regimen is interrupted or discontinued for any reason, and then restarted at a later time point but 1 or more other regimens were administered in between, or the regimen is modified through the addition of 1 or more agents, then it should be counted as 2 lines. We recognize that in a subset of trials testing rechallenge with the same drug, it may be important to capture the detail that a rechallenge occurred in addition to the regimen count for clarity in this particular setting.

Modification of the dosing of the same regimen should not be considered a new line of therapy.

Illustrative examples are given below.

• RVD and disease progression at some point, and then VCD is used; then, RVD is used again as a salvage strategy: this is counted as 3 lines.

• RD as initial therapy for 2 years, then stopped due to plateau phase (or any other cause), and then restarted 6 months later due to progression: this should be counted as 1 line.

We believe that the counting of regimens as recommended above will help ensure data are more comparable across trials, reduce inter- and intraobserver variation in estimating lines of prior therapy, and provide greater clarity and hence validity in the rapidly developing area of clinical trials in multiple myeloma.

Contribution: S.V.R., P.R., and J.F.S.M. wrote the paper after reviewing literature and discussion; reviewed the draft, provided detailed input and comments, and contributed to the final paper; and approved the final paper.

Conflict-of-interest disclosure: The authors declare no competing financial interests.