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Short-Term Velcade-Based Combination Therapies May Be Effective And Safe For Multiple Myeloma

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Published: Jan 31, 2013 2:37 pm

Results from a recent, small-scale study conducted at the MD Anderson Cancer Center in Houston suggest that three Velcade-based combination therapies given at lower doses over a short period of time may be safe and effective in newly diagnosed multiple myeloma patients .

In particular, two out of the three combinations showed overall response rates of above 90 percent, and all combinations were associated with few side effects.

Based on their findings, the researchers conclude that the tested combinations are viable alternatives to standard Velcade (bortezomib)-based combinations given over longer periods of time, which can be associated with frequent side effects.

The researchers also recommend that the combinations be studied further in larger patient populations.  They are particularly interested in further study of Velcade in combination with Revlimid (lenalidomide), cyclophosphamide (Cytoxan), and dexamethasone (Decadron), which appeared to be the most effective and safest combination among those tested.

According to the researchers, major advances have been made in the management of multiple myeloma in the past decade due to the use of novel agents, such as thalidomide (Thalomid), Velcade, and Revlimid.

They added that rapid disease control continues to be a high priority in the management of the disease. Velcade-based initial therapies have been quite successful in this regard, with overall response rates of 85 percent to 90 percent in newly diagnosed patients.

However, the researchers note that the novel agent-based therapies have been associated with frequent – often serious – side effects, such as peripheral neuropathy (nerve damage that causes pain, tingling, and loss of sensation in the extremities), infections, and the formation of blood clots.

The researchers therefore sought to identify drug combinations that are as effective as current combina­tions, but less toxic, by administering the drugs in small doses over a short period of time.

They chose, in particular, to assess three different Velcade-based regimens due to the drug's efficacy and frequent use in myeloma therapies.

Between January 2010 and May 2012, the investigators treated 40 newly diagnosed myeloma patients with one of the following three combinations: Velcade- cyclophosphamide-dexamethasone (referred to as VCD or CyBorD), Velcade-Revlimid-Doxil (liposomal doxorubicin)-dexamethasone (RVDD), or Velcade-Revlimid-cyclophosphamide-dexamethasone (RVCD).

The median patient age was 63 years, and 37 percent had Stage III disease based on the International Staging System scale.

The patients received no more than two cycles of initial treatment, and they could proceed to high dose therapy and stem cell transplant if they wished to and qualified for the procedure.

Each cycle of therapy lasted 28 days, but drug treatment occurred on only the first 11 days.

Velcade was administered on days 1, 4, 8 and 11 of the cycle, at 1.3 mg/m2 in the VCD regimen, and 1.0 mg/m2 in the other two regimens.  Revlimid was administered on days 1-11 at 25 mg per day. Dexa­metha­sone was administered on days 1-4 and 8-11 at 20 mg/m2 per day.  Cyclo­phos­phamide was administered on days 1-4 of each cycle in the VCD and RVCD regimens, at 75 mg/m2 twice daily in the VCD regimen and 60 mg/m2 twice daily in the RVCD regimen.

Patients also were given 81 mg of aspirin per day to prevent the development of blood clots during treatment, and 500 mg per day of Valtrex (valacyclovir) to reduce chances of a shingles infection.

Overall, the investigators found that overall response rates (partial response or better) were high in all three treatment groups: 92 percent of patients in both the RVDD and RVCD treatment groups and 73 percent in the VCD group responded.

According to the researchers, these response rates are similar to those they observed in two other commonly used Velcade-based initial therapies they had investigated previously: Velcade-thalidomide-dexamethasone (87 percent) and Velcade-Revlimid-dexamethasone (89 percent).

The investigators also found that the safety profiles of the three combination therapies tested were favorable. They described the side effects as infrequent, mild, and reversible. The most common side effects included infections (16 percent), rash (13 percent), and constipation (13 percent).

Overall, the rate of side effects was much lower than observed in patients receiving Velcade combination regimens dosed over longer periods of time.

In particular, the rate of neuropathy of all grades was much lower in the three regimens in this study (13 percent). Furthermore, none of the three regimens in this study caused blood clots or severe neuropathy.

A total of 31 of the 40 patients treated with the three short-term combination regimens went on to receive high-dose chemotherapy followed by a stem cell transplant.  The procedure deepened response in the patients, in that seven of the patients who had only achieved a partial response prior to stem cell  transplantation went on to achieve a complete response after transplantation.

Two patients in the study died, one after 5 months and one after 14 months.  Both had achieved a partial response, but the responses were short-lived.  Neither patient went on to receive a stem cell transplant.

For more information, please refer to the study in Clinical Lymphoma, Myeloma and Leukemia (abstract).

