When is the ideal time to collect (harvest) stem cells? Do myeloma cells get included in the stem cell collection and the stem cell re-infusion ?

When is the ideal time to collect stem cells?

So the ideal time, we think, is about 3 to 4 rounds of standard induction therapy at this time. That's with typically three, a combination of three drugs. But every case is a little bit different. And so we have had patients who've had more therapy than that and we've successfully been able to collect stem cells. And some patients require just three cycles and that's good enough for them. So a little bit of variability, but somewhere around 3 to 4 is what is our standard practice. Clearly the more therapy someone gets, the more damage can there can be in the bone marrow. There are also supporting cells in the bone marrow called stromal cells that keep the stem cells there. And sometimes with further therapy, the stem cells don't respond the same way to the growth factors we give. This can be overcome with the use of newer growth factors and chemotherapy by giving low doses of chemotherapy like a drug called cytokines, and it can actually help push the cells out from the bone marrow into the blood when the growth factor alone is not working.

In general, stem cell collection is something that's done early in the treatment natural history of multiple myeloma. Our practice is to perform stem cell collection after four or six cycles of induction or initial therapy. One can completely collect stem cells later than that, but it becomes more difficult sometimes and also the efficiency of the collection and perhaps even the quality of the stem cells may be affected in the sense that after a prolonged period of treatment, the stem cells in the cells may get damaged by the treatment.

Do most individuals collect enough stem cells to go to transplant?

Most of the time when we want to collect stem cells, we're successful, I would say 99% of the cases, it's not an issue. There are rare patients where it's very challenging and then if you really want to get stem cells from those patients, those patients can undergo some procedure called the bone marrow harvest, where we actually poke needles into the hip bones and collect the stem cells from their homes in the bone marrow.

Why wait until after a few cycles of treatment to collect stem cells?

The reason we have a certain number of cycles before we collect your stem cells is twofold. One is you want to control your disease, right? You want to show that you're disease in remission. We know the outcomes are better, the better remission you're in. And so that's why you get at least 3 to 4 cycles of therapy. The reason we don't go to 8 to 12 cycles, ideally, is because even though we may be able to get you into a deeper remission, you also start to accumulate more side effects. But we also know that the subsequent cycles sort of have less and less of an effect on clearing your myeloma cells. But the real reason we don't like to go in too much further is that some of the drugs, including REVLIMID, can actually start affecting your ability to collect your stem cells and so it will make it more difficult to collect those stem cells.

So for many reasons, we have sort of this truly arbitrary number of cycles that we do before we collect your stem cells. So there has always been some concern about patients having prolonged courses of treatment before collecting stem cell therapy. And I think that that was concern and that was probably predating the medicines that we have now to help patients liberate their stem cells out of their bone marrow. So with regards to REVLIMID or Lenalidomide, there was previously concerns that if you had too much lenalidomide before we collect the stem cells, that it might make it more difficult to get all the stem cells we need for one or even two transplants.

And in the current era where we have access to not just to fill in or the G-CSF to mobilize the stem cells, but also another medicine called plerixafor, which we can access either when we think we're going to run into problems upfront or as rescue. If we after a few days of G-CSF, if we think we're not going to quite make it, we can give that medicine as an additional boosting way to get up in stem cells.

Stem cell collection failure really hasn't been a huge issue in at least in countries where those two medicines are available and routinely used. With regards to daratumumab as induction therapy. So where we're adding is to that initial combination and there have been analyzes performed of trials that use those combinations. So the Griffin trial, which is dara plus RVd and the MASTER trial, which is dara plus KRd and although there was a different scene in terms of the use of what's called plerixafor, that additional medicine, overall, the overwhelming majority of patients were able to mobilize well and collected well, although there was an increased use, as they said, of plerixafor in the daratumumab cohort, some institutions preferring to use it like straight off the board in all those patients and some institutions using it, as they said, as rescue only if there's a thought that the patients are going to collect enough. But generally speaking, well over 95% of patients were able to collect successfully.

There's actually just in the last few weeks been a study published by the Swedish Registry, which is a huge registry of all the patients in Sweden. And they found similar things. So patients who get daratumumab as part of their induction therapy needed a little bit more time to collect and also had a slightly lower overall collection yields. That’s a number of cells that they managed to collect, but the overwhelming majority still managed to collect enough for more than two transplants and definitely for one and there was an increased use of, as I said, that extra medicine, the plerixafor where basically 37% of patients needed plerixafor as opposed to only 6% who didn't get dara upfront. So yes, there probably is some degree of an impact in terms of how many cells we can collect and how quickly we can collect them, but it still doesn't seem to affect the end result, which is do we get enough stem cells for the transplant and do patients have what's called collection failure? And both of those things seem to be relatively only impacted if you've got access to plerixafor.

Do myeloma cells get included in the stem cell collection and infusion during ASCT?

In terms of whether your cells could be contaminated with myeloma. The answer is yes. And that will happen regardless of how many cycles of therapy we get, because, as you know, we can't get rid of all myeloma cells with just initial treatments. The good news is that the processing of the stem cells and the subsequent freezing of the stem cells is very toxic to myeloma cells. And they don't usually survive very well. And so in general, once we give you back your product, it tends to be pretty clean of myeloma cells.

And actually these very large studies done in like the eighties and early nineties about what we call purging of cancer cells in the stem cell product by using antibodies trying to really clear the cancer cells and just giving you back the stem cells. And what we found was that actually that did not translate to any benefit. But what happened is it really caused some damage to the stem cells, that it took much longer to recover. And people were staying in neutropenic phases longer and having more complications.

So whatever residual cells are there, even in their presence, patients can still get very deep responses and durable responses. So of course we and others have tried to remove those cells from the graft. So those studies were done. But unfortunately the technology and the available methods are not good enough to do that. So when people have tried to remove myeloma cells from the graft in the lab, either by using antibodies or only by selecting stem cells so that you can get rid of myeloma cells. And when they did the transplants with that approach, number one, it did not improve their remission status. So those patients had almost the same progression free survival as the one who got the so-called unpurged, unmanipulated stem cells.

And the second thing was that not only we could not adequately remove the myeloma cells from the graft or from the harvest, we adversely affected the quality of the graft. So these patients actually had somewhat a little delay in the recovery of their white blood cells and platelets. And not only that, we were actually removing some of the competent cells of immune system from the graft and trying to remove the myeloma cell. So these patients actually suffered more infection. So based on the available technique, yes, it's actually safer and in some ways better to go with what you have rather than trying to manipulate and remove more cells from the graft.