| Tracks 1-18 | ||||||||||||||||||||||||||||||||||||||
|
Select Excerpts from the Interview
Track 1
DR LOVE: Can you discuss recent research results in induction therapy for
patients with multiple myeloma?
DR LONIAL: Historically, the selection of agents as induction therapy did not
matter because transplant was the big hammer that equalized whatever was used
and few induction regimens resulted in high complete response (CR) rates. Now
regimens such as bortezomib/dexamethasone, lenalidomide/dexamethasone and
lenalidomide/bortezomib/dexamethasone (RVD) are achieving much higher
CR rates (Harousseau 2008; Zonder 2007; Richardson 2008).
This leads to questions such as, how can we maximize the CR rates up front, and does every patient need a transplant if we achieve that depth of response up front? We are also beginning to evaluate the depth of the CR, and I believe that’s a testament to the success of our new drugs.
Track 4
DR LOVE: Would you discuss the ECOG-E4A03 study, which evaluated
lenalidomide combined with high-dose versus low-dose dexamethasone in
patients with multiple myeloma?
DR LONIAL: The most recent analysis suggested that approximately 22 percent
of the patients achieved a CR or near CR and about half achieved a very good
partial response or better (≥VGPR) when they received primary therapy with
lenalidomide and low-dose dexamethasone beyond four cycles (Rajkumar
2008). Controversy remains regarding high-dose versus low-dose dexamethasone,
but I believe tolerability is clearly better with the low dose. The first
analysis of ECOG-E4A03 evaluated overall survival and demonstrated superiority
for low-dose dexamethasone compared to high-dose dexamethasone.
It is interesting that when those data are parsed by age, no difference is evident between high-dose and low-dose dexamethasone for patients younger than age 65 compared to the older patients, among whom we clearly saw a big difference (Rajkumar 2007; [3.1]). Age and performance status are important determinants for dexamethasone dosing in my opinion.
The other aspect of those data is that the response rate was higher for the patients receiving lenalidomide/high-dose dexamethasone than for those receiving lenalidomide/low-dose dexamethasone. In fact, the ≥VGPR rate was approximately 10 to 12 percent higher with high-dose dexamethasone.
This is one of the few trials in which the response rate did not appear to correlate with survival, and I believe that has to do partly with the effect of age (Rajkumar 2007).
Track 6
DR LOVE: Would you discuss the trial (IFM 2005/01) comparing
bortezomib/dexamethasone to vincristine/doxorubicin/dexamethasone
(VAD) as induction therapy prior to autologous stem cell transplant
(ASCT) in multiple myeloma?
DR LONIAL: The investigators reported superior up-front responses with
bortezomib/dexamethasone compared to VAD. The CR/near-CR rate with
bortezomib/dexamethasone was about 20 percent, and — a unique finding —
the up-front response translated to a better post-transplant response (Harousseau
2008).
IFM 2005/01 was the first trial to demonstrate that the agents you use as induction therapy make a difference in terms of long-term outcomes. The difference between IFM 2005/01 and all of the preceding trials that didn’t show a difference was that bortezomib/dexamethasone had a higher CR/near-CR rate than the regimens used in those older trials.
Tracks 7-8
DR LOVE: What are your thoughts about the trial by Cavo evaluating
bortezomib/thalidomide/dexamethasone (VTD)?
DR LONIAL: The Cavo trial takes what is now my second-preferred regimen,
VTD, and compares it to thalidomide/dexamethasone. A number of trials
have evaluated thalidomide/dexamethasone versus VAD or dexamethasone as
induction therapy. While the response rates with thalidomide/dexamethasone
were better up front, after transplant they were all nullified.
Cavo reported that the CR/near-CR rates were significantly higher for VTD up front, almost 36 percent. This also translated to better post-transplant CR/near-CR rates (Cavo 2007). This was the second trial to report that the agents administered as induction therapy affect post-transplant outcomes.
DR LOVE: What is your preferred regimen for treating patients with newly
diagnosed multiple myeloma?
DR LONIAL: My first-choice regimen is RVD, which is a combination of our
most active drugs — lenalidomide, bortezomib and dexamethasone. I believe
the real power of RVD lies in the high responses reported with that regimen.
The overall response rate was 98 percent in the Phase II portion of the trial evaluating that regimen, and the VGPR or better rate for induction was higher than 70 percent (Richardson 2008).
The question we are now asking is, do all patients who achieve a CR up front need to proceed to transplant? For some of the patients we’ve treated, we’ve elected to delay the transplant, not completely omitting it. We’re critically evaluating the timing of the transplant, early versus late.
DR LOVE: How do you approach harvesting stem cells for these patients?
DR LONIAL: We harvest them all after four cycles, which is important because
it can be more difficult to harvest after four cycles. This is true with the other
newer regimens also. I’ve heard some concern about thalidomide and stem
cell collection or mobilization. Data suggest perhaps you don’t collect quite as
many cells, but clinically it is not a significant problem, so I don’t believe an
issue exists in harvesting stem cells in patients receiving thalidomide.
Bortezomib does not appear to be associated with any problems in stem cell mobilization. Lenalidomide, while it’s not a stem cell toxin, does appear to arrest maturation of cells in the bone marrow, which is why some myelosuppression is observed. It appears that it can complicate the collection of stem cells with growth factors alone, but most patients can be rescued with either AMD3100 or cyclophosphamide.
Track 9
DR LOVE: Can you discuss the next generation of ongoing or planned
studies in the up-front setting?
DR LONIAL: A Phase III SWOG trial (SWOG-S0777) is evaluating RVD
versus RD as induction therapy in order to evaluate the number and depth of
CRs. The transplantation question is not built into that trial, but it is important
to investigate the tolerability of RVD in a Phase III trial. ECOG-E1A05
is also a Phase III study, which is evaluating RVD versus VD as up-front
therapy. It was initially designed as a trial of consolidation therapy but has
been changed to address these regimens as induction therapy. These are both
important clinical trials.
The French are designing a trial in which most patients will receive RVD up front as their induction therapy, with a secondary assignment, based on response, to transplant or not. This is the important question: If a patient with low-risk disease achieves a CR, does he or she need to have an immediate transplant or can it wait? Do patients with high-risk disease who achieve a CR need an immediate transplant, or will they fare better with continued RVD and avoidance of exposure to melphalan, as cytotoxic agents don’t appear to be beneficial to these patients?
Track 13
DR LOVE: What’s your clinical algorithm for patients who relapse after
transplantation?
DR LONIAL: My questions are, how long was that first remission, which
induction therapy did they receive and what response was achieved?
If patients are in an unmaintained remission and they relapse, and they received RVD up front, then you can consider a doublet combination — bortezomib/pegylated liposomal doxorubicin (PLD), bortezomib/dexamethasone or lenalidomide/dexamethasone. The utility of bortezomib/PLD has clearly been established in the relapsed setting, with an improvement in overall survival compared to bortezomib alone (Orlowski 2007). Data are also emerging for PLD in combination with lenalidomide.
In the up-front setting, a couple of trials have evaluated bortezomib/PLD and dexamethasone, or bortezomib/PLD alone, which is a steroid-sparing induction regimen that can be attractive for diabetic patients. In a trial through the Multiple Myeloma Research Consortium, we’re combining PLD with the RVD regimen to determine whether we can go to a four-drug CHOP-like regimen that will result in a significantly higher rate of complete remissions.
| Table of Contents | Top of Page |
EDITOR
Neil Love, MD
INTERVIEWS
Bruce D Cheson, MD
- Select publications
Hagop M Kantarjian, MD
- Select publications
Sagar Lonial, MD
- Select publications