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  • SMAH said:

    Is this the Mayo goal towards reducing the treatment cost, and shoving the NDMM patients to a SCT as soon as possible ? (SCT was found by Mayo researchers to be the cheapest treatment in long term; ASCO 2012). With 8 cycles of VRD these patients might have as long or longer PFS as the ones going through SCT, and no months of isolation or no months off work (if they are still in work-life). I am not impressed.

  • Eric Erhard said:

    I found the idea of lighter treatment most interesting. Personally I was given Velcade, prednisone and Melphelan in a reduced strength treatment call VMP lite. I did not desire a SCT, and any blood transfusion was not an option.

    This lite treatment consisted of 9 - 35 day cycles, with the first 4 days being Melphelan and prednisone and once weekly Velcade interveinously for 4 weeks. Then a one week rest period free from any treatment.

    This was done in 2011-12 at the London Regional Cancer Program, London Ontario Canada.

    My experience was a VGPR with minimal neuropathy.

    If lighter treatments can give equivalent response to more intense regimen, with fewer side effects, that is great.

  • Maike Haehle said:

    Thanks for the comments, smah and Eric.

    You are most likely correct, smah, that the researchers who published this study mainly intend these shorter-term regimens to be used for newly diagnosed patients who expect to have a stem cell transplant after their initial therapy.

    At least that's the impression one gets from the journal article summarizing the results of the study.

    We've emailed the study authors to get feedback on the issue and will let you know what we hear.

  • Joey said:

    As general information regarding ASCTs, I would like to know what fraction of patients who only achieved a partial response prior to lethal chemotherapy/stem cell rescue went on to achieve a complete response after lethal chemotherapy/stem cell rescue. The description below does not tell you:

    A total of 31 of the 40 patients treated with the three short-term combination regimens went on to receive high-dose chemotherapy followed by a stem cell transplant. The procedure deepened response in the patients, in that seven of the patients who had only achieved a partial response prior to stem cell transplantation went on to achieve a complete response after transplantation.

    In fact, it could have been as low as 25% - which ain't too impressive, given the toxicty of the procedure. If so, would you say yes, if the doctor said, "You have a 1 in 4 chance of achieving a better response after we obliterate your entire bone marrow and wreak havoc on every other stem cell in your body, with a whole myriad of long-term damaging effects on your peripheral organs, such as those in your cardiac system, that we cannot predict or tell you about at this time.

  • Steve said:

    Having not read the orignal study one hesitates to make too many definitive conclusions, much less speak to the researchers' motivations or biases (as was suggested by an earlier poster). That said, I find the idea quite intriguing that reduced dosage and duration of therapy may be just as effective as "trial established" protocols. It's obvious to most, if not all MM patients that we each respond differently to identical drug therapies. So why not, in cases that don't require urgent and "kitchen sink" type treatment, begin drug therapy with lower doses and titrate upwards as tolerability permits, thereby minimizing adverse side effects?

  • TerryH said:

    Actually, Joey, the impact of transplants on response rates may be much greater than you think.

    See the table in this abstract:


    In this patient population with high-risk myeloma, a stem cell transplant had at least a two-thirds chance of moving a patient with an initial PR to a better response.

    Prior to ASCT, 15 patients in the study had achieved a PR. After ASCT, only 5 were in PR; the rest had a better than PR response.

    (And some of the 5 in PR after ASCT may have been patients who didn't have even a PR before ASCT; so the two-thirds estimate may even be a lower bound.)

    These data don't mean that transplants will improve overall survival. That's why the timing of transplants in the age of novel therapies is an open question.

    But transplants will deepen response, and apparently for quite a number of patients.

  • Joey said:

    Terry H

    You may well be right - but if you are, then I think it means that only 10 of the 31 patients who went on to receive HDT/ASCT began with partial response, the other 21 presumably being already in CR. And that latter assumption does not seem to square with the expected efficacy of short term therapy.

    The simple truth is that the experimental details of the paper - which I do not have access to - will resolve this....so I guess we will know at some point.

    And actually with respect to the study you cite, only 10 out of 27 patients improved to an sCR or CR after an ASCT -- OK - but it ain't 2 out of 3. (12 of out 27 improved to a VPGR or better, but who knows what type of improvement this really means in terms of reduction of M protein; it could be just a few percent - the cancer is still alive and well.)

  • nancy shamanna said:

    Hi Joey and All, Although I don't think I will do this myself, I see that if you go into the abstract of this paper, published in Blood magazine, there is an opportunity for non-subscribers to the journal to purchase the whole article for a 24 hr. period, for $35. So that's not too bad a price if it is really important to you to access the information! And as Maike has written, she is inquiring to the authors about some key points.